Dataset Information

Abundance of Multidrug Resistance Efflux Pumps in the Urinary Metagenome of Kidney Transplant Patients.

ABSTRACT: Antibiotic resistance including the emergence of multidrug resistant microbes has become a public health crisis. In this study, we analyzed the antibiotic resistance genes (ARGs) in the urinary metagenome of the kidney transplant and healthy subjects using metagenomic shotgun sequencing. Our data suggest an increased abundance of antibiotic resistance genes in the kidney transplant subjects. In addition, the antibiotic resistance genes identified in the transplant subjects were predominantly composed of multidrug efflux pumps (MDEPs) which are evolutionarily ancient, commonly encoded on chromosomes rather than plasmids, and have a low rate of mutation. Since the MDEPs had a low abundance in the healthy subjects, we speculate that the MDEPs may enhance the fitness of bacteria to survive in the high stress environment of transplantation that includes multiple stressors including surgery, antibiotics, and immunosuppressive agents.

SUBMITTER: Rani A

PROVIDER: S-EPMC7093903 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Abundance of Multidrug Resistance Efflux Pumps in the Urinary Metagenome of Kidney Transplant Patients.

Rani Asha A Ranjan Ravi R Metwally Ahmed A AA Brennan Daniel C DC Finn Patricia W PW Perkins David L DL

BioMed research international 20200312

Antibiotic resistance including the emergence of multidrug resistant microbes has become a public health crisis. In this study, we analyzed the antibiotic resistance genes (ARGs) in the urinary metagenome of the kidney transplant and healthy subjects using metagenomic shotgun sequencing. Our data suggest an increased abundance of antibiotic resistance genes in the kidney transplant subjects. In addition, the antibiotic resistance genes identified in the transplant subjects were predominantly com ...[more]

PMID: 32258127

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Project description:Many human activities contaminate terrestrial and aquatic environments with numerous chemical pollutants that not only directly alter the environment but also affect microbial communities in ways that are potentially concerning to human health, such as selecting for the spread of antibiotic-resistance genes (ARGs) through horizontal gene transfer. In the present study, metagenomes available in the public domain from polluted (with antibiotics, with petroleum, with metal mining, or with coal-mining effluents) and unpolluted terrestrial and aquatic environments were compared to examine whether pollution has influenced the abundance and composition of ARGs and mobile elements, with specific focus on IS26 and class 1 integrons (intI1). When aggregated together, polluted environments had a greater relative abundance of ARGs than unpolluted environments and a greater relative abundance of IS26 and intI1. In general, chemical pollution, notably with petroleum, was associated with an increase in the prevalence of ARGs linked to multidrug efflux pumps. Included in the suite of efflux pumps were mexK, mexB, mexF, and mexW that are polyspecific and whose substrate ranges include multiple classes of critically important antibiotics. Also, in some instances, β-lactam resistance (TEM181 and OXA-541) genes increased, and genes associated with rifampicin resistance (RNA polymerases subunits rpoB and rpoB2) decreased in relative abundance. This meta-analysis suggests that different types of chemical pollution can enrich populations that carry efflux pump systems associated with resistance to multiple classes of medically critical antibiotics.IMPORTANCEThe United Nations has identified chemical pollution as being one of the three greatest threats to environmental health, through which the evolution of antimicrobial resistance, a seminally important public health challenge, may be favored. While this is a very plausible outcome of continued chemical pollution, there is little evidence or research evaluating this risk. The objective of the present study was to examine existing metagenomes from chemically polluted environments and evaluate whether there is evidence that pollution increases the relative abundance of genes and mobile genetic elements that are associated with antibiotic resistance. The key finding is that for some types of pollution, particularly in environments exposed to petroleum, efflux pumps are enriched, and these efflux pumps can confer resistance to multiple classes of medically important antibiotics that are typically associated with Pseudomonas spp. or other Gram-negative bacteria. This finding makes clear the need for more investigation on the impact of chemical pollution on the environmental reservoir of ARGs and their association with mobile genetic elements that can contribute to horizontal gene transfer events.

Project description:RND (Resistance-Nodulation-Division) family transporters are widespread especially among Gram-negative bacteria, and catalyze the active efflux of many antibiotics and chemotherapeutic agents. They have very large periplasmic domains, and form tripartite complexes with outer membrane channels and periplasmic adaptor proteins. AcrAB-TolC complex of Escherichia coli, which pumps out a very wide range of drugs, has been studied most intensively. Early studies showed that the transporter captures even those substrates that cannot permeate across the cytoplasmic membrane, such as dianionic beta-lactams, suggesting that the capture can occur from the periplasm. It was also suggested that the capture occurs from the cytoplasmic membrane/periplasm interface, because most substrates contain a sizable hydrophobic domain; however, this may simply be a reflection of the nature of the binding site within AcrB. Genetic studies of chimeric transporters showed that much of the substrate specificity is determined by their periplasmic domains. Biochemical studies with intact cells recently led to the determination of the kinetic constants of AcrB for some beta-lactams, and the result confirms the old prediction that AcrB is a rather slow pump. Reconstitution of purified AcrB and its relatives showed that the pump is a drug/proton antiporter, that AcrA strongly stimulates the activity of the pump, and that AcrB seems to have a highest affinity for conjugated bile salts. Structural study with mutants of the network of charged residues in the transmembrane domain showed that protonation here produced a far-reaching conformational change, which was found to be present in one of the protomers in the asymmetric crystal structure of the wild-type AcrB. The functional rotatory hypothesis then predicts that the drug bound in the periplasmic domain is extruded through this conformational change initiated by the protonation of one of the residues in the aforementioned network, an idea that was recently supported by disulfide cross-linking as well as by the behavior of linked AcrB protomers.

Dataset Information

Abundance of Multidrug Resistance Efflux Pumps in the Urinary Metagenome of Kidney Transplant Patients.

Publications

Abundance of Multidrug Resistance Efflux Pumps in the Urinary Metagenome of Kidney Transplant Patients.

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