gyrA and gyrB mutations in quinolone-resistant strains of Escherichia coli

Nakamura, Shinichi; Nakamura, Mami; Kojima, Tsuyoshi; Yoshida, Hiroaki

doi:10.1128/aac.33.2.254

Cited by 155 publications

(101 citation statements)

References 11 publications

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“…Development of resistance to quinolones entails multiple mechanisms [232,233]. The primary mechanism of quinolone resistance in Gram-negative bacteria is through mutations in target genes gyrA and gyrB [234][235][236][237]. Overexpression of MDR efflux pumps can also add significantly to the quinolone resistance especially in the presence of target mutations [238].…”

Section: Fluoroquinolone Resistancementioning

confidence: 99%

Cell-wall recycling and synthesis in Escherichia coli and Pseudomonas aeruginosa – their role in the development of resistance

Dhar

Kumari

Balasubramanian

et al. 2018

Journal of Medical Microbiology

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The bacterial cell-wall that forms a protective layer over the inner membrane is called the murein sacculus -a tightly crosslinked peptidoglycan mesh unique to bacteria. Cell-wall synthesis and recycling are critical cellular processes essential for cell growth, elongation and division. Both de novo synthesis and recycling involve an array of enzymes across all cellular compartments, namely the outer membrane, periplasm, inner membrane and cytoplasm. Due to the exclusivity of peptidoglycan in the bacterial cell-wall, these players are the target of choice for many antibacterial agents. Our current understanding of cell-wall biochemistry and biogenesis in Gram-negative organisms stems mostly from studies of Escherichia coli. An incomplete knowledge on these processes exists for the opportunistic Gram-negative pathogen, Pseudomonas aeruginosa. In this review, cell-wall synthesis and recycling in the various cellular compartments are compared and contrasted between E. coli and P. aeruginosa. Despite the fact that there is a remarkable similarity of these processes between the two bacterial species, crucial differences alter their resistance to b-lactams, fluoroquinolones and aminoglycosides. One of the common mediators underlying resistance is the amp system whose mechanism of action is closely associated with the cell-wall recycling pathway. The activation of amp genes results in expression of AmpC blactamase through its cognate regulator AmpR which further regulates multi-drug resistance. In addition, other cell-wall recycling enzymes also contribute to antibiotic resistance. This comprehensive summary of the information should spawn new ideas on how to effectively target cell-wall processes to combat the growing resistance to existing antibiotics.

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Section: Fluoroquinolone Resistancementioning

confidence: 99%

Cell-wall recycling and synthesis in Escherichia coli and Pseudomonas aeruginosa – their role in the development of resistance

Dhar

Kumari

Balasubramanian

et al. 2018

Journal of Medical Microbiology

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“…Unfortunately, fluoroquinolone-resistant clinical isolates of Mycobacterium tuberculosis have already appeared (3, 31, 33). Mutations conferring resistance to quinolones have been reported for several bacterial species (2), including the gram-negative bacteria Escherichia coli (5,10,22) and Pseudomonas aeruginosa (4, 16, 28) and the gram-positive bacterium Staphylococcus aureus (11,23,24,36). Two principal mechanisms have been described: (i) alteration of DNA gyrase and (ii) decreased drug accumulation in the cell as a result of either decreased influx or increased efflux.…”

mentioning

confidence: 99%

Active efflux of fluoroquinolones in Mycobacterium smegmatis mediated by LfrA, a multidrug efflux pump

1996

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The lfrA gene cloned from chromosomal DNA of quinolone-resistant Mycobacterium smegmatis mc 2 -552 conferred low-level resistance to fluoroquinolones when present on multicopy plasmids. Sequence analysis suggested that lfrA encodes a membrane efflux pump of the major facilitator family (H. E. Takiff, M. Cimino, M. C. Musso, T. Weisbrod, R. Martinez, M. B. Delgado, L. Salazar, B. R. Bloom, and W. R. Jacbos, Jr., Proc. Natl. Acad. Sci. USA 93: [362][363][364][365][366] 1996). In this work, we studied the role of LfrA in the accumulation of fluoroquinolones by M. smegmatis. The steady-state accumulation level of a hydrophilic quinolone, norfloxacin, by M. smegmatis harboring a plasmid carrying the lfrA gene was about 50% of that by the parent strain but was increased to the same level as that of the parent strain by addition of a proton conductor, carbonyl cyanide m-chorophenylhydrazone. Norfloxacin efflux mediated by LfrA was competed for strongly by ciprofloxacin but not by nalidixic acid. Furthermore, we showed that portions of norfloxacin accumulated by starved cells were pumped out upon reenergization of the cells, and the rates of this efflux showed evidence of saturation at higher intracellular concentrations of the drug. These results suggest that the LfrA polypeptide catalyzes the active efflux of several quinolones.The reemergence of tuberculosis worldwide has once again produced a major public health problem. Tuberculosis and other mycobacterial infections are often difficult to treat because mycobacteria are intrinsically resistant to most common antibiotics, apparently because of their extremely low cell wall fluidity and permeability (1,13,14,18,35). The situation is made worse by the dramatic increase in multidrug-resistant strains (6, 7). Fluoroquinolones inhibit bacterial DNA gyrase and are active against mycobacteria in vitro; thus, they seem to be promising for development as antituberculous agents. Unfortunately, fluoroquinolone-resistant clinical isolates of Mycobacterium tuberculosis have already appeared (3, 31, 33). Mutations conferring resistance to quinolones have been reported for several bacterial species (2), including the gram-negative bacteria Escherichia coli (5,10,22) and Pseudomonas aeruginosa (4, 16, 28) and the gram-positive bacterium Staphylococcus aureus (11,23,24,36). Two principal mechanisms have been described: (i) alteration of DNA gyrase and (ii) decreased drug accumulation in the cell as a result of either decreased influx or increased efflux. Alteration of DNA gyrase is usually the result of a mutation in the gyrA or, less frequently, the gyrB gene. The genes that encode the DNA gyrase of M. tuberculosis H37Rv have been cloned and sequenced, and mutations associated with quinolone resistance have been found in the gyrA gene from clinical isolates (3, 33).In gram-positive bacteria, it has been shown that active efflux pumps play an important role in the decreased accumulation of quinolones. An example is the norA gene product of S. aureus, which confers resistance to quin...

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“…Plasmid pAW012 allowing expression of E. coli gyrA (12) (2,3,18). KNK453 is viable at 37 C but not at 42 C because that strain carries the mutant gyrA (temperature sensitive) allele.…”

mentioning

confidence: 99%

Analysis of the NH₂‐Terminal 83rd Amino Acid of Escherichia coli GyrA in Quinolone‐Resistance

Yonezawa

Takahata

Banzawa

et al. 1995

Microbiology and Immunology

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Artificial mutations of Gyrase A protein (GyrA) in Escherichia coli by site-directed mutagenesis were generated to analyze quinolone-resistant mechanisms. By genetic analysis of gyrA genes in a gyrA temperature sensitive (Ts) background, exchange of Ser at the NH2-terminal 83rd position of GyrA to Trp, Leu, Phe, Tyr, Ala, Val, and Ile caused bacterial resistance to the quinolones, while exchange to Gly, Asn, Lys, Arg and Asp did not confer resistance. These results indicate that it is the most important for the 83rd amino acid residue to be hydrophobic in expressing the phenotype of resistance to the quinolones. These findings also suggest that the hydroxyl group of Ser would not play a major role in the quinolone-gyrase interaction and Ser83 would not interact directly with other amino acid residues.

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gyrA and gyrB mutations in quinolone-resistant strains of Escherichia coli

Cited by 155 publications

References 11 publications

Cell-wall recycling and synthesis in Escherichia coli and Pseudomonas aeruginosa – their role in the development of resistance

Cell-wall recycling and synthesis in Escherichia coli and Pseudomonas aeruginosa – their role in the development of resistance

Active efflux of fluoroquinolones in Mycobacterium smegmatis mediated by LfrA, a multidrug efflux pump

Analysis of the NH₂‐Terminal 83rd Amino Acid of Escherichia coli GyrA in Quinolone‐Resistance

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gyrA and gyrB mutations in quinolone-resistant strains of Escherichia coli

Cited by 155 publications

References 11 publications

Cell-wall recycling and synthesis in Escherichia coli and Pseudomonas aeruginosa – their role in the development of resistance

Cell-wall recycling and synthesis in Escherichia coli and Pseudomonas aeruginosa – their role in the development of resistance

Active efflux of fluoroquinolones in Mycobacterium smegmatis mediated by LfrA, a multidrug efflux pump

Analysis of the NH2‐Terminal 83rd Amino Acid of Escherichia coli GyrA in Quinolone‐Resistance

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Analysis of the NH₂‐Terminal 83rd Amino Acid of Escherichia coli GyrA in Quinolone‐Resistance