Quinolone-resistant mutants of escherichia coli DNA topoisomerase IV parC gene

Kumagai, Yoshito; Kato, Junichi; Hoshino, Kazuki; Akasaka, Tomoyuki; Sato, Kenichi; Ikeda, Hideo

doi:10.1128/aac.40.3.710

Cited by 89 publications

(68 citation statements)

References 24 publications

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“…In addition, a single mutation in the parC gene was detected in the same enrofloxcin treatment group involving an amino acid change into lysine at site 61. The mutation in parC and gyrA was predicted to induce a higher level of drug resistance than that achieved by the mutation in gyrA only (Kumagai et al 1996), and this hypothesis is consistent with our experimental results.…”

Section: Mechanisms Of Bacterial Adaptation To Drug Stresssupporting

confidence: 90%

“…parC encodes topoisomerase IV which is one of the targets of enrofloxacin. The increased expression of target genes such as parC is useful in preserving physiological functioning during drug stress (Kumagai et al 1996). OmpW is an outer membrane channel protein encoded by the ompW gene and is involved in the transmembrane transport of hydrophobic molecules.…”

Section: Mechanisms Of Bacterial Adaptation To Drug Stressmentioning

confidence: 99%

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Analysis of mechanisms of resistance and tolerance of Escherichia coli to enrofloxacin

Bai

et al. 2011

Ann Microbiol

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The mechanisms behind reduced bacterial sensitivity to drugs and the nature of this phenomenon were explored. Escherichia coli were treated with a subinhibitory dose or a repeatedly doubled dose of enrofloxacin (EN) in vitro. After 10 serial passages, the minimal inhibitory concentration (MIC) of EN to the bacteria was assessed by changes in expression of genes involved in the SOS response, drug efflux pumps, porins and EN targets, and the mutation of the quinolone resistance determining region (QRDR). The results showed that the MIC of EN to E. coli was higher after a single passage when treated with either concentration of EN compared with that of the controls (0.5 μg/ml). From this point onwards, the MIC of E. coli treated with the sub-inhibitory concentration tended to be stable, whilst it increased continuously to 64 μg/ml when treated with the doubling dose. Regardless of the EN concentration that bacteria were exposed to, their efflux pumps were started, the expression of the SOS regulatory genes recA and umuC and EN target gene parC were significantly up-regulated, and the expression of the porins gene ompW was significantly down-regulated. No mutations were detected in the QRDR of E. coli treated with the sub-inhibitory concentration of EN, but mutations at three sites occurred after treatment with the repeatedly doubling dose. The current results suggest that the reduction in sensitivity of bacteria to drugs is positively, but nonlinearly, correlated with the concentration of drugs used. The E. coli studied initiated mechanisms to adapt to the enrofloxacin stress which included an SOS response, target gene mutations and efflux pump activity and so on. These adaptive mechanisms are interactive, but the inherited and non-inherited mechanisms play different roles in the adaptation of bacteria to drugs.

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Section: Mechanisms Of Bacterial Adaptation To Drug Stresssupporting

confidence: 90%

Section: Mechanisms Of Bacterial Adaptation To Drug Stressmentioning

confidence: 99%

Analysis of mechanisms of resistance and tolerance of Escherichia coli to enrofloxacin

Bai

et al. 2011

Ann Microbiol

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“…In several species of Enterobacteriaceae , decreased susceptibility or resistance to FQs is associated with specific point mutations in gyrA [21,22]. An additional mutation in parC results in greater resistance [10,20]. We examined whether the Δ lon mutation affects the resistance to LVFX in E. coli gyrA and parC mutants.…”

Section: Resultsmentioning

confidence: 99%

Effects of disruption of heat shock genes on susceptibility of Escherichia coli to fluoroquinolones

et al. 2003

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Background: It is well known that expression of certain bacterial genes responds rapidly to such stimuli as exposure to toxic chemicals and physical agents. It is generally believed that the proteins encoded in these genes are important for successful survival of the organism under the hostile conditions. Analogously, the proteins induced in bacterial cells exposed to antibiotics are believed to affect the organisms' susceptibility to these agents.

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“…The in vitro selection of E. coli mutants with a reduced susceptibility to ciprofloxacin, or to the related drug norfloxacin, led to the identification of several different amino acid substitutions at a small number of positions in the quinolone resistance determining regions (QRDR) of DNA gyrase (Yoshida et al 1990; Heisig and Tschorny 1994; Komp Lindgren et al 2005) and topoisomerase IV (Heisig 1996; Kumagai et al 1996). In addition, mutations that cause upregulation of drug efflux pumps were also shown to reduce susceptibility to ciprofloxacin (Li et al 2015; Pietsch et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Mutation supply and relative fitness shape the genotypes of ciprofloxacin-resistant Escherichia coli

et al. 2017

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Ciprofloxacin is an important antibacterial drug targeting Type II topoisomerases, highly active against Gram-negatives including Escherichia coli. The evolution of resistance to ciprofloxacin in E. coli always requires multiple genetic changes, usually including mutations affecting two different drug target genes, gyrA and parC. Resistant mutants selected in vitro or in vivo can have many different mutations in target genes and efflux regulator genes that contribute to resistance. Among resistant clinical isolates the genotype, gyrA S83L D87N, parC S80I is significantly overrepresented suggesting that it has a selective advantage. However, the evolutionary or functional significance of this high frequency resistance genotype is not fully understood. By combining experimental data and mathematical modeling, we addressed the reasons for the predominance of this specific genotype. The experimental data were used to model trajectories of mutational resistance evolution under different conditions of drug exposure and population bottlenecks. We identified the order in which specific mutations are selected in the clinical genotype, showed that the high frequency genotype could be selected over a range of drug selective pressures, and was strongly influenced by the relative fitness of alternative mutations and factors affecting mutation supply. Our data map for the first time the fitness landscape that constrains the evolutionary trajectories taken during the development of clinical resistance to ciprofloxacin and explain the predominance of the most frequently selected genotype. This study provides strong support for the use of in vitro competition assays as a tool to trace evolutionary trajectories, not only in the antibiotic resistance field.

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Quinolone-resistant mutants of escherichia coli DNA topoisomerase IV parC gene

Cited by 89 publications

References 24 publications

Analysis of mechanisms of resistance and tolerance of Escherichia coli to enrofloxacin

Analysis of mechanisms of resistance and tolerance of Escherichia coli to enrofloxacin

Effects of disruption of heat shock genes on susceptibility of Escherichia coli to fluoroquinolones

Mutation supply and relative fitness shape the genotypes of ciprofloxacin-resistant Escherichia coli

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