Quinolone Resistance Due to Reduced Target Enzyme Expression

İnce, Dilek; Hooper, David C.

doi:10.1128/jb.185.23.6883-6892.2003

Cited by 58 publications

(47 citation statements)

References 55 publications

(59 reference statements)

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“…In support of this notion, S. aureus mutants overexpressing penicillin-binding protein 4, one of the drug targets of ␤-lactams, leads to elevated ␤-lactam resistance expression (12,16). On the other hand, Ince and Hooper (19) reported that decreased transcription of the parEC operon in first-step fluoroquinolone-resistant mutants of S. aureus led to increased resistance to fluoroquinolones, making our findings somewhat contradictory. Furthermore, in contrast to our findings, growth in the presence of salicylate actually reduces fusA transcription in E. coli and M. tuberculosis (8,40).…”

Section: Resultscontrasting

confidence: 72%

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Response of Staphylococcus aureus to Salicylate Challenge

et al. 2007

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Growth of Staphylococcus aureus with the nonsteroidal anti-inflammatory salicylate reduces susceptibility of the organism to multiple antimicrobials. Transcriptome analysis revealed that growth of S. aureus with salicylate leads to the induction of genes involved with gluconate and formate metabolism and represses genes required for gluconeogenesis and glycolysis. In addition, salicylate induction upregulates two antibiotic target genes and downregulates a multidrug efflux pump gene repressor (mgrA) and sarR, which represses a gene (sarA) important for intrinsic antimicrobial resistance. We hypothesize that these salicylate-induced alterations jointly represent a unique mechanism that allows S. aureus to resist antimicrobial stress and toxicity.In 1985, Judah L. Rosner reported on a "nonheritable" antibiotic resistance mechanism that could be induced in Escherichia coli by the nonsteroidal anti-inflammatory salicylate or aspirin (acetylsalicylate) (47). It was later reported that nonsteroidal anti-inflammatories induce expression of the E. coli multiple antibiotic resistance operon (marRAB) and that repression of marRAB by the winged-helix DNA-binding repressor MarR is alleviated upon exposure to salicylate (1,6,31). Since these initial discoveries, the ability of salicylate to induce antimicrobial resistance in multiple bacterial species has been reported (for a review, see reference 44).Growth of the gram-positive pathogen Staphylococcus aureus with salicylate also induces reduced susceptibility to multiple antimicrobials, including membrane-active cleaners/disinfectants and plant essential oils, the DNA topoisomerase inhibitor ciprofloxacin, the protein synthesis inhibitor fusidic acid, and the DNA-intercalating dye ethidium (14,15,42,43,45,46). The salicylate-induced phenotype is partially due to the activation of antimicrobial efflux and a proton motive forceindependent reduction in antimicrobial accumulation (43). The drugs for which salicylate reduces accumulation are substrates of the well-characterized multidrug efflux pump NorA, yet NorA does not play a role in this mechanism (23, 43). In addition, salicylate also increases the frequency at which S. aureus acquires genotypic resistance to ciprofloxacin and fusidic acid (14, 45).The S. aureus genome also contains numerous marR paralogs, historically referred to as the staphylococcal accessory regulator (sarA) family of genes (for a review, see reference 29). Some of these S. aureus marR paralogues (e.g., sarA, mgrA, and mepR) have already been implicated in the control of intrinsic antimicrobial resistance (21,22,36,51,52,53).We now characterize transcriptome alterations that occur in S. aureus cells exposed to salicylate and support some of these findings with physiological experimentation. The implications of our findings with respect to the salicylate-inducible multiple antimicrobial resistance mechanism of S. aureus are discussed. MATERIALS AND METHODSBacterial strains, culture conditions, growth curves, and antibiotic susceptibility determination...

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Section: Resultscontrasting

confidence: 72%

“…Both parE and fusA were identified as salicylate inducible via SCOTS analysis, and this was confirmed by real-time PCR (Table 2). Even though parE and parC are carried on a polycistronic transcript (19), neither was upregulated on the array. fusA was also upregulated by salicylate on the array analysis, but this proved insignificant.…”

Section: Resultsmentioning

confidence: 95%

Response of Staphylococcus aureus to Salicylate Challenge

et al. 2007

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“…In addition, as has been previously demonstrated with the isogenic strains SS1 and 1734-J-AE-15, bearing the Ser84Leu and the Gly82Asp mutations in GyrA, respectively, the MIC of ciprofloxacin was similar to or only twofold higher than that of the wild type (30). Therefore, to account for the additional resistance phenotype of these mutants, we sequenced the entirety of the gyrA, gyrB, parC, and parE genes as well as the promoter region of parE or gyrB, the former of which has been recently described as a quinolone resistance mechanism through reduced enzyme expression (16). We found only a novel deletion of amino acids Arg, Gln, and Glu at positions 215 to 217 of ParE in DX-619-E but no additional mutation in DX-619-C.…”

Section: Characterization Of Dx-619-selected Single-step Mutantsmentioning

confidence: 99%

DX-619, a Novel Des-Fluoro(6) Quinolone Manifesting Low Frequency of Selection of Resistant Staphylococcus aureus Mutants: Quinolone Resistance beyond Modification of Type II Topoisomerases

Strahilevitz

Truong-Bolduc

Hooper

2005

Antimicrob Agents Chemother

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DX-619, a novel des-fluoro(6) quinolone, was 16-to 32-fold, twofold, and four-to eightfold more potent than ciprofloxacin, gemifloxacin, and garenoxacin, respectively, against wild-type Staphylococcus aureus. DX-619 manifested equal fourfold increases in MIC against a common parC mutant and a common gyrA mutant and selected for mutants at up to two-to fourfold its MIC, consistent with dual-targeting properties. Of the four independent single-step mutants selected, two had new single mutations in parC (V87F and R17H), and two shared a new gyrA mutation (A26V), one with an additional deletion mutation in parE (⌬215-7). By allelic exchange, the ParC but not the GyrA or ParE mutation was shown to be fully responsible for the resistance phenotypes, suggesting an as yet undefined mechanism of resistance operating in conjunction with type II topoisomerase mutations contributed to resistance to DX-619. Studies with purified topoisomerase IV and gyrase from S. aureus also showed that DX-619 had similar activity against topoisomerase IV and gyrase (50% stimulation of cleavage complexes concentration, 1.25 and 0.62 to 1.25 g/ml, respectively). Susceptibility studies with DX-619 and an array of efflux pump substrates with and without reserpine, an inhibitor of efflux pumps, suggested that resistance in DX-619-selected mutants is affected by mechanisms other than mutations in topoisomerases or known reserpine-inhibitable pumps in S. aureus and thus are likely novel.To execute their bactericidal activity, quinolones interact with the type II topoisomerases, DNA gyrase, and topoisomerase IV (topo IV) (7). Quinolone resistance occurs stepwise by mutations in the two topoisomerase target enzymes, with the first mutation generally occurring in the more sensitive enzyme (11). Staphylococcus aureus mutants selected stepwise with quinolones usually first manifest a mutation in topo IV followed by a mutation in gyrase (18,25,30), or as has been recently reported for topo IV, mutation in the promoter region leading to reduced enzyme expression (16). In addition, several chromosomally encoded efflux pumps in S. aureus, including NorA (24, 34), NorB (32), and MepA (20), mediate low-level quinolone resistance when overexpressed.With the increased use of quinolones and the subsequent emergence of resistance (4, 10), new quinolones should be active against pathogens carrying multiple resistance mechanisms in order to remain clinically effective. An important characteristic of fluoroquinolones to limit the selection of resistance in wild-type bacteria is dual activity, in which the activity against both DNA gyrase and topo IV is the same (6, 37).DX-619 is a novel des-fluoro(6) quinolone with enhanced activity against resistant gram-positive bacteria that is currently under development (9; H. Ishida, K. Fujikawa, M. Chiba, M. Tanaka, T. Otani, and K. Sato, Abstr. 44th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-1935, 2004; M. Tanaka, K. Fujikawa, Y. Murakami, T. Akasaka, M. Chiba, T. Otani, and K. Sato, Abstr. 43rd Intersci. Conf...

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“…Fluoroquinolones vary in their antibacterial activity by preferentially targeting DNA gyrase, DNA topoisomerase IV, or both. Bacterial resistance to fluoroquinolone activity may also occur through alteration in quinolone targets, decreased uptake of the drugs, expression of efflux pump systems, and mobile elements which may confer resistance (Ince andHooper 2003, Ruiz 2003).…”

Section: Discussionmentioning

confidence: 99%

Antimicrosporidial activity of (fluoro)quinolones in vitro and in vivo

Didier

Bowers²,

Stovall³

et al. 2005

FOLIA PARASIT

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Abstract. Microsporidia are a cause of emerging and opportunistic infections in humans and animals. Although two drugs are currently being used to treat microsporidiosis, concerns exist that albendazole is only selective for inhibiting some species of microsporidia that infect mammals, and fumagillin appears to have been found to be toxic. During a limited sequence survey of the Vittaforma corneae (syn. Nosema corneum Shadduck, Meccoli, Davis et Font, 1990) genome, a partial gene encoding for the ParC topoisomerase IV subunit was identified. The purpose of this set of studies was to determine if fluoroquinolones, which target topoisomerase IV, exert activity against Encephalitozoon intestinalis (syn. Septata intestinalis Cali, Kotler et Orenstein, 1993) and V. corneae in vitro, and whether these compounds could prolong survival of V. corneae-infected athymic mice. Fifteen fluoroquinolones were tested. Of these, norfloxacin and ofloxacin inhibited E. intestinalis replication by more than 70% compared with non-treated control cultures, while gatifloxacin, lomefloxacin, moxifloxacin, and nalidixic acid (sodium salt) inhibited both E. intestinalis and V. corneae by at least 60% at concentrations not toxic to the host cells. These drugs were tested in vivo also, where gatifloxacin, lomefloxacin, norfloxacin, and ofloxacin prolonged survival of V. corneae-infected athymic mice (P < 0.05), whereas moxifloxacin and nalidixic acid failed to prolong survival. Therefore, these results support continued studies for evaluating the efficacy of the fluoroquinolones for treating microsporidiosis and for characterizing the target(s) of these fluoroquinolones in the microsporidia.

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Quinolone Resistance Due to Reduced Target Enzyme Expression

Cited by 58 publications

References 55 publications

Response of Staphylococcus aureus to Salicylate Challenge

Response of Staphylococcus aureus to Salicylate Challenge

DX-619, a Novel Des-Fluoro(6) Quinolone Manifesting Low Frequency of Selection of Resistant Staphylococcus aureus Mutants: Quinolone Resistance beyond Modification of Type II Topoisomerases

Antimicrosporidial activity of (fluoro)quinolones in vitro and in vivo

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