Drug efflux pump deficiency and drug target resistance masking in growing bacteria

Fange, David; Nilsson, Karin; Tenson, Tanel; Ehrenberg, Måns

doi:10.1073/pnas.0811514106

Cited by 28 publications

(39 citation statements)

References 23 publications

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“…The dissociation of macrolidebound ribosome promoted by ORF-16 TYL 10 is believed to reset the stalled ribosome to allow productive translation. Concerning the apparent AcrAB dependency of the ORF-16 TYL 10 -conferred resistance, observations highly similar to ours, in which the macrolide resistance caused by ribosomal mutation was "masked" by drug efflux pump deficiency, have been reported for several bacteria, including E. coli (39). This so-called "drug target mutation masking" effect in response to efflux pump inhibition is fundamentally linked to growth bistability and is favored by factors including high-affinity drug binding to its target and high target abundance within bacterial cells (39), both of which are applicable in the case of macrolide antibiotics and their ribosomal target.…”

Section: Figsupporting

confidence: 72%

Novel Antibiotic Resistance Determinants from Agricultural Soil Exposed to Antibiotics Widely Used in Human Medicine and Animal Farming

Lau

Engelen

Gordon

et al. 2017

Appl Environ Microbiol

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Antibiotic resistance has emerged globally as one of the biggest threats to human and animal health. Although the excessive use of antibiotics is recognized as accelerating the selection for resistance, there is a growing body of evidence suggesting that natural environments are "hot spots" for the development of both ancient and contemporary resistance mechanisms. Given that pharmaceuticals can be entrained onto agricultural land through anthropogenic activities, this could be a potential driver for the emergence and dissemination of resistance in soil bacteria. Using functional metagenomics, we interrogated the "resistome" of bacterial communities found in a collection of Canadian agricultural soil, some of which had been receiving antibiotics widely used in human medicine (macrolides) or food animal production (sulfamethazine, chlortetracycline, and tylosin) for up to 16 years. Of the 34 new antibiotic resistance genes (ARGs) recovered, the majority were predicted to encode (multi)drug efflux systems, while a few share little to no homology with established resistance determinants. We characterized several novel gene products, including putative enzymes that can confer high-level resistance against aminoglycosides, sulfonamides, and broad range of beta-lactams, with respect to their resistance mechanisms and clinical significance. By coupling high-resolution proteomics analysis with functional metagenomics, we discovered an unusual peptide, PPP AZI 4 , encoded within an alternative open reading frame not predicted by bioinformatics tools. Expression of the proline-rich PPP AZI 4 can promote resistance against different macrolides but not other ribosome-targeting antibiotics, implicating a new macrolidespecific resistance mechanism that could be fundamentally linked to the evolutionary design of this peptide.IMPORTANCE Antibiotic resistance is a clinical phenomenon with an evolutionary link to the microbial pangenome. Genes and protogenes encoding specialized and potential resistance mechanisms are abundant in natural environments, but understanding of their identity and genomic context remains limited. Our discovery of several previously unknown antibiotic resistance genes from uncultured soil microorganisms indicates that soil is a significant reservoir of resistance determinants, which, once acquired and "repurposed" by pathogenic bacteria, can have serious impacts on therapeutic outcomes. This study provides valuable insights into the diversity and identity of resistance within the soil microbiome. The finding of a novel peptide-mediated resistance mechanism involving an unpredicted gene product also highlights the usefulness of integrating proteomics analysis into metagenomicsdriven gene discovery.

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Section: Figsupporting

confidence: 72%

Novel Antibiotic Resistance Determinants from Agricultural Soil Exposed to Antibiotics Widely Used in Human Medicine and Animal Farming

Lau

Engelen

Gordon

et al. 2017

Appl Environ Microbiol

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“…In addition, the rate of lac gene expression itself can depend on growth [13], [14]. Similar growth feedback mechanisms have been argued to play an important role in bacterial drug resistance [15], [16], and to generate diversity in an isogenic population [13], [15], [17].…”

Section: Introductionmentioning

confidence: 82%

Nonlinear Fitness Landscape of a Molecular Pathway

et al. 2011

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Genes are regulated because their expression involves a fitness cost to the organism. The production of proteins by transcription and translation is a well-known cost factor, but the enzymatic activity of the proteins produced can also reduce fitness, depending on the internal state and the environment of the cell. Here, we map the fitness costs of a key metabolic network, the lactose utilization pathway in Escherichia coli. We measure the growth of several regulatory lac operon mutants in different environments inducing expression of the lac genes. We find a strikingly nonlinear fitness landscape, which depends on the production rate and on the activity rate of the lac proteins. A simple fitness model of the lac pathway, based on elementary biophysical processes, predicts the growth rate of all observed strains. The nonlinearity of fitness is explained by a feedback loop: production and activity of the lac proteins reduce growth, but growth also affects the density of these molecules. This nonlinearity has important consequences for molecular function and evolution. It generates a cliff in the fitness landscape, beyond which populations cannot maintain growth. In viable populations, there is an expression barrier of the lac genes, which cannot be exceeded in any stationary growth process. Furthermore, the nonlinearity determines how the fitness of operon mutants depends on the inducer environment. We argue that fitness nonlinearities, expression barriers, and gene–environment interactions are generic features of fitness landscapes for metabolic pathways, and we discuss their implications for the evolution of regulation.

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“…In addition, increased expression of efflux pumps may permit bacteria to survive otherwise lethal concentrations of substrate antibiotics and thus allow selection for target mutations that increase drug resistance levels. This phenomenon is known as "drug target resistance masking" (14). Together, this underlines the role of efflux pumps in the development of high levels of multidrug resistance.…”

Section: Resultsmentioning

confidence: 99%

Functional and Genetic Characterization of the Tap Efflux Pump in Mycobacterium bovis BCG

Ramón-García

Mick

Dainese

et al. 2012

Antimicrob Agents Chemother

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Efflux pumps extrude a wide variety of chemically unrelated compounds conferring multidrug resistance and participating in numerous physiological processes. Mycobacterium tuberculosis possesses many efflux pumps, and their roles in drug resistance and physiology are actively investigated. In this work we found that tap mutant cells showed changes in morphology and a progressive loss of viability upon subcultivation in liquid medium. Transcriptome analysis in Mycobacterium bovis BCG revealed that disruption of the Rv1258c gene, encoding the Tap efflux pump, led to an extensive change in gene expression patterns during stationary phase, with no changes during exponential growth. In stationary phase, Tap inactivation triggered a general stress response and led to a general repression of genes involved in cell wall biosynthesis, in particular the formation of the peptidoglycan; this suggested the accumulation of an unknown Tap substrate that reaches toxic concentrations during stationary phase. We also found that both disruption and overexpression of tap altered susceptibility to many clinically approved antibiotics in M. bovis BCG. Acriflavine and tetracycline accumulation assays and carbonyl cyanide m-chlorophenylhydrazone (CCCP) potentiation experiments demonstrated that this phenotype was due to an active efflux mechanism. These findings emphasize the important role of the Tap efflux pump in bacterial physiology and intrinsic drug resistance.

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Drug efflux pump deficiency and drug target resistance masking in growing bacteria

Cited by 28 publications

References 23 publications

Novel Antibiotic Resistance Determinants from Agricultural Soil Exposed to Antibiotics Widely Used in Human Medicine and Animal Farming

Novel Antibiotic Resistance Determinants from Agricultural Soil Exposed to Antibiotics Widely Used in Human Medicine and Animal Farming

Nonlinear Fitness Landscape of a Molecular Pathway

Functional and Genetic Characterization of the Tap Efflux Pump in Mycobacterium bovis BCG

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