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      Development of botanicals to combat antibiotic resistance

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          Abstract

          The discovery of antibiotics in the previous century lead to reduction in mortality and morbidity due to infectious diseases but their inappropriate and irrational use has resulted in emergence of resistant microbial populations. Alteration of target sites, active efflux of drugs and enzymatic degradations are the strategies employed by the pathogenic bacteria to develop intrinsic resistance to antibiotics. This has led to an increased interest in medicinal plants since 25–50% of current pharmaceuticals are plant derived. Crude extracts of medicinal plants could serve as an alternate source of resistance modifying agents owing to the wide variety of secondary metabolites. These metabolites (alkaloids, tannins, polyphenols etc.) could act as potentials for antimicrobials and resistance modifiers. Plant extracts have the ability to bind to protein domains leading to modification or inhibition protein–protein interactions. This enables the herbals to also present themselves as effective modulators of host related cellular processes viz immune response, mitosis, apoptosis and signal transduction. Thus they may exert their activity not only by killing the microorganism but by affecting key events in the pathogenic process, thereby, the bacteria, fungi and viruses may have a reduced ability to develop resistance to botanicals. The article is meant to stimulate research wherein the cidal activity of the extract is not the only parameter considered but other mechanism of action by which plants can combat drug resistant microbes are investigated. The present article emphasizes on mechanisms involved in countering multi drug resistance.

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          ARDB—Antibiotic Resistance Genes Database

           Bo Liu,  Mihai Pop (2009)
          The treatment of infections is increasingly compromised by the ability of bacteria to develop resistance to antibiotics through mutations or through the acquisition of resistance genes. Antibiotic resistance genes also have the potential to be used for bio-terror purposes through genetically modified organisms. In order to facilitate the identification and characterization of these genes, we have created a manually curated database—the Antibiotic Resistance Genes Database (ARDB)—unifying most of the publicly available information on antibiotic resistance. Each gene and resistance type is annotated with rich information, including resistance profile, mechanism of action, ontology, COG and CDD annotations, as well as external links to sequence and protein databases. Our database also supports sequence similarity searches and implements an initial version of a tool for characterizing common mutations that confer antibiotic resistance. The information we provide can be used as compendium of antibiotic resistance factors as well as to identify the resistance genes of newly sequenced genes, genomes, or metagenomes. Currently, ARDB contains resistance information for 13 293 genes, 377 types, 257 antibiotics, 632 genomes, 933 species and 124 genera. ARDB is available at http://ardb.cbcb.umd.edu/.
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            Microbial biofilms: from ecology to molecular genetics.

            Biofilms are complex communities of microorganisms attached to surfaces or associated with interfaces. Despite the focus of modern microbiology research on pure culture, planktonic (free-swimming) bacteria, it is now widely recognized that most bacteria found in natural, clinical, and industrial settings persist in association with surfaces. Furthermore, these microbial communities are often composed of multiple species that interact with each other and their environment. The determination of biofilm architecture, particularly the spatial arrangement of microcolonies (clusters of cells) relative to one another, has profound implications for the function of these complex communities. Numerous new experimental approaches and methodologies have been developed in order to explore metabolic interactions, phylogenetic groupings, and competition among members of the biofilm. To complement this broad view of biofilm ecology, individual organisms have been studied using molecular genetics in order to identify the genes required for biofilm development and to dissect the regulatory pathways that control the plankton-to-biofilm transition. These molecular genetic studies have led to the emergence of the concept of biofilm formation as a novel system for the study of bacterial development. The recent explosion in the field of biofilm research has led to exciting progress in the development of new technologies for studying these communities, advanced our understanding of the ecological significance of surface-attached bacteria, and provided new insights into the molecular genetic basis of biofilm development.
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              Natural Antibiotic Resistance and Contamination by Antibiotic Resistance Determinants: The Two Ages in the Evolution of Resistance to Antimicrobials

              The study of antibiotic resistance has been historically concentrated on the analysis of bacterial pathogens and on the consequences of acquiring resistance for human health. The development of antibiotic resistance is of course extremely relevant from the clinical point of view, because it can compromise the treatment of infectious diseases as well as other advanced therapeutic procedures as transplantation or anticancer therapy that involve immunosuppression and thus require robust anti-infective preventive therapies. Nevertheless, the studies on antibiotic resistance should not be confined to clinical-associated ecosystems. It was evident soon after introducing antibiotics for human therapy, that bacteria were able to develop resistance, not just as the consequence of mutations in the targets of antibiotics, but by acquiring genes conferring resistance to antimicrobials (Abraham and Chain, 1940). Since those genes were not present before in the human bacterial pathogens, the only suitable source for them was the environmental microbiota, and indeed the presence of R-factors (resistance plasmids) in pristine environments without any record of contact with antibiotics was described in the first studies of antibiotic resistance in the field (Gardner et al., 1969). Given that the origin of antibiotic resistance is the environmental microbiota, it would be necessary to study resistance in natural, non-clinical habitats in order to fully understand the cycle of acquisition of resistance by human pathogens. However, until recently the studies on antibiotic resistance in natural ecosystems have been fragmentary. The availability of metagenomic tools as well as high-throughput sequencing techniques is allowing describing in depth the presence of resistance genes in different ecosystems. Indeed, the use of functional genomic and metagenomic techniques has served to show that natural ecosystems, including not just soils but human gut as well, contain a large number of elements that, upon transfer to a new host, can confer resistance to any type of antimicrobial (D'Costa et al., 2006; Sommer et al., 2009). These include natural antibiotics, which are produced by the environmental microbiota, and synthetic antimicrobials, as quinolones. One important question from an evolutionary point of view is the function of these resistance genes in their natural environmental hosts (Davies and Davies, 2010). Whereas for naturally produced antibiotics a protective role for resistance genes in the producers organisms (or those coexisting with producers Laskaris et al., 2010) might be foreseen (Benveniste and Davies, 1973), this explanation is not suitable for synthetic antibiotics as quinolones. Indeed, it has been described that the origin of the quinolone resistance gene QnrA, which is now widespread in plasmids present in human pathogens is the environmental non-antibiotic producer Shewanella algae (Poirel et al., 2005). This means that a gene that confers resistance in a human pathogen does not necessary play the same role in its original host (Martinez et al., 2009a). The finding that several proteins, involved in basic processes of the bacterial physiology, contribute to intrinsic resistance to antibiotics (Fajardo et al., 2008; Laskaris et al., 2010; Linares et al., 2010), further supports the concept that resistance genes, acquired through horizontal gene transfer by human pathogens, might have evolved in their original host to play a different role than resisting the activity of antimicrobials in natural ecosystems. We can thus distinguish two ages in the evolution of antibiotic resistance genes. For billions of years (until the use of antibiotics by humans), these genes have been usually chromosomally encoded and had evolved for different purposes. Some of them, as those found in antibiotic producers, likely evolved for detoxifying the original host from the antibiotic it produces, although a role in the biosynthesis of the antibiotic itself has been proposed as well for some of them (Benveniste and Davies, 1973; Doyle et al., 1991). Others, as beta-lactamases might be involved in the biosynthesis of the cell wall (Jacobs et al., 1994; Massova and Mobashery, 1998), whereas others as multidrug efflux pumps might serve for different purposes including the trafficking of signaling molecules, detoxification of metabolic intermediates, or extrusion of plant-produced compounds among others (Martinez et al., 2009b). Like in the case of antibiotics, which do not necessarily have an inhibitory function at the concentrations in which they are present in natural ecosystems (Linares et al., 2006; Yim et al., 2007; Fajardo and Martinez, 2008), the fact that a plasmid-encoded gene produces resistance to antibiotics upon its expression in a new host, is not an unequivocal prove that it confers resistance as well in its original host. This reflection serves to show the relevance of the second age in the evolution of antibiotic resistance determinants. Once a gene is introduced in a new host in which it lacks its original biochemical and genetic context, its function is limited to antibiotic resistance (Baquero et al., 2009). This change of function without changing the sequence of the gene itself, has been named as exaptation (Gould and Vrba, 1982), and is the consequence of the strong selective pressure exerted by antibiotics in the last decades from the time they were introduced for therapy. Two important aspects are emerging from the studies of natural resistome. First, the environmental microbiota contains a much larger number of resistance genes than those seen to be acquired by bacterial pathogens (Wright, 2007; Davies and Davies, 2010). Furthermore, different ecosystems contain different resistance genes, which means that we are still far away to have a consistent estimation on the number of potential resistance genes present in natural ecosystems. Finally, the origin of most resistance genes currently found in transferrable elements is still ignored, despite genes (and genetic structures) belonging to the same families are regularly found in different ecosystems, including deep terrestrial subsurface (Brown and Balkwill, 2009), ice (Miteva et al., 2004), and even the permafrost (D'Costa et al., 2011), which have not been in contact with human contaminants. Second, those genes present in mobile elements in human bacterial pathogens can be found nearly everywhere, including pristine ecosystems or wild animals not supposed to be in contact with antibiotics (Martinez, 2009). This indicates that pollution with antibiotic resistance genes is widely spread and that resistance genes can persist even in the absence of a positive selection pressure. The analysis of historical soil archives has shown a consistent increase on the presence of antibiotic resistance genes since 1940 (Knapp et al., 2010), which is a clear prove of the contamination by antibiotic resistance elements of natural ecosystems and the resilience of those elements for their elimination. In this situation, which type of studies are needed to analyze in depth the role that natural ecosystems may have on the development of resistance in human bacterial pathogens? In my opinion, these studies have two faces (Martinez, 2008). One consists on the analysis of the genes already present in bacterial pathogens. In other words, we will study mainly contamination by antibiotic resistance determinants and how this contamination might increase the risks for the dissemination of those elements (Martinez, 2009). These studies might serve to define reservoirs, elements for enrichment and dissemination of resistance (as wild birds Simoes et al., 2010) or hotspots for the transfer of resistance as waste-water treatment plants (Baquero et al., 2008). For instance, a recent study has shown that soil composition and in particular the presence of heavy metals might enrich for the presence of antibiotic resistance genes in natural ecosystems (Knapp et al., 2011). The other type of studies consists on the analysis, using functional assays, of novel resistance genes in different ecosystems (D'Costa et al., 2006, 2011; Sommer et al., 2009). These studies are useful for defining novel mechanisms of resistance, but making risks assessments on whether those novel antibiotic resistance genes will be transferred to new hosts is likely unsuitable (Martinez et al., 2007). On the other hand tracking the source of currently known resistance gene has demonstrated to be a very difficult task. We have to be extremely careful for assigning the origin of resistance determinants. Only when the genes are nearly identical (as QnrA) and the gene is present in several strains of the original host, with the same synteny and without any sign of a recent acquisition event, we can firmly establish this host being the origin. The report of genes that are highly similar (even above 90%) to antibiotic resistance genes demonstrate their belonging to the same phylogenetic group, not that one is the origin of the other. Does it mean that we will be unable of tracking the source of resistance genes and to propose from this information valuable strategies for reducing antibiotic resistance? I do not believe that. It has been already determined that QnrA was originated in S. algae (Poirel et al., 2005) and that chromosomally encoded qnr genes are mainly present in water-dwelling bacteria (Sanchez et al., 2008). This suggests that the source of transferrable quinolone resistance is the water microbiota and puts a focus on the effect that the use of quinolones in aquaculture might have had for the emergence and dissemination of these resistance elements (Cabello, 2006). The study on antibiotic resistance in natural ecosystems and its role on the maintenance and spread of clinically relevant resistance determinants is still in its infancy. It is surprising that large efforts have been used to study the risks for the dissemination of resistance that may have the release of genetic modified organisms containing resistance genes in their chromosomes, whereas the study of the effect of the discharge of human wastes, which contain bacterial pathogens harboring the resistance genes that have demonstrated to be really relevant, in the elements that are important for their dissemination has received few attention if any. Studies in this new field are needed in order to understand the mechanisms involved in the emergence, spread, maintenance, and evolution of antibiotic resistance.
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                Author and article information

                Contributors
                Journal
                J Ayurveda Integr Med
                J Ayurveda Integr Med
                Journal of Ayurveda and Integrative Medicine
                Elsevier
                0975-9476
                0976-2809
                30 August 2017
                Oct-Dec 2017
                30 August 2017
                : 8
                : 4
                : 266-275
                Affiliations
                The Foundation for Medical Research, 84-A, R.G. Thadani Marg, Worli, Mumbai, 400 018, Maharashtra, India
                Author notes
                []Corresponding author. fmr@ 123456fmrindia.org
                Article
                S0975-9476(16)30448-X
                10.1016/j.jaim.2017.05.004
                5747506
                28869082
                © 2017 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Publishing Services by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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