Quorum Sensing and Biofilm Formation and Natural Compounds that Disrupt these Processes

by John & Barbara Connor, M.Ac., L.Ac.

Introduction
What is Quorum Sensing?
What are Biofilms?
Rationale for Using Anti-Quorum Sensing and Biofilm Disrupting Natural Compounds
Anti Quorum Sensing and Biofilm Disrupting Herbs, Spices, Foods and Essential Oils


Introduction
While researching the problem of antibiotic resistance John and I gained insight into the significance of the phenomena known as quorum sensing and biofilm formation. We would like to share with you some of the studies we came across on these two processes and their relationship to bacterial infections. We would also like to share with you some of the studies we have found that have been done on herbs, spices, foods and essential oils that can inhibit quorum sensing and disrupt biofilm formation. 

Alarming trends in the spread of antibiotic resistance among top pathogens, including Staphylococcus aureus, have placed mankind at the brink of what has been coined as the ‘post-antibiotic era’. Since the widespread introduction of antibiotics in the 1940s, the same storyline has repeated itself over and over again: a new antibiotic is introduced and then resistant variants emerge and quickly spread, effectively limiting the utility and lifespan of the drug. (Quave et al 2015)

As is well known, the major cause of mortality and morbidity in human beings is bacterial infection. However, bacteria have developed resistance to most of the antibiotics primarily due to large-scale and indiscriminate usage. (Kailia et al 2014)

What is Quorum Sensing?

Quorum sensing (QS) refers to the capacity of bacteria to monitor their population density and regulate gene expression accordingly: the QS-regulated processes deal with multicellular behaviors (e.g. growth and development of biofilm), horizontal gene transfer and host-microbe (symbiosis and pathogenesis) and microbe-microbe interactions. (Grandclement et al 2015)

The emergence of antibiotic-resistant bacterial pathogens, especially Gram-negative bacteria, has driven investigations into suppressing bacterial virulence via quorum sensing inhibition strategies instead of bactericidal and bacteriostatic approaches. (Gemiarto et al 2015)

The QS mechanism enables bacteria to detect their population density through the production, release, and perception of small diffusible molecules called autoinducers and to coordinate gene expression accordingly. A wide array of functions in bacteria ranging from bacterial cell motility to complex behaviors such as biofilm formation and production of virulence factors are regulated by QS in pathogenic bacteria.  (Husain et al 2015)

Typical QS involves the generation and release of small diffusible signal molecules—autoinducers; they accumulate in the environment to a certain threshold concentration, followed by recognition by receptor proteins that regulate the expression of a particular set of genes and control manifold activities. Since this mechanism is responsible for bacterial virulence induction, QS targeting could be a promising strategy to control pathogenic bacteria, and some medicinal plants are capable of inhibiting QS-related processes. (Deryabin & Tolmacheva 2015)

Quorum sensing cell communication is widely used by bacterial pathogens to coordinate the expression of several collective traits, including the production of multiple virulence factors, biofilm formation, and swarming motility once a population threshold is reached. (Castillo-Juarez  et al 2015)

Quorum sensing along with subversion of the immune system are the main factors that determine the bacterial infectious doses. Hence those bacterial pathogens that need small doses to infect, generally lack QS systems but are very effective at inactivating the immune response by killing professional phagocytes. In contrast, those bacterial pathogens that need high infectious doses rely on QS for the coordination of the expression of virulence. (Castillo-Juarez  et al 2015)

Several bacterial pathogens, like Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), and Vibrio cholerae, utilize quorum sensing cell communication to coordinate the expression of multiple virulence factors and associated behaviors such as swarming and biofilm formation, once a population size threshold is reached. (Castillo-Juarez  et al 2015)

What are Biofilms?

Biofilms can be defined as structured aggregation of surface-attached microorganisms encased in an extracellular matrix. In all these [four] phases of biofilm formation, quorum-sensing system is involved in the regulation of population density and metabolic activity. (Chung & Toh 2014)

Biofilms are responsible for most chronic and recurrent infections. Biofilm-related infections reoccur in approximately 65-80% of cases. Bacteria associated with the biofilm are highly resistant to antibiotics. (Venkatesan et al 2015)

Biofilms are colonies of bacteria encased within extracellular polymeric matrix. Sessile (immobile) biofilm bacteria are phenotypically different than planktonic (drifting or floating) bacteria, conferring increased resistance to desiccation, antibiotics, and the immune response. Antibiotics are able to kill the planktonic cells released by the biofilm after its maturation stages, but bacteria within the biofilm can persist, causing chronic infections. In biofilm formation, bacteria attach reversibly to a surface, and then begin to produce extracellular polysaccharides. As the bacterial number grows, quorum sensing allows a phenotypic change in the bacteria. The biofilm matures and grows. Eventually, proteins break down parts of the matrix so that bacteria within the biofilm can disperse. (Ulrey et al 2014)

About 80% of the infections caused by microorganisms are biofilm based. Biofilm architecture consists of structured and aggregated communities of bacteria encased in a self-secreted exopolymeric substance. Several studies have revealed that bacteria have developed resistance because of the prolonged treatment with conventional antibiotics possessing a broad-range efficacy via toxic or growth-inhibitory effects on target organisms rendering the traditional antibiotic treatment virtually ineffective. It has been found that bacteria living in the biofilm mode of growth are resistant to antibiotics up to 1000 times more than their planktonic counterparts. (Husain et al 2015)

The presence of biofilms has been mostly seen in medical implants and urinary catheters. Various signalling events including two-component signalling, extra cytoplasmic function and quorum sensing are involved in the formation of biofilms. The presence of an extracellular polymeric matrix in biofilms makes it difficult for the antimicrobials to act on them and make the bacteria tolerant to antibiotics and other drugs. (Gupta et al 2015)

Rationale for Using Anti-Quorum Sensing and Biofilm Disrupting Natural Compounds

Acinetobacter frequently causes infections associated with medical devices, e.g. vascular catheters, cerebrospinal fluid shunts or Foleys catheter. Biofilm formation is a well-known pathogenic mechanism in such infections. The potential of Acinetobacter to form biofilm may explain its exceptional antibiotic resistance and survival in the hospital environment. This study concludes that there a positive correlation between biofilm formation and multiple drug resistance in A. baumannii. (Badave & Kulkarni 2015)

Usage of antibiotics has caused pathogenic bacteria to become resistant and poses a global threat to public health. QS provides an alternative solution because by targeting bacterial communication the expression of the virulence phenotype is inhibited. (Tan et al 2013)

Blocking quorum sensing pathways are viewed as viable anti-virulent therapy in association with traditional antimicrobial therapy. Anti-quorum sensing dietary phytochemicals with may prove to be a safe and viable choice as anti-virulent drug candidates. (Kumar et al 2015)

Compounds that interfere with the QS system to attenuate bacterial pathogenicity are termed as anti-QS compounds. Such compounds neither kill the bacteria nor stop their growth and are less expected to develop resistance toward antibiotics. (Husain et al 2015)

The likelihood of bacteria developing resistance to quorum sensing inhibitors is less probable than that observed with conventional antibiotics. (Kalia et al 2014)

Natural products play a pivotal role for treating and preventing infectious diseases. Plant compounds usually target the bacterial QS system via three different ways, by either stopping the signaling molecules from being synthesized by the luxI encoded AHL synthase, by degrading the signaling molecules and/or by targeting the luxR signal receptor. (Koh et al 2013)

Plant-derived anti-QS compounds such as oroidin, ursolic acid, naringenin, cinnamaldehyde, salicylic acid, methyl eugenol, and extracts from garlic and edible fruits, have shown antibiofilm properties against several pathogens. (Olivero-Verbel et al 2014)

The following are summaries of 29 studies on anti quorum sensing and biofilm disrupting herbs, spices, foods and essential oils:

Anti Quorum Sensing and Biofilm Disrupting Herbs, Spices, Foods and Essential Oils

6-gingerol (a pungent oil of fresh ginger)
Agaricus blazei Murill (edible mushroom)
Ajoene (from Allium sativum)
Areca catechu
Armoracia rusticana (horseradish)
Centella asiatica (gotu kola)
Chamomile (Chamaemelum nobile)
Cinnamon oil (Ceylon type)
Citrus essential oil
Clove essential oil
Cranberry proanthocyanidins
Colloidal silver
Curcumin (from curcuma longa)
Eucalyptus essential oil
European Chestnut leaf (Castanea sativa)
Garlic
Geranium essential oil
Gnetum gnemon (belinjo leaves)
Imperata cylindrica
Lavender essential oil
Lemon essential oil
Marjoram essential oil
Menthol
Nelumbo nucifera
Nymphaea tetragona (water lily)
Oxyresveratrol
Panax notoginseng (root and flower)
Phyllanthus amarus (chanca piedra)
Piceatannol
Piper betle (betle leaves)
Piper nigrum (peppercorn), and Proanthocyanidin (from dried cranberry juice)
Propolis
Punica granatum
Prunella vulgaris
Prunus armeniaca
Quercetin
Resveratrol
Rose essential oil
Rosemary essential oil
Utica dioica (Nettles)
Wheat-bran 

6-gingerol (a pungent oil of fresh ginger) reduced biofilm formation experimentally, several virulence factors (e.g., exoprotease, rhamnolipid, and pyocyanin), and mice mortality. Further transcriptome analyses demonstrated that 6-gingerol successfully repressed QS-induced genes, specifically those related to the production of virulence factors. These results strongly support our hypothesis and offer insight into the molecular mechanism that caused QS gene repression. (Kim et al 2015)

Agaricus blazei Murill (an edible mushroom) is known to induce protective immunomodulatory action against a variety of infectious diseases. In the present study we report potential anti-quorum sensing properties of A. blazei hot water extract. (Sokovic et al 2014)

Armoracia rusticana (horseradish) stood out from a group of active crude extracts as highly active with respect to QSI activity against P. aeruginosa. Bioassay-guided fractionation and purification led to identification of 1-isothiocyanato-3-(methylsulfinyl) propane, commonly known as iberin, as an active QS inhibiting compound in horseradish. Real-time PCR (RT-PCR) and DNA microarray analysis of global gene expression revealed that iberin specifically and extremely effectively targets two of the major QS networks in P. aeruginosa, the LasIR and the RhlIR systems, and was found to downregulate QS-controlled rhamnolipid production in P. aeruginosa wild-type batch cultures. (Jakobsen et al 2012)

Centella asiatica (gotu kola) – The anti-quorum sensing (QS) nature of Centella asiatica herb can be further exploited for the formulation of drugs targeting bacterial infections where pathogenicity is mediated through QS. (Vasavi et al 2014)

Chamomile (Chamaemelum nobile) – The anti-QS property of C. nobile may play an important role in its antibacterial activity, thus offering an additional strategy in the fight against bacterial infections. However, molecular investigation is required to explore the exact mechanisms of the antibacterial action and functions of this phytocompound. (Kazemian et al 2015)

Cinnamon oil (Ceylon type) – This work is the first to demonstrate that cinnamon oil can influence various quorum sensing (QS)-based phenomena in Pseudomonas aeruginosa PAO1, including biofilm formation. (Kalia et al 2015)

Clove oil – The results of this study confirmed that the QS systems play an important role in the pathogenicity of P. aeruginosa infections. Consequently, compounds that attenuate QS may offer significant promise as potential therapeutic agents. These compounds provide alternative medicine for treating emerging bacterial infections without leading to antibiotic resistance as they do not pause selection pressure. Our study also revealed the anti-QS and biofilm inhibitory activity of clove oil against P. aeruginosa isolates. (Aboushleib et al 2015)

Clove essential oil – Presence of anti-QS activity in clove oil and other essential oils has indicated new anti-infective activity. The identification of anti-QS phytoconstituents is needed to assess the mechanism of action against both C. violaceum and Ps. aeruginosa. (Khan et al 2009)

Colloidal silver directly attenuates in vitro Staphylococcus aureus biofilms. (Goggin it al 2014)

Cranberry proanthocyanidins (PACs) reduced P. aeruginosa swarming motility. Cranberry PACs significantly disrupted the biofilm formation of P. aeruginosa. Proteomics analysis revealed significantly different proteins expressed following PAC treatment. In addition, we found that PACs potentiated the antibiotic activity of gentamicin in an in vivo model of infection using G. mellonella. Results suggest that A-type proanthocyanidins may be a useful therapeutic against the biofilm-mediated infections caused by P. aeruginosa and should be further tested. ((Ulrey et al 2014)

Cranberry proanthocyanidins – These findings indicate that cranberry proanthocyanidins (PACs) have excellent in vitro activity against C. albicans biofilm formation in artificial urine. We present preliminary evidence that cranberry PAC activity against C. albicans biofilm formation is due to anti-adherence properties and/or iron chelation. (Rane et al 2014)

Curcumin (Curcuma longa) – Urinary tract infection is caused primarily by the quorum sensing (QS)-dependent biofilm forming ability of uropathogens. In the present investigation, an anti-quorum sensing (anti-QS) agent curcumin from Curcuma longa (turmeric) was shown to inhibit the biofilm formation of uropathogens, such as Escherichia coli, Pseudomonas aeruginosa PAO1, Proteus mirabilis and Serratia marcescens, possibly by interfering with their QS systems. The antibiofilm potential of curcumin on uropathogens as well as its efficacy in disturbing the mature biofilms was examined under light microscope and confocal laser scanning microscope. The treatment with curcumin was also found to attenuate the QS-dependent factors, such as exopolysaccharide production, alginate production, swimming and swarming motility of uropathogens. Furthermore, it was documented that curcumin enhanced the susceptibility of a marker strain and uropathogens to conventional antibiotics. (Packiavathy et al 2014)

Curcumin, from Curcuma longa, Ajoene from Allium sativum, Iberin from Armoracia rusticana attenuate P. aeruginosa virulence by downregulating the expression of QS genes. (Sarabhi et al 2013)

European Chestnut leaf (Castanea sativa) extract – Here, we report the quorum sensing inhibitory activity of refined and chemically characterized European Chestnut leaf extracts, rich in oleanene and ursene derivatives (pentacyclic triterpenes), against all Staphylococcus aureus accessory gene regulator (agr) alleles. (Quave et al 2015)

Garlic (Allium sativum) is considered a rich source of many compounds, which shows antimicrobial effects. The ability of microorganisms to adhere to both biotic and abiotic surfaces and to form biofilm is responsible for a number of diseases of chronic nature, demonstrating extremely high resistance to antibiotics. Bacterial biofilms are complex communities of sessile microorganisms, embedded in an extracellular matrix and irreversibly attached to various surfaces. A. sativum L. extracts were efficient to inhibit biofilm structures and the concentration of each extract had a direct relation with the inhibitory effect. (Mohsenipour & Hassanshahian 2015)

Marjoram essential oil (EO) and Lemon EO   Marjoram EO inhibited Bacillus cereus, Pichia anomala, Pseudomonas putida and mixed-culture biofilm formation of Ps. putida and Escherichia coli and showed the best QS inhibitor effect on Chromobacterium violaceum. For B. cereus, all components showed better antibiofilm capacity than the parent EOs. Lemon EO inhibited E. coli and mixed-culture biofilms, and cinnamon was effective against the mixed forms. Scanning electron microscopy showed the loss of three-dimensional structures of biofilms. (Kerekes et al 2013)

Menthol – Our data identified menthol as a novel broad spectrum QS inhibitor. (Husain et al 2015)

Nymphaea tetragona (water lily) 50% methanol extract was demonstrated to have significant concentration-dependent inhibitory effects on quorum sensing-mediated virulence factors of bacteria with non-toxic properties, and could thus be a prospective quorum sensing inhibitor. (Hossain et al 2015)

Phyllanthus amarus (chanca piedra) – Our data suggest that P. amarus could be useful for attenuating pathogens and hence, more local traditional herbs should be screened for its anti-quorum sensing properties as their active compounds may serve as promising anti-pathogenic drugs. ((Priya et al 2013)

Piper nigrum (peppercorn), Piper betle (betle leaves) and Gnetum gnemon (belinjo leaves) – Various parts of Piper nigrum, Piper betle and Gnetum gnemon are used as food sources by Malaysians. The purpose of this study is to examine the anti-quorum sensing (anti-QS) properties of P. nigrum, P. betle and G. gnemon extracts. The hexane, chloroform and methanol extracts of these plants were assessed in bioassays involving Pseudomonas aeruginosa PA01, Escherichia coli [pSB401], E. coli [pSB1075] and Chromobacterium violaceum CV026. It was found that the extracts of these three plants have anti-QS ability. Interestingly, the hexane, chloroform and methanol extracts from P. betle showed the most potent anti-QS activity as judged by the bioassays. (Tan et al 2013)

Proanthocyanidin Extracts of the purified proanthocyanidin were prepared from dried cranberry juice. The proanthocyanidin exhibited anti-adherence property with multi-drug resistant strains of uropathogenic P-fimbriated E. coli with in vitro study. Hence proanthocyanidin may be considered as an inhibitory agent for multi-drug resistant strains of E. coli adherence to uroepithelial cells. (Gupta et al 2011) Foods high in proanthocyanidins include: ground cinnamon, dried grape seeds, sorghum, unsweetened baking chocolate, red kidney beans, hazelnuts, pecans, chokeberries and cranberries.

PropolisTogether, we present evidence that propolis contain compounds that suppress QS responses. In this regard, anti-pathogenic compounds from bee harvested propolis could be identified and isolated and thus will be valuable for the further development of therapeutics to disrupt QS signaling systems which regulate the virulome in many pathogenic bacteria. (Bulman et al 2011)

Propolis – These results suggest that Tunisian propolis ethanol extract (EEP) is able to inhibit cancer cell proliferation, cariogenic bacteria and oral biofilms formation. It could have a promising role in the future medicine and nutrition when used as antibiotic or food additive. (Kouidhi et al 2010)

Prunus armeniaca, Prunella vulgaris, Nelumbo nucifera, Panax notoginseng (root and flower), Punica granatum, Areca catechu, and Imperata cylindrica – Eight of the selected traditional Chinese medicine herbs (80%) yielded QS inhibitors: Prunus armeniaca, Prunella vulgaris, Nelumbo nucifera, Panax notoginseng (root and flower), Punica granatum, Areca catechu, and Imperata cylindrica. Compounds that interfere with QS are present in TCM herbs and these medicines may be a rich source of compounds to combat pathogenic bacteria and reduce the development of antibiotic resistance. (Koh & Tham 2011)

Quercetin – This study suggests that quercetin can act as a competitive inhibitor for signaling compound towards LasR receptor pathway and can serve as a novel QS-based antibacterial/anti-biofilm drug to manage food-borne pathogens. (Gopu et al 2015)

Resveratrol, piceatannol and oxyresveratrol – In the present study, quorum sensing inhibition activity of ten stilbenoids were tested using Chromobacterium violaceum CV026 as the bio-indicator strain and the structure-activity relationship was also investigated. Among them, resveratrol (1), piceatannol (2) and oxyresveratrol (3) showed potential anti-QS activities. (Sheng et al 2015)

Rose, geranium, lavender and rosemary, eucalyptus and citrus essential oils – Of the tested essential oils, rose, geranium, lavender and rosemary essential oils were the most potent QS inhibitors. Eucalyptus and citrus essential oils moderately reduced pigment production by Chromobacterium violaceum CV026, whereas the chamomile, orange and juniper oils were ineffective. (Szabo et al 2010)

Urtica dioica (Nettles) – The aim of this study was to assess the antibacterial and antifungal potential of some Romanian medicinal plants, arnica-Arnica montana, wormwood–Artemisia absinthium and nettle–Urtica dioica. In order to perform this antimicrobial screening, we obtained the vegetal extracts and we tested them on a series of Gram-positive and Gram-negative bacteria, and also against two fungal strains. The vegetal extracts showed antimicrobial activity preferentially directed against the planktonic fungal and bacterial growth, while the effect against biofilm formation and development was demonstrated only against S. aureus and C. albicans. Our in vitro assays indicate that the studied plant extracts are a significant source of natural alternatives to antimicrobial therapy, thus avoiding antibiotic therapy, the use of which has become excessive in recent years. (Stanciuc et al 2011)

Wheat-bran (WB) – The soluble extract of WB at 0.5% showed anti-biofilm activity, inhibiting biofilm formation and also destroying it. Similarly, the > 300 kDa fraction from WB had significant anti-biofilm activity in both in vitro assays. The WB also showed a potential to interfere with bacterial QS systems, as it was demonstrated to contain certain lactonase activity able to reduce AHL concentration in the medium. The present study reveals two additional beneficial properties of WB extract never explored before, which may be related to the presence of defence compounds in the plant extract able to interfere with microbial biofilms and also QS systems. (Gonzalez-Ortiz et al 2014)

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Antibiotic Resistance and Antimicrobial Actions of Natural Compounds

John G. Connor, M.Ac., L.Ac. and Barbara Connor M.Ac., L.Ac.

John and I would like to share with you today some of the recent studies on the serious issue of antibiotic resistance. These studies will review how we got into this situation, what is being done about it and what possible solutions and alternatives are being explored. In the last section of the article we will share with you studies on the anti-microbial actions of various herbs, spices, foods and essential oils. We hope you find this article helpful in your quest for optimal health.

Introduction
The development of antibiotics changed the world of medicine and has saved countless human and animal lives. However, bacterial resistance and tolerance to antibiotics has spread silently across the world and has emerged as a major public health concern. The recent emergence of pan-resistant bacteria that can overcome virtually any antibiotic poses a major problem for their successful control. (Hodzic E 2015)

Antibiotic resistance can be defined as the ability of a microorganism to survive and resist exposure to antimicrobial drugs, threatening the effectiveness of successful treatment of infection. Resistance can be transferred genetically from one microorganism to another. (Kandelaki et al 2015)

The increasing antibiotic resistance is now threatening to take us back to a pre-antibiotic era. (Xie et al 2015) Despite great progress in better knowledge of the resistance mechanisms, the solution to this problem remains elusive. (Chernysh et al 2015)

Each year in the United States, at least 2 million people acquire serious infections with bacteria that are resistant to one or more of the antibiotics designed to treat those infections. At least 23,000 people die each year as a direct result of these antibiotic-resistant infections. Many more die from other conditions that were complicated by an antibiotic resistant infection. (CDC. 2013. Antibiotic resistance threats in the United States, 2013)

In the last decade we have witnessed a dramatic increase both in the proportion and absolute number of bacterial pathogens presenting multidrug resistance to antibacterial agents. The US Centers for Disease Control and Prevention (CDC), the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) are considering infections caused by multidrug-resistant (MDR) bacteria as an emergent global disease and a major public health problem. (Roca et al 2015)

Causes of Antibiotic Resistance and its Impact on Our Lives
The process of resistance acquisition by bacterial cells can apparently be divided into two major stages: 1) a first and fast response which includes the reorganization of the membrane and its permeability (change in lipopolysaccharide composition, decrease of porin content and/or over expression of efflux pumps), and 2) a second, slow response that would involve genetic changes. Other mechanisms may also determine the process of resistance acquisition, like horizontal gene transfer between organisms, or activation of cell signalling responses which are closely related to the behaviour of bacteria in the wild; bacterial communication (quorum sensing) and biofilm formation. (Martins et al 2013)

The driving force behind the increasing rates of resistance can ultimately be found in the abuse and misuse of antibacterial agents, whether used in patients and livestock or released into the environment. This is no longer a medical issue. Antimicrobial resistance has become a global health threat that will require the coordinated action of many different stakeholders to tackle antibiotic resistance at its very root. (Roca et al 2015)

Antibiotic overuse persists for illnesses where they confer little to no benefit, such as bronchitis. (Shapiro et al 2013) In the US, the antibiotic prescribing rate for acute bronchitis is about 70%, and in Australia (for GP registrars) about 73% (11), despite evidence suggesting that the antibiotic prescribing rate for this should be near 0. (Hansen et al 2015) In one study among patients with acute rhinosinusitis, a 10-day course of amoxicillin compared with placebo did not reduce symptoms at day 3 or day 10 of treatment. (Garbutt et al 2012)

In a prospective study done on 600 patients who were clinically diagnosed with acute tonsillitis or acute pharyngitis the results showed that 24 % of the patients needed antibiotics while the rest did well without antibiotics. (Agarwal et al 2015)

Growing resistance to standard antibiotics leads to increased use of broad-spectrum regimens, including carbapenems and combinations, with consequent collateral damage, including the selection of carbapenem- and multidrug resistant pathogens, predisposition to fungal infections and Clostridium difficile-associated diarrhea. (El-Mahallawy et al 2015)

The gradual increase in resistance rates of several important pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), multidrug-resistant (MDR) Pseudomonas aeruginosa, imipenem-resistant Acinetobacter baumannii, and third-generation cephalosporin-resistant Escherichia coli and Klebsiella pneumonia, has become an increasingly severe problem in many hospitals worldwide. (Lee et al 2015)

In one study patients who had received antibiotics, within 3 months prior to hospital admission, had 3.8 times higher odds to acquire an infection caused by multidrug-resistant gram negative bacilli (MDR-GNB). (Alexiou et al 2011)

Cancer patients have a very high incidence of infection during their management and this circumstance is an unavoidable consequence of advances in cancer treatment that have resulted in greatly increased survival; therefore, infection in cancer patients offers a particular clinical challenge because the pathogens are often unusual, and appropriate treatment must begin early in the course of the illness. (Kalantar et al 2015)

An estimated 3,421 cancers (2.9% of all cancers) in Australia in 2010 were attributable to infections. Infectious agents causing the largest numbers of cancers were HPV (n=1,706), H. pylori (n=793) and HBV/HCV (n=518). Cancer sites with the greatest number of cancers caused by infections were cervix (n=818), stomach (n=694) and liver (n=483). Cancers with highest proportions attributable to infectious agents were Kaposi’s sarcoma (100%), cervix (100%), nasopharynx (87%), anus (84%) and vagina (70%). (Antonsson it al 2015)

While clinical settings may be the source of highest antibiotic and antibiotic resistant bacteria loads, the natural environment has recently drawn attention as a reservoir of transferable antibiotic resistance genes potentially implicating environments highly contaminated with antibiotic resistance genes as a human health risk. (Tan et al 2015)

Antibiotics are commonly used in animal husbandry, bee-keeping, fish farming and other forms of aquaculture, ethanol production, horticulture, antifouling paints, food preservation, and domestically. This provides multiple opportunities for the selection and spread of antibiotic-resistant bacteria. (Meek et al 2015)

Antibiotics began to be used in large scale as growth promoters and prophylactics in livestock, usually administered by addition to the feed. This new application also meant that the environment began to be massively exposed to antibiotics. Other non-clinical large-scale uses of antibiotics include their usage in aquaculture and poultry farming. It is widely believed that this excessive use of antibiotics has contributed to the development and dissemination of antibiotic resistance. (Berglund B 2015)

Use of antibiotics in aquaculture production systems is considered a major risk factor contributing to antibiotic resistance in aquaculture products and the ecosystem. In a recent study, we have uncovered a rich profile of antibiotic-resistant bacteria in samples from a domestic aquaculture farm with no known history of antibiotic application, by culture-dependent and -independent methods. (Huang et al 2015)

A strong body of evidence has now clearly demonstrated that the use of antibiotics does have several short and long-term implications in the ecology of the normal gut microbiota. The major concern that stems out of the use of broad-spectrum antibiotics, besides alteration of the normal gut microbial diversity, is the phenomenon of propagating the resistance strain via horizontal gene transfer. (Jandhyala et al 2015)

Staphylococcus aureus is found in the human microbiota and may become pathogenic under certain conditions. It is a human pathogen distinguished by its ability to cause infection in virtually every tissue and organ system of the body, leading to serious illnesses. The use of methicillin and other synthetic penicillins, such as oxacillin started in 1959, and represented a significant step in antistaphylococcal therapy worldwide. However, the identification of strains of Methicillin-resistant S. aureus (MRSA) was recorded in 1962 (hereafter called Oxacillin-resistant S. aureus [ORSA]), thus spreading fast around the world in subsequent years. (da Silva, Jr. et al 2014)

Another study found that after short-term antibiotic treatment for H. pylori although the diversity of the microbiota subsequently recovered to resemble the pre treatment states, the microbiota remained perturbed in some cases for up to four years post treatment. In addition, four years after treatment high levels of the macrolide resistance gene erm(B) were found, indicating that antibiotic resistance, once selected for, can persist for longer periods of time than previously recognized. This highlights the importance of a restrictive antibiotic usage in order to prevent subsequent treatment failure and potential spread of antibiotic resistance. (Jakobsson et al 2010)

Bacterial resistance has major implications for urological practice, particularly in relation to catheter-associated urinary tract infections (UTIs) and infectious complications following transrectal-ultrasonography-guided biopsy of the prostate or urological surgery. (Zowawi et al 2015)

The over use of broad spectrum antibiotics has led to the emergence of antibiotic resistant bacteria. As a consequence, the treatment of UTIs, especially chronic UTIs, becomes a very difficult clinical problem. Modulating the powerful innate and adaptive immune systems of the urinary tract would have important therapeutic and prophylactic implications for the treatment of UTIs, particularly when treatment of antibiotics alone is ineffective. (Yin, X. et al 2010)

Possible Solutions to Antibiotic Resistance
It has been suggested that as long as resistance is biochemically possible, it will occur, regardless of whether antibiotic compounds are synthetic or natural. The standard modern solution to this ongoing problem is the introduction of multi-drug therapy (MDT), where combinations of several antibiotics are employed to overcome the defence mechanisms of resistant bacteria. (Potroz & Cho 2015)

Together with developed tools for whole-genome sequencing (WGS) data analysis (e.g., Rainbow) and unifying genome-wide database (e.g., M. tuberculosis Variation Database (GMTV), The Bacterial Isolate Genome Sequence Database (BIGSdb) containing the broad spectrum information about individual mutations of pathogens, WGS can be a powerful tool for the preliminary prediction of drug resistance, geographical origin, as well clinical strategies and outcomes. (Punina et al 2015)

It has been estimated that microbial species comprise about 60% of the Earth’s biomass. This, together with the fact that their genetic, metabolic and physiological diversity is extraordinary, makes them a major threat to the health and development of populations across the world. Widespread antibiotic resistance, the emergence of new pathogens in addition to the resurgence of old ones, and the lack of effective new therapeutics exacerbate the problems. (Radulovic et al 2013)

Available antibiotics have lost their effectiveness in managing these infections. Invasive pathogens may acquire resistance genes which enable bacteria to produce enzymes like beta-lactamase and carbapenemase, express efflux systems, and modify the drug’s target site and an alternative metabolic pathway. (Izadpanah & Khalili 2015)

Currently, there is an open catalog of more 13,000 antibiotic resistance genes, composing the resistome, with rich information, including resistance profile, mechanisms, requirements, epidemiology, coding sequences, and their mutations for more than 250 bacterial genera. (Punina et al 2015)

The development of novel therapeutic strategies, however, seems to have reached a dead end. Despite the urgent need to find new antibacterial products, many pharmaceutical companies have abandoned antibiotic drug discovery programs. (Roca et al 2015)

There have been no new broad-spectrum antibiotics developed in the last 40 years, and the drugs we have currently are quickly becoming ineffective. (Gill et al 2014)

Antibiotic resistance is a clear and present danger to human health, and there are worryingly few new antibiotics in the developmental pipeline. A rich source of new antimicrobials potentially resides in medieval and early modern medical texts: microbial infection has been a constant presence throughout human history, and manuscript evidence shows that early modern and premodern societies used a range of natural compounds to treat conditions that are clearly recognizable as microbial infections. (Harrison et al 2015)

Medicinal plants are considered new resources for producing agents that could act as alternatives to antibiotics in the treatment of antibiotic-resistant bacteria. (Al-Mariri & Safi 2014)

The therapeutic potential of phytochemicals for the development of anti-MRSA agents has been progressively recognized. Several studies have been conducted using phytochemicals combined with antimicrobial agents. These interactions can enhance the efficacy of the antimicrobial agents and are an alternative to treat infections caused by multi-drug resistant microorganisms, especially MRSA strains for which an effective therapy is limited and expensive. (Macedo et al 2013)

To address the problem of resistance, it will be necessary to change the protocols of use of antimicrobials so that these drugs are administered only when all other treatment options have failed; and joint efforts of governments and academic networks are needed to fight against the global spreading of multidrug resistant pathogens. Today, there is a need to seek alternative treatments. Non-traditional antibacterial agents are thus of great interest to overcome resistance that develops from several pathogenic microorganisms against most of the commonly used antibiotics. (Franci et al 2015)

Due to the multi-drug resistance problem the use of combinations of antibiotics with different mechanisms of action is often necessary for the treatment of severe staphylococcal infections. The augmented action of antibiotics along with natural substances may have positive synergistic effects toward specific, drug resistant microorganisms which are difficult to eradicate, particularly in hospital settings. The synergy between berberine and antibiotics demonstrates the potential application of compound combinations as an efficient, novel therapeutic tool for antibiotic-resistant bacterial infections. (Wojtyczka et al 2014)

Enormous efforts have been invested in the discovery of novel antimicrobial compounds and antimicrobial adjuvants for the control of bacterial infections with only modest success to date. Therefore, many alternative treatments are in use. Other unusual and more complex treatments have also been applied including phage therapy or the use of competitive beneficial micro-organisms. There is evidence that these methods provide at least a modicum of effectiveness and must be considered as a possible substitute in the complete absence of useful antibiotics. (Gill et al 2014) T

he application of natural products in the treatment of infectious diseases may be considered an interesting alternative to common antibiotics, possessing different side effects. In addition, cinnamon can be suggested as an alternative to synthetic antibiotics, especially for the treatment of antibiotic-resistant bacterial infections. (Nabavi et al 2015)

It is likely that even with new natural compounds it will be necessary to employ a multi-drug therapy (MDT) approach. It is also important to consider that traditional formulations are natural examples of MDT, and the modern concept of MDT may help to explain how some traditional herbal formulations may be successful in treating various bacterial infections. Drug synergies may occur through the use of several compounds which exhibit inhibitory effects through various mechanisms of actions, and this may also lead to a reduction in the rate of acquired drug resistance. (Potroz & Cho 2015)

Antimicrobial Actions of Natural Compounds
Bacterial infections result in 17 million deaths worldwide annually, mostly in children and the elderly. The morbidity and mortality associated with bacterial infections have remained significant, despite advances in antimicrobial chemotherapy. The situation has worsened with bacterial resistance increasing to available antibiotics. Today, multiple drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Acinetobacter baumannii, Klebsiella pneumonia, Escherichia coli, and Pseudomonas aeruginosa pose a serious threat to human and animal health. (Iqbal et al 2013)

Due to the lack of new synthetic antimicrobials in development for the treatment of MDR Gram-negative infections, attention is increasingly focused on natural compounds either as stand-alone or adjunctive therapies. (Betts & Warhead 2014)

The worldwide increased bacterial resistance to antibiotics and the undesirable side effects associated with constant use of synthetic drugs has prompted the search for novel antimicrobial agents, particularly those manufactured from plants. (Shrestha et al 2013)

The World Health Organization (WHO) has compiled a list of 20,000 plants that are used for phytotherapy in herbal systems of medicine all over the world (Manavalan and Manian 2001)

The widespread use of antibiotics in food animal production systems has resulted in the emergence of antibiotic resistant zoonotic [passed between animals and humans] bacteria that can be transmitted to humans through the food chain. (Walsh & Fanning 2008)

Bacterial resistance to antibiotics and the emergence of new kinds of microorganisms are becoming an increasing problem all over the world, causing significant morbidity and mortality. In order to combat this problem, novel antibiotic and anti-inflammatory compounds need to be found which are both effective and safe. (Muluye et al 2014)

The increasing failure of antibiotics has led to the screening of several plant extracts for potential antimicrobial activity. If found effective, such alternative antimicrobial agents could be explored further to overcome the problem of microbial drug resistance to antibiotics. (Revati et al 2015)

The following is a list of herbs, spices and foods that have shown antimicrobial activity followed by their respective studies:

Anti-Microbial Herbs, Spices, Foods and Essential Oils
Acanthopanax senticosus
Acetic acid
Achillea hamzaoglui
Achillea millefolium (yarrow)
Achillea wilhelmsii
Allium species eg. garlic, onions, shallots, leeks, chives, etc.
Arnica montana
Artemisia absinthium (wormwood)
Artemisia nilagirica (Indian wormwood)
Artemisia vulgaris (A. vulgaris)
Akebia quinata
Astragalus
Azadirachta Indica (neem)
Acacia nilotica (babul)
Aloe barbadensis Miller (aloe vera)
Bishop’s weed
Blackberry leaves
Black cumin
Blue gum tree
Boneset (Eupatorium perfoliatum)
Cambodge
Celery
Ceylon cinnamon
Chelidonium
Chili
Chokeberry leaves
Cinnamon
Cinnamon bark essential oil
Cinnamon (Cinnamomum verum) essential oil
Cinnamon oil (Ceylon type)
Cinnamomum zeylanicum (Ceylon cinnamon) 
Cinnamomum zeylanicum essential oil
Citron essential oil
Clove (Syzygium aromaticum) essential oil  
Coptic chinensis
Coriander
Coriander essential oil
Coriander/cumin seed oil combination
Cumin (Cuminum cyminum)
Curcumin and epigallocatechin gallate (EGCG) combination
Curry leaves
Echinacea purpura (Purple coneflower)
Epigallocatechin-3-gallate (EGCG), from green tea (Camellia sinesis)
Eucalyptus camaldulensis (eucalyptus)
Eucalyptus oleosa essential oil
Eucalyptus and citron essential oil
Eucommia ulmoides
Flos Lonicera
Forsythia suspensa
Garlic (Allium sativum)
Ginger
Goldenseal (Hydrastis canadensis)
Guava
Kalonji
Hawthorn leaves
Hedyotis diffusa
Hibiscus sabdariffa (sorrel)
Honey
Honokiol
Horseradish
Hungarian thyme
Isatidis Radix
Juniperus foetidissima Wild (stinking juniper)
Lady’s mantle
Laurus nobilis (bay leaf)
Lavender essential oil
Lemongrass essential oil
Lonicera japonica (Japanese honeysuckle)
Magnolol
Mangifera indica (mango)
Mango
Meadowsweet
Mentha longifolia (mint) 
Murraya koenigii L. (curry leaves)
Myristica fragrans Houtt. (nutmeg) oils
Neem
Nigella sativa (black cumin)
Nutmeg
Ocimum sanctum (tulsi)
Onion
Oregano (Syrian)
Origanum (oregano) essential oil
Papaya seed
Peppermint essential oil
Perilla essential oil
Polygonum aviculare (common knotgrass)
Polygonum cuspidatum
Pomegranate seeds
Poria cocos
Potentilla fruticosa
Prickly ash bark
Propolis
Psidium guajava (guava)
Raspberry leaves
Rhaponticum carthamoides
Rhodiola rosea
Rosa indica (rose)
Rosemary (Rosmarinus officinalis)
Rosemary oil
Sambucus australis (elderberry)
Sambucus ebulus and Sarcandra glabre
Scutellaria barbata (skullcap)
Scutellaria baicalensis
Silver
Silver nanoparticles
Skullcap
Tamarind Tea tree essential oil
Tejpat
Terminalia chebula
Thyme (Syrian)
Thyme essential oil
Thyme (Thymus vulgaris)
Tulsi
Uncaria rhyncophylla
Urtica dioica (nettles)
Usnea
Viola yedoensis V
itamin D
Zingiber officinale (ginger)

Acanthopanax senticosus, Eucommia ulmoides, Polygonum cuspidatum, P. cocos, Uncaria rhyncophylla and Hedyotis diffusa extracts showed significant inhibitory activity against only A. baumannii bacteria. (Zhang et al 2013)

Acetic acid is to be kept in mind as one of the alternatives when infection is caused by multiple antibiotic resistant strains of Pseudomonas aeruginosa. At a time when bacterial resistance to antibiotics is a matter of increasing concern, the value of topical agents such as acetic acid should not be forgotten. (Nagoba et al 2013)

Acetic acid -The tests showed excellent bactericidal effect of acetic acid, particularly with problematic Gram-negative bacteria such as P. vulgaris, P. aeruginosa and A. baumannii. The microbiological spectrum of acetic acid is wide, even when tested at a low concentration of 3%. In comparison to our currently used antiseptic solutions, it showed similar – in some bacteria, even better – bactericidal properties. It can be concluded that acetic acid in a concentration of 3% has excellent bactericidal effect and, therefore, seems to be suitable as a local antiseptic agent, but further clinical studies are necessary. (Ryssel et al 2009)

Achillea hamzaoglui – The essential oil of the plant exhibited much more prominent antimicrobial activity against tested microorganisms than that of methanol extract. Because of its strong antibacterial activity against Staphylococcus aureus (ATCC BAA-1026) and moderate antibacterial activity against Pseudomonas aeruginosa (ATTC 10145) and Propionibacterium acnes (ATCC 6919), the essential oil could be effectively used for skin infections. This study is the first report on essential oil composition and antioxidant and antimicrobial activities of A. hamzaoglui. (Turkmenoglu et al 2015)

Achillea millefolium (yarrow) – Four plant species exhibited antimicrobial properties as expected (Achillea millefolium, Ipomoea pandurata, Hieracium pilosella, and Solidago canadensis), with particularly strong effectiveness against Salmonella typhimurium. In addition, extractions from two of the introduced species (Hesperis matronalis and Rosa multiflora) were effective against this pathogen. (DFrey & Meyers 2010)

Achillea wilhelmsii oil exhibited higher antibacterial and antifungal activities with a high effectiveness against Escherichia coli and Candida albicans with the lowest minimum inhibitory concentration and minimum bactericidal concentration/minimum fungicidal concentration value (2 ± 0.0-2 ± 0.0 g/mL, 1 ± 0.5-1 ± 0.5 g/mL), respectively. These results support the use of the essential oil and its main compounds for their antioxidant properties and antimicrobial activity. (Kazemi & Rostami 2015)

Allium species eg. garlic, onions, shallots, leeks, chives, etc. – The antimicrobial activity of Allium species has long been recognized, with allicin, other thiosulfinates, and their transformation products having antimicrobial activity. Alliums are inhibitory against all tested microorganisms such as bacteria, fungi, viruses, and parasites. Alliums inhibit multi-drug-resistant microorganisms and often work synergistically with common antimicrobials. Allium-derived antimicrobial compounds inhibit microorganisms by reacting with the sulfhydryl (SH) groups of cellular proteins. Evidence has accumulated that allicin and other thiosulfinates also react with non-SH amino acids. (Kyung 2011)

Arnica montana – The aim of this study was to assess the antibacterial and antifungal potential of some Romanian medicinal plants, arnica–Arnica montana, wormwood–Artemisia absinthium and nettle–Urtica dioica. In order to perform this antimicrobial screening, we obtained the vegetal extracts and we tested them on a series of Gram-positive and Gram-negative bacteria, and also against two fungal strains. The vegetal extracts showed antimicrobial activity preferentially directed against the planktonic fungal and bacterial growth, while the effect against biofilm formation and development was demonstrated only against S. aureus and C. albicans. Our in vitro assays indicate that the studied plant extracts are a significant source of natural alternatives to antimicrobial therapy, thus avoiding antibiotic therapy, the use of which has become excessive in recent years. (Stanciuc et al 2011)

Artemisia – An exhaustive survey of literature revealed that the different species of Artemisia have a vast range of biological activities including antimalarial, cytotoxic, antihepatotoxic, antibacterial, antifungal and antioxidant activity. Some very important drug leads have been discovered from this genus, notably artemisinin, the well known antimalarial drug isolated from the Chinese herb Artemisia annua. Terpenoids, flavonoids, coumarins, caffeoylquinic acids, sterols and acetylenes constitute major classes of phytoconstituents of the genus.Various species of Artemisia seems to hold great potential for in-depth investigation for various biological activities, especially their effects on the central nervous and cardiovascular systems. (Bora & Sharma 2011)

Artemisia – Our results indicate that A. annua infusion is useful to control T. gondii infection, due to its low toxicity and its inhibitory action directly against the parasite, resulting in a well tolerated therapeutic tool. (de Oliveira et al 2009)

Artemisia absinthium (wormwood) – The aim of this study was to assess the antibacterial and antifungal potential of some Romanian medicinal plants, arnica–Arnica montana, wormwood–Artemisia absinthium and nettle–Urtica dioica. In order to perform this antimicrobial screening, we obtained the vegetal extracts and we tested them on a series of Gram-positive and Gram-negative bacteria, and also against two fungal strains. The vegetal extracts showed antimicrobial activity preferentially directed against the planktonic fungal and bacterial growth, while the effect against biofilm formation and development was demonstrated only against S. aureus and C. albicans. Our in vitro assays indicate that the studied plant extracts are a significant source of natural alternatives to antimicrobial therapy, thus avoiding antibiotic therapy, the use of which has become excessive in recent years. (Stanciuc et al 2011)

Artemisia nilagirica (Indian wormwood) – Extracts of A. nilagirica showed the broad spectrum of antibacterial activity on the tested microorganisms. Hexane extract exhibited high inhibitory potency against phytopathogens and methanol extract showed maximum inhibition against clinical pathogens except S. aureus, E. faecalis and K. pneumoniae. The isolation and purification of therapeutic potential compounds from A. nilagirica could be used as an effective source against bacterial diseases in human and plants. (Ahameethunisa & Hopper 2010)

Artemisia vulgaris (A. vulgaris), Sarcandra glabre, Polygonum aviculare (common knotgrass) , Akebia quinata and Scutellaria barbata (skullcap) – Plant extracts of these exhibited high inhibitory activity against both of the gram-negative strains tested (A. baumannii and P. aeruginosa). (Zhang et al 2013)

Astragalus polysaccharide – was effective in inducing TLR4 expression and enhancing the anti-bacterial activity of bladder epithelial cells (BECs). In this study, we applicated astragalus injection and antibiotics simultaneously to treat chronic UTI patients, the TLR4 expression levels on monocytes in the patients increased after recovery. Thus we think that astragalus as an immunomodulator enhanced TLR4 expression and thereby increased the innate immune capability of patients with chronic UTI and promoted clearance of infection. (Yin et al 2010)

Azadirachta Indica (neem), Ocimum sanctum (tulsi), Murraya koenigii L. (curry leaves), Acacia nilotica (babul), Eucalyptus camaldulensis (eucalyptus), Hibiscus sabdariffa (sorrel), Mangifera indica (mango), Psidium guajava (guava), Rosa indica (rose), and Aloe barbadensis Miller (aloe vera) – The extracts of Azadirachta Indica, Ocimum sanctum, Murraya koenigii L., Acacia nilotica, Eucalyptus camaldulensis, Hibiscus sabdariffa, Mangifera indica, Psidium guajava, Rosa indica, and Aloe barbadensis Miller have all been found to inhibit certain dental caries and periodontal pathogens. The current evidence suggests all the 10 plant extracts have antimicrobial efficacy against dental caries and periodontal pathogens. Most of these studies have been conducted using individual plant extracts on certain bacteria that are involved in either dental caries or periodontitis. (Shekar et al 2015)

Boneset (Eupatorium perfoliatum) – The cytotoxic and antibacterial activity of an ethanol extract of leaves of a herbal drug, boneset (Eupatorium perfoliatum), was investigated. The extract showed potent cytotoxicity with EC(50) values (12-14 microg/mL) comparable to a standard cytotoxic agent, chlorambucil. The extract showed a weak antibacterial activity against gram-positive test organisms (Staphylococcus aureus and Bacillus megaterium). (Habtemariam & Macpherson 2000)

Ceylon cinnamon, blue gum tree, Hungarian thyme – Extracts and oils of 28 plants used in this work have been traditionally employed by people for various purposes in different parts of the world. Cinnamomum zeylanicum (Ceylon cinnamon) essential oil has antibacterial and antifungal activities; Citrus aurantium has immunological effects in humans; Eucalyptus globulus (blue gum tree) oil has good antimicrobial activities; Thymus pannonicus (Hungarian thyme) essential oil has an excellent effect against E. coli O157:H7; light thyme essential oil inhibits the growth of E. coli O157:H7 in foods; Brillantaisia lamium extract exhibits antibacterial and antifungal effects against Staphylococcus aureus, Enterococcus faecalis, Candida tropicalis, and Cryptococcus neoformans; and finally Crinum purpurascens (starry crinum) herb extract has antimicrobial activities against Salmonella paratyphi A and B. (Al-Mariri & Safi 2014)

Chelidonium – The overall results provided important information for the potential application of the 8-hydroxylated alkaloids from Chelidonium majus in the therapy of serious infection caused by drug-resistant fungi. (Meng et al 2009)

Cinnamomum zeylanicum (cinnamon) and Zingiber officinale (ginger) showed the maximum antibacterial activity against the enterococcal isolates followed by S. aromaticum (clove) and C. cyminum (cumin). The findings of the study show that spices used in the study can contribute to the development of potential antimicrobial agents for inclusion in the anti-enterococcal treatment regimen. (Revati et al 2015)

Cinnamon (Cinnamomum verum) essential oil – The chemical composition of essential oils from four Pakistani spices cumin (Cuminum cyminum), cinnamon (Cinnamomum verum), cardamom (Amomum subulatum) and clove (Syzygium aromaticum) were analyzed on GC/MS. Most of the essential oils included in this study possessed good antibacterial activities against selected multi drug resistant clinical and soil bacterial strains. Cinnamaldehyde was identified as the most active antimicrobial component present in the cinnamon essential oil which acted as a strong inhibitory agent in MIC assay against the tested bacteria. (Naveed et al 2013)

Cinnamon (Cinnamomum zeylanicum) and clove (Syzygium aromaticum) showed the strongest in vitro antibacterial activity followed by cumin (Cuminum cyminum) against MRSA, and such findings could be considered a valuable support in the treatment of infection and may contribute to the development of potential antimicrobial agents for inclusion in anti- S. aureus regimens. (Mandal et al 2011)

Cinnamon bark, lemongrass, thyme, perilla, peppermint, tea tree, coriander, lavender, eucalyptus and citron essential oils – Cinnamon bark, lemongrass and thyme (wild and red) oils showed the highest activity, with the exception of lemongrass oil, which exhibited weak activity against E. coli. Perilla, thyme (geraniol), peppermint, tea tree, coriander and lavender (spike and true) oils showed moderate activity against all isolates except E. coli. However, tea tree and coriander oils showed activity against E. coli comparable to that against other strains. Eucalyptus (radiata) oil, and especially citron oil, were weakest in activity. Gram-positive bacteria are known to be more susceptible to essential oils than Gram-negative bacteria. The high degree of susceptibility of H. influenzae (to tea tree and lemon grass essential oil) was unexpected. One reason for this might be the hydrophobic nature of the outer membrane of H. influenzae forming rough colonies, in contrast to E. coli and Pseudomonas aeruginosa, which form smooth colonies. (Inouye et al 2001)

Clove, cinnamon, mint, coriander, garlic and kalonji – Increasing incidence rate of multiple drug resistance in Escherichia coli (E. coli) due to extensive uses of antibiotics is a serious challenge to disease treatment. Contaminated retail chicken meat is one of the major sources of spread of multi drug resistant (MDR) E. coli. Current study has been conducted to study the prevalence of MDR E. coli in retail chicken meat samples from Lahore city of Pakistan and it was found that 73.86% of E. coli isolates have MDR pattern. In vitro evaluation of antibacterial activity of crude ethanolic extracts of six herbs against MDR E. coli phenotypes has revealed that clove and cinnamon have maximum zones of inhibition as compared to other herbal extracts. Mint and coriander gave the intermediate results while garlic and kalonji showed the least antibacterial activity against the MDR E. coli phenotypes using the agar well diffusion technique. (Shaheen et all 2015)

Clove (Syzygium aromaticum and rosemary (Rosmarinus officinalis) – In the present study, the antimicrobial activity of the essential oils from clove (Syzygium aromaticum) and rosemary (Rosmarinus officinalis) was tested alone and in combination. The antimicrobial activity of combinations of the two essential oils indicated their additive, synergistic or antagonistic effects against individual microorganism tests. (Fu et al 2007)

Clove, cinnamon, bishop’s weed, chili, horseradish, cumin, tamarind, black cumin, pomegranate seeds, nutmeg, garlic, onion, tejpat, celery, and cambodge – A preliminary screening of 35 different Indian spices and herbs indicated that clove, cinnamon, bishop’s weed, chili (Capsicum annum), horseradish, cumin, tamarind, black cumin, pomegranate seeds, nutmeg, garlic, onion, tejpat, celery, and cambodge had potent antimicrobial activities against the test organisms Bacillus subtilis, Escherichia coli, and Saccharomyces cerevisiae. Garlic and cloves also possess antimicrobial activity against some human pathogenic bacteria and yeasts in vitro; some bacteria that showed resistance to certain antibiotics were sensitive to extracts of both garlic and clove. (Lampe 2003)

Coptic chinensis showed antimicrobial effects against E.coli. (Muluye et al 2014)

Coriander/cumin seed oil combination exhibited both synergistic antibacterial and antioxidant activity and may be used as a potential source of safe and potent natural antibacterial and antioxidant agents in pharmaceutical and food industries. Their synergistic interactions may increase their antibacterial and antioxidant efficacy at sufficiently low concentration which may reduce their adverse side effects and facilitate their use in food preservation system. Chemical analysis revealed that linalool from coriander seed oil and p-coumaric acid from cumin seed oil were the bioactive compounds responsible for both synergistic antibacterial and antioxidant activities. (Bag & Chattopadhyay 2015)

Curcumin and epigallocatechin gallate (EGCG) – This study demonstrates that despite little antibacterial activity alone, curcumin activity is greatly enhanced in the presence of EGCG resulting in antibacterial activity against MDR A. baumannii. The combination may have a potential use in medicine as a topical agent to prevent or treat Acinetobacter baumannii infections. (Betts & Wareham 2014) Echinacea purpura (Purple coneflower) contains biologically active compounds that have an antibacterial effect. Studies on bacteriostatic properties of purple coneflower extracts conducted by Jurkštienė et al. (1998) and Gorchen (2003) showed that the best effect was achieved against Staphylococcus aureus and Escherichia coli. Antibacterial properties of coneflower are related to echinacoside whose effect equals to that of penicillin. (Jurkstiene et al 2011)

Echinacea purpura (EP) – Along with evidence of enhanced macrophage function, we found that oral EP reduces bacterial burden during infection by Listeria monocytogenes, demonstrating its efficacy in vivo. (Sullivan et al 2008)

Epigallocatechin-3-gallate (EGCG), from green tea (Camellia sinesis) – These findings demonstrate that EGCG is an effective bactericidal agent against antibiotic-resistant A. baumannii clinical strains in laboratory settings. EGCG has previously been shown to be safe, and therefore may be an attractive addition for the treatment of cutaneous A. baumannii infections where high concentrations of the drug can be applied to the wound surface. (Osterburg et al 2009)

Eucalyptus oleosa essential oil – Essential oils obtained by hydrodistillation from the different parts (stems, adult leaves, immature flowers and fruits) of Eucalyptus oleosa were screened for their antioxidant and antimicrobial properties and their chemical composition. The essential oils showed a better antibacterial activity against Gram-positive and Gram-negative bacteria, and a significant antifungal activity also was observed against yeast-like fungi. A strong correlations between oxygenated monoterpenes and antimicrobial activity (especially 1,8-cineole) were noted (R2 = 0.99, 0.97 and 0.79 for B. subtilis, P. aeruginosa and C. albicans, respectively). (Ben Marzouq et al 2011)

Flos Lonicerae showed antimicrobial effects against H. pylori, Po. gingivalis, Str. mutants, Streptococcus sanguis. (Muluye et al 2014)

Forsythia suspensa – The results exhibited that the triterpenoids from the methanol extracts of fruits of F. suspensa possessed antibacterial activities against the common bacteria. It also provided evidence for the traditional uses of the fruits of F. suspensa as herbal medicines in the treatment of bacterial diseases. Although these purified compounds did not display better inhibition of the bacterial growth compared with the reported synthetic antibiotics, the extracts and principles from the natural sources usually possessed lower toxicity. (Kuo et al 2014)

Forsythia suspensa showed antimicrobial effects against E. coli, Sta. aureus, B. subtilis, Str. mutants, As. flavus, R. stolonifer, Pe. citrinum, As. niger and Sac. carlsbergensis. (Muluye et al 2014)

Garlic and ginger – It was interesting to note that clinical isolates, both Gram negative and Gram positive bacteria were sensitive to all tested extracts of garlic and ginger but Gram positive bacteria were more sensitive than Gram negative bacteria. This result is in accordance with the findings of Chandarana; Onyeagba and de-Souza. In this study heat effect on antimicrobial activity of garlic and ginger was not checked as it is already reported that antimicrobial activity of garlic is affected by heating at 100°C for 30–60 minutes. Therefore, it is recommended to use garlic and ginger in different raw forms like pickle, garlic/ginger bread, curry powder, sauces, raw juices and without extensive cooking. (Gull et al 2012)

Garlic and ginger – Natural spices of garlic and ginger possess effective anti-bacterial activity against multi-drug clinical pathogens and can be used for prevention of drug resistant microbial diseases and further evaluation is necessary. It is interesting to note that even crude extracts of these plants showed good activity against multidrug resistant strains where modern antibiotic therapy has limited effect. The effect of these spices on these organisms in vivo cannot be predicted from this study. (Karuppiah and Rajaram 2012)

Garlic – In terms of antibiotic potency against Gram-positive and Gram-negative bacteria, authentic allicin (an antibacterial principle of garlic) had roughly 1-2% of the potency of streptomycin (vs. S. aureus), 8% of that of vancomycin (vs. S. aureus), and only 0.2% of that of colistin (vs. E. coli). (Fujisawa et al 2009)

Goldenseal – Crude extracts and isolated compounds from goldenseal have demonstrated antibacterial activity in vitro and in clinical trials. The antibacterial activity of goldenseal has typically been attributed to alkaloids, especially berberine, which has shown activity against various Gram-positive bacteria, including MRSA. (Ettafagh et al 2011)

Goldenseal – The phytochemical berberine from Hydrastis canadensis inhibited the growth of all Neisseria gonorrhoeae isolates. (Cybulska et al 2011)

Honey and silver have been used since ancient times for treating wounds.With the recent increase in multiresistant bacteria due to the overuse of antibiotics in the past few decades, the potential of honey and silver in the management of various chronic wounds such as diabetic foot ulcers, venous ulcers, and pressure ulcers has spurred new interest in the wound care community. However, some reports have documented bacterial resistance to silver on possible wound pathogens. (Tsang et al 2015)

Honey – The healing property of honey is due to the fact that it offers antibacterial activity, maintains a moist wound condition, and its high viscosity helps to provide a protective barrier to prevent infection. Its immunomodulatory property is relevant to wound repair too. The antimicrobial activity in most honeys is due to the enzymatic production of hydrogen peroxide. However, another kind of honey, called non-peroxide honey (viz., manuka honey), displays significant antibacterial effects even when the hydrogen peroxide activity is blocked. Its mechanism may be related to the low pH level of honey and its high sugar content (high osmolarity) that is enough to hinder the growth of microbes. The medical grade honeys have potent in vitro bactericidal activity against antibiotic-resistant bacteria causing several life-threatening infections to humans. But, there is a large variation in the antimicrobial activity of some natural honeys, which is due to spatial and temporal variation in sources of nectar. (Mandal MD & Mandal S 2011)

Honokiol and magnolol – The antimicrobial effects of an ethanol extract of Magnolia dealbata seeds (MDE) and its active compounds honokiol (HK) and magnolol (MG) were tested against the phytopathogen Clavibacter michiganensis subsp. michiganensis and several human multi-drug resistant pathogens using the disk-diffusion assay. The effects of MDE and its active compounds on the viability of human peripheral blood mononuclear cells (PBMC) were evaluated using MTT assay. MDE and its active compounds had antimicrobial activity (inhibition zone > 10 mm) against C. michiganensis, Pseudomonas aeruginosa, Acinetobacter baumannii, Acinetobacter lwoffii, Candida albicans, Candida tropicalis and Trichosporon belgeii. The results suggest that M. dealbata and its active compounds have selective antimicrobial effects against drug-resistant fungal and Gram (-) bacteria and exert minimal toxic effects on human PMBC. (Jacobo-Salcedo et al 2011)

Isatidis Radix showed antimicrobial effects against Sta. aureus. (Muluye et al 2014)

Lonicera japonica (Japanese honeysuckle) – The ethanol extract of the flowering aerial parts of L. japonica exhibited significant antimicrobial activity against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Candida albicans, and Candida tropicalis. (Chen et al 2012)

Meadowsweet, blackberry leaves, lady’s mantle, raspberry leaves and hawthorn leaves, chokeberry leaves – All six extracts showed an activity against genetically modified E. coli. The bioluminescence signal decreased within few minutes after exposition of the bacteria to herb extracts and stayed low during the entire experiment. Meadowsweet showed the highest antibacterial activity (75% inhibition of control, Fig. 3) followed by blackberry leaves (60%), lady’s mantle (56%), raspberry leaves (52%) and hawthorn leaves (27%). A very low activity was found for chokeberry leaves with only 4% growth inhibition. (Denev et al 2014)

Mentha longifolia (mint) – The isolation of an antimicrobial compound from M. longifolia leaves validates the use of this plant in the treatment of minor sore throat and minor mouth or throat irritation. (Al-Bayati FA 2009)

Oregano (Syrian), thyme (Syrian), clove, Ceylon cinnamon, garlic, nutmeg and bay leaf – Origanum syriacum. L.(oregano, Syrian), Thymus syriacus Boiss (thyme, Syrian)., Syzygium aromaticum L (clove)., Cinnamomum zeylanicum L (Ceylon cinnamon)., Juniperus foetidissima Wild )(stinking juniper), Allium sativum L (garlic), and Myristica fragrans Houtt. (nutmeg) oils and Laurus nobilis L. (bay leaf) extract were the most effective plant extracts against the Gram-negative bacteria studied in this work. These plant extracts could be a potential source of new antibacterial agents. (Al-Mariri & Safi 2014)

Nigella sativa (black cumin) – The essential oil (EO) of Nigella sativa (black cumin) was formulated in water-based microemulsion system and its antibacterial activity against six pathogenic bacteria was evaluated using the agar well diffusion method. This activity was compared with two other well known biologically active natural and synthetic antimicrobials namely eugenol and Ceftriaxone(®). Results showed that N. sativa EO microemulsion was highly effective against S. aureus, B. cereus and S. typhimurium even at the lowest tested concentration of that EO in the microemulsion (100.0 μg/well). Interestingly, the EO microemulsion showed higher antibacterial activity than Ceftriaxone solution against S. typhimurium at 400.0 μg/well and almost comparable activity against E. coli at 500.0 μg/well. (Shaaban et al 2015)

Papaya seed could be used as an effective antibacterial agent for the tested organisms (Escherichia coli, Staphylococcus aureus, Salmonella typhi, and Pseudomonas aeruginosa). Nevertheless, preclinical studies including invivo animal models and clinical trial on the effect of the seed are essential before advocating large-scale therapy. (Yismaw et al 2008)

Peppermint, cinnamon bark and lavender essential oils – Substantial susceptibility of the bacteria toward natural antibiotics and a considerable reduction in the minimum inhibitory concentrations (MIC) of the antibiotics were noted in some paired combinations of antibiotics and essential oils. The finding highlighted the potential of peppermint, cinnamon bark and lavender essential oils being as antibiotic resistance modifying agent. Reduced usage of antibiotics could be employed as a treatment strategy to decrease the adverse effects and possibly to reverse the beta-lactam antibiotic resistance. (Yap et al 2013)

Prickly ash bark – We have demonstrated activity associated with extracts from Southern prickly ash bark, Zanthoxylum clava-herculis. This compound exhibited potent activity against strains of MRSA, which were highly resistant to clinically useful antibiotics via multidrug efflux mechanisms. (Gibbons et al 2003)

Propolis – Based on the results, one may conclude that Bulgarian propolis showed an important antibacterial action, as well as a synergistic effect with antibiotics acting on the ribosome, which points out a possible therapeutic strategy evaluating the use of propolis preparations for the treatment of Salmonella Typhi infection. (Orsi et al 2011)

Propolis – Soft and purified propolis extracts possess antimicrobial activity. They could be recommended as natural preservatives in the manufacture of pharmaceutical products. (Pavilonis et al 2008)

Rhaponticum carthamoides and Potentilla fruticosa – The studied preparations – viscous extracts of rhaponticum and shrubby cinquefoil – are substances with antimicrobial activity against gram-positive (Staphylococcus aureus and Enterococcus faecalis) and gram-negative (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis) bacteria, spore-forming bacteria (Bacillus subtilis and Bacillus cereus), and fungi (Candida albicans). (Jurkstiene et al 2011)

Rhodiola rosea – The phytochemicals, salidroside and rosavin, present in R. rosea, also showed inhibitory activity against Neisseria gonorrhoeae strains. (Cybulska et al 2011)

Rosemary oil – Our findings suggest that characterization and isolation of the active compound(s) from the rosemary oil may be useful in counteracting gram-positive bacterial, fungal, and drug-resistant infections. (Luqman et al 2007)

Sambucus australis (elderberry) – Ursolic acid, an important bioactive compound, was isolated from ethanol extract of aerial parts of Sambucus australis. This study showed that ursolic acid and some of its derivatives have significant antibacterial activity against several bacterial species, and that these compounds show synergistic activities with the aminoglycoside antibiotics neomycin, amikacin, kanamycin and gentamicin. These results suggest that Sambucus australis could be a potential natural source of free radical scavengers. (do Nascimento et al 2014)

Sambucus ebulus and Urtica dioica – The research showed extracts of Sambucus ebulus and Urtica dioica possess antibacterial potency against MRSA isolates and may be used as a natural antiseptics and antimicrobial agents in medicine. (Salehzadeh et al 2014) Scutellaria baicalensis showed antimicrobial effects against H. pylori, E. coli, coagulase-negative staphylococci and Saccharomyces. (Muluye et al 2014)

Scutellaria barbata (skullcap) – Essential oils including hexahydrofarnesylacetone, 3,7,11,15-tetramethyl-2-hexadecen-1- ol, menthol and 1-octen-3-ol, which have been isolated from Scutellaria barbata (skullcap) showed anti-microbial activity against 17 microorganisms. Interestingly, the studies carried out by Yu et al. and also the results of the present study demonstrate that S. aureus is highly sensitive to the extract of Scutellaria barbata. (Zhang et al 2013) 

Silver nanoparticles (AgNPs) – It is now clear that AgNPs possess a strong antibacterial and antiviral activity, highlighted by several studies. AgNPs have the ability to interact with various microorganisms (such as bacteria) and also impact both the growth of and mature bacterial biofilms and, therefore, could be used as broad spectrum antimicrobials. The antibacterial effect appears to be conferred by their ultrasmall size and increased surface area, through which they destroy the membrane, cross the body of the microbe and create intracellular damage. (Franci et al 2015)

Silver nanoparticles (SNPs) – Here we have studied the adsorption and toxicity of SNPs on bacterial species such as Pseudomonas aeruginosa, Micrococcus luteus, Bacillus subtilis, Bacillus barbaricus and Klebsiella pneumoniae. The survival rate of bacterial species decreased with increase in adsorption of SNPs. (Khan et al 2011)

Silver nanoparticles (SNPs) – The antimicrobial action of silver or silver compounds is proportional to the bioactive silver ion (Ag(+)) released and its availability to interact with bacterial or fungal cell membranes. The silver ion is biologically active and readily interacts with proteins, amino acid residues, free anions and receptors on mammalian and eukaryotic cell membranes. Bacterial (and probably fungal) sensitivity to silver is genetically determined and relates to the levels of intracellular silver uptake and its ability to interact and irreversibly denature key enzyme systems. Silver exhibits low toxicity in the human body, and minimal risk is expected due to clinical exposure by inhalation, ingestion, dermal application or through the urological or haematogenous route. (Lansdown 2006)

Terminalia chebula – Organic and aqueous extracts of T. chebula exhibit antioxidant, antimicrobial, antianaphylactic, antidiabetic, antimutagenic, anticancerous, apoptotic, anticaries, antifungal and antiviral activities. T. chebula fruit extract is effective antimicrobial against methicillin resistant Staphylococcus aureus and trimethoprim-sulphamethoxazole resistant uropathogenic E. coli strain. (Sarabhai et al 2013)

Thyme – According to the potential of Thymus vulgaris (T. vulgaris) extracts to inhibit the test bacteria in planktonic and biofilm form, it can be suggested that Thymus vulgaris (T. vulgaris) extracts can be applied as antimicrobial agents against the pathogenic bacteria particularly in biofilm forms. (Mohsenipour & Hassanshahian 2015)

Thyme, origanum, mint, cinnamon, salvia and clove – This paper gives an overview on the susceptibility of human and food-borne bacteria and fungi towards different essential oils and their constituents. Essential oils of spices and herbs (thyme, origanum, mint, cinnamon, salvia and clove) were found to possess the strongest antimicrobial properties among many tested. (Kalemba and Kunicka 2003)

Urtica dioica (Nettles) – The aim of this study was to assess the antibacterial and antifungal potential of some Romanian medicinal plants, arnica–Arnica montana, wormwood–Artemisia absinthium and nettle–Urtica dioica. In order to perform this antimicrobial screening, we obtained the vegetal extracts and we tested them on a series of Gram-positive and Gram-negative bacteria, and also against two fungal strains. The vegetal extracts showed antimicrobial activity preferentially directed against the planktonic fungal and bacterial growth, while the effect against biofilm formation and development was demonstrated only against S. aureus and C. albicans. Our in vitro assays indicate that the studied plant extracts are a significant source of natural alternatives to antimicrobial therapy, thus avoiding antibiotic therapy, the use of which has become excessive in recent years. (Stanciuc et al 2011)

Usnea – Usnic acid has a strong and dose-dependent activity against H. pylori strains. The synergism between usnic acid and clarithromycin may be effective in the treatment of H. pylori infection. (Safak et al 2009) Usnea – Six species of lichens, such as Usnea florida, Usnea barbata, Usnea longissima, Usnea rigida, Usnea hirta and Usnea subflorida, were collected from different areas of Anatolia (district of Antalya, Karabük, Qankiri, Giresun and Trabzon) in Turkey. Antimicrobial activities of these extracts were determined against Escherichia coli, Enterococcus faecalis, Proteus mirabilis, Staphylococcus aureus, Bacillus subtilis and Bacillus megaterium. It was shown that with increasing amount of usnic acid, the antimicrobial activity increased. (Cansaran et al 2006)

Viola yedoensis showed antimicrobial effects against B. subtitles and Pseudomonas syringae. (Muluye et al 2014)

Vitamin D – These data show that vitamin D is able to mitigate the deleterious effects of Adherent-invasive Escherichia coli (AIEC) on the intestinal mucosa, by maintaining intestinal epithelial barrier homeostasis and preserving tight-junction architecture. This study highlights the association between vitamin D status, dysbiosis, and Crohn’s disease. (Assa et al 2015)

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