Creeping baselines and adaptive resistance to antibiotics

Fernández, Lucía; Breidenstein, Elena B. M.; Hancock, Robert E. W.

doi:10.1016/j.drup.2011.01.001

Cited by 178 publications

(171 citation statements)

References 244 publications

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“…Some of these modifications confer to the bacterium a greater ability to withstand an antimicrobial challenge. There are many environmental cues that can lead to the temporary acquisition of resistance to a given antibiotic, including ion concentrations, temperature, and, very importantly, exposure to nonlethal doses of antimicrobials (59). It is becoming increasingly clear that the adaptations that bacterial cells undergo during the infection, together with repeated and/or prolonged exposure to antimicrobials throughout treatment, provide one explanation as to why apparently sensitive strains often cannot be efficiently eradicated in the clinic with antimicrobial therapy.…”

Section: Adaptive Resistancementioning

confidence: 99%

“…These small changes in the MIC are hard to detect and are often missed during the analysis of clinical isolates; therefore, we have insufficient information on their occurrence in the clinic. Despite this, a growing number of authors believe that low-level resistance might play a decisive role in the gradual increase in global resistance, in particular in the creeping up over time of the baseline MICs (effectively, the concentration of the average "susceptible" organism) (13,59). Indeed, there is laboratory evidence that the accumulation of independent mutations with a low impact on antibiotic susceptibility can lead to highlevel resistance in a stepwise manner.…”

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confidence: 99%

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Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

2012

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SUMMARY The substantial use of antibiotics in the clinic, combined with a dearth of new antibiotic classes, has led to a gradual increase in the resistance of bacterial pathogens to these compounds. Among the various mechanisms by which bacteria endure the action of antibiotics, those affecting influx and efflux are of particular importance, as they limit the interaction of the drug with its intracellular targets and, consequently, its deleterious effects on the cell. This review evaluates the impact of porins and efflux pumps on two major types of resistance, namely, mutational and adaptive types of resistance, both of which are regarded as key phenomena in the global rise of antibiotic resistance among pathogenic microorganisms. In particular, we explain how adaptive and mutational events can dramatically influence the outcome of antibiotic therapy by altering the mechanisms of influx and efflux of antibiotics. The identification of porins and pumps as major resistance markers has opened new possibilities for the development of novel therapeutic strategies directed specifically against these mechanisms.

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Section: Adaptive Resistancementioning

confidence: 99%

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confidence: 99%

Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

2012

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“…Antibiotic concentration gradients develop during treatment because of the tissue-dependent drug-penetration and periodic administration of the drug (Mukhopadhyay et al, 1994;Kaiser et al, 2014). Such gradients may act as safe havens for susceptible bacteria by providing regions that (transiently) support growth (Baquero and Negri, 1997;Fernández et al, 2011;Meredith et al, 2015). In addition to clinical settings, antibiotic gradients also arise in, for example, soil communities where narrow-spectrum antibiotics are locally released by antibiotic-producing bacteria establishing short-lived gradients (Romero et al, 2011;Vetsigian et al, 2011;.…”

Section: Introductionmentioning

confidence: 99%

Density-dependent adaptive resistance allows swimming bacteria to colonize an antibiotic gradient

et al. 2015

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During antibiotic treatment, antibiotic concentration gradients develop. Little is know regarding the effects of antibiotic gradients on populations of nonresistant bacteria. Using a microfluidic device, we show that high-density motile Escherichia coli populations composed of nonresistant bacteria can, unexpectedly, colonize environments where a lethal concentration of the antibiotic kanamycin is present. Colonizing bacteria establish an adaptively resistant population, which remains viable for over 24 h while exposed to the antibiotic. Quantitative analysis of multiple colonization events shows that collectively swimming bacteria need to exceed a critical population density in order to successfully colonize the antibiotic landscape. After colonization, bacteria are not dormant but show both growth and swimming motility under antibiotic stress. Our results highlight the importance of motility and population density in facilitating adaptive resistance, and indicate that adaptive resistance may be a first step to the emergence of genetically encoded resistance in landscapes of antibiotic gradients.

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“…Overexpression of genes encoding ␤-lactam and efflux pump can be triggered through regulatory genes (9). Interestingly, it has been demonstrated that the interplay between chromosomal ␤-lactamase and efflux systems or between efflux pumps also plays an important role in intrinsic resistance to antibiotics in P. aeruginosa (10,11).…”

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confidence: 99%

A PhoPQ-Regulated ABC Transporter System Exports Tetracycline in Pseudomonas aeruginosa

Chen

Duan

2016

Antimicrob Agents Chemother

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bPseudomonas aeruginosa is an important human pathogen whose infections are difficult to treat due to its high intrinsic resistance to many antibiotics. Here, we show that the disruption of PA4456, encoding the ATP binding component of a putative ATP-binding cassette (ABC) transporter, increased the bacterium's susceptible to tetracycline and other antibiotics or toxic chemicals. Fluorescence spectroscopy and antibiotic accumulation tests showed that the interruption of the ABC transporter caused increased intracellular accumulation of tetracycline, demonstrating a role of the ABC transporter in tetracycline expulsion. Site-directed mutagenesis proved that the conserved residues of E170 in the Walker B motif and H203 in the H-loop, which are important for ATP hydrolysis, were essential for the function of PA4456. Through a genome-wide search, the PhoPQ twocomponent system was identified as a regulator of the computationally predicted PA4456-4452 operon that encodes the ABC transporter system. A >5-fold increase of the expression of this operon was observed in the phoQ mutant. The results obtained also show that the expression of the phzA1B1C1D1E1 operon and the production of pyocyanin were significantly higher in the ABC transporter mutant, signifying a connection between the ABC transporter and pyocyanin production. These results indicated that the PhoPQ-regulated ABC transporter is associated with intrinsic resistance to antibiotics and other adverse compounds in P. aeruginosa, probably by extruding them out of the cell.

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Creeping baselines and adaptive resistance to antibiotics

Cited by 178 publications

References 244 publications

Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

Density-dependent adaptive resistance allows swimming bacteria to colonize an antibiotic gradient

A PhoPQ-Regulated ABC Transporter System Exports Tetracycline in Pseudomonas aeruginosa

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