Efflux Pump-Mediated Quinolone Resistance in
 Staphylococcus aureus
 Strains Wild Type for
 gyrA
 ,
 gyrB
 ,
 grlA
 , and
 norA

Muñoz‐Bellido, Juan Luis; Manzanares, Miguel; Andrés, Jonathan; Zufiaurre, Ma Nieves Gutiérrez; Ortiz, Guadalupe; Hernández, M. Segovia; Garcı́a-Rodrı́guez, J.A.

doi:10.1128/aac.43.2.354

Cited by 44 publications

(10 citation statements)

References 16 publications

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“…This might be due to decreased efflux of this agent, as ciprofloxacin has been observed to being subjected to cellular efflux by pump activity of multiple efflux systems, e.g., NorA (Yamada et al, 1997; Muñoz-Bellido et al, 1999). Moreover, it was confirmed that inactivation of the stress response sigma factor σ B encoded by rpoF and the σ B activator RsbU potentiated the effect of ciprofloxacin, which is in agreement with previous observations in S. aureus (Riordan et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Identification of Antimicrobial Intrinsic Resistance Determinants in Staphylococcus aureus

et al. 2016

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The emergence of antimicrobial resistance severely threatens our ability to treat bacterial infections. While acquired resistance has received considerable attention, relatively little is known of intrinsic resistance that allows bacteria to naturally withstand antimicrobials. Gene products that confer intrinsic resistance to antimicrobial agents may be explored for alternative antimicrobial therapies, by potentiating the efficacy of existing antimicrobials. In this study, we identified the intrinsic resistome to a broad spectrum of antimicrobials in the human pathogen, Staphylococcus aureus. We screened the Nebraska Transposon Mutant Library of 1920 single-gene inactivations in S. aureus strain JE2, for increased susceptibility to the anti-staphylococcal antimicrobials (ciprofloxacin, oxacillin, linezolid, fosfomycin, daptomycin, mupirocin, vancomycin, and gentamicin). Sixty-eight mutants were confirmed by E-test to display at least twofold increased susceptibility to one or more antimicrobial agents. The majority of the identified genes have not previously been associated with antimicrobial susceptibility in S. aureus. For example, inactivation of genes encoding for subunits of the ATP synthase, atpA, atpB, atpG and atpH, reduced the minimum inhibitory concentration (MIC) of gentamicin 16-fold. To elucidate the potential of the screen, we examined treatment efficacy in the Galleria mellonella infection model. Gentamicin efficacy was significantly improved, when treating larvae infected with the atpA mutant compared to wild type cells with gentamicin at a clinically relevant concentration. Our results demonstrate that many gene products contribute to the intrinsic antimicrobial resistance of S. aureus. Knowledge of these intrinsic resistance determinants provides alternative targets for compounds that may potentiate the efficacy of existing antimicrobial agents against this important pathogen.

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Section: Resultsmentioning

confidence: 99%

Genome-Wide Identification of Antimicrobial Intrinsic Resistance Determinants in Staphylococcus aureus

et al. 2016

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“…The NorA efflux pump has been shown to contribute to antibacterial resistance in S. aureus [24][25][26][27]. The effect of increased NorA expression on gatifloxacin and ciprofloxacin activity was recently investigated by Ince et al [19].…”

Section: Efflux Mechanisms Of Resistancementioning

confidence: 97%

Mechanisms of Action and Resistance of Older and Newer Fluoroquinolones

Hooper

2000

Clinical Infectious Diseases

337

223

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The fluoroquinolones interact with 2 bacterial targets, the related enzymes DNA gyrase and topoisomerase IV, both of which are involved in DNA replication. Quinolones form complexes of these enzymes with DNA, complexes that block movement of the DNA-replication fork and thereby inhibit DNA replication. Many older quinolones differ in their relative activities against gyrase and topoisomerase IV in a bacterial cell, having greater potency against gyrase than against topoisomerase IV in many gram-negative bacteria and greater potency against topoisomerase IV than against gyrase in many gram-positive bacteria. Several newer quinolones appear to have more closely balanced activity against these enzymes. Resistance to fluoroquinolones occurs as a result of mutational amino acid substitutions in the subunits of the more sensitive (or primary-target) enzyme within the cell. If, however, both enzymes are similarly susceptible to a fluoroquinolone, then the level of resistance caused by a primary-target mutation may be low and may be limited by the sensitivity of the secondary target. Fluoroquinolones also differ in the extent to which common bacterial multidrug efflux pumps affect their activity, with some compounds being unaffected by resistance mechanisms because of overexpression of such pumps. Newer fluoroquinolone interaction with dual targets and avoidance of efflux-resistance mechanisms may each contribute to the lower frequencies of selection of resistant mutants in the laboratory.

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“…Resistance to fluoroquinolones is primarily caused by target mutations, which occur in general in the primary target enzyme (thus more often in GyrA subunit of DNA gyrase in Gramnegative bacteria; ParC subunit of topoisomerase IV in Gram-positive bacteria, except S. pneumoniae [12,28]). Active efflux also contributes to decrease susceptibility, with narrow spectrum transporters expressed in Gram-positive pathogens and conferring resistance to fluoroquinolones only (like NorA, NorB, NorC, MdeA or the plasmid-encoded QacA and QacB [29][30][31] in S. aureus, or PmrA and the heterodimer PatA/ DRug EvAluATiOn Van Bambeke future science group PatB in S. pneumoniae [32,33]), and broad-spectrum transporters expressed in Gram-negative pathogens and conferring cross-resistance to several antibiotic classes [34]. More anecdotal resistance mechanisms include the production of the protein Qnr, which impairs the binding of fluoroquinolones to DNA [35], or of a AAC(6')-Ib-cr enzyme originally inactivating …”

Section: Pharmacology Of Delafloxacinmentioning

confidence: 99%

Delafloxacin, A Non-Zwitterionic Fluoroquinolone in Phase III of Clinical Development: Evaluation of its Pharmacology, Pharmacokinetics, Pharmacodynamics and Clinical Efficacy

Bambeke

2015

Future Microbiol.

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Delafloxacin is a fluoroquinolone lacking a basic substituent in position 7. It shows MICs remarkably low against Gram-positive organisms and anaerobes and similar to those of ciprofloxacin against Gram-negative bacteria. It remains active against most fluoroquinolone-resistant strains, except enterococci. Its potency is further increased in acidic environments (found in many infection sites). Delafloxacin is active on staphylococci growing intracellularly or in biofilms. It is currently evaluated as an intravenous and intravenous/oral stepdown therapy in Phase III trials for the treatment of complicated skin/skin structure infections. It was also granted as Qualified Infectious Disease Product for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, due to its high activity on pneumococci and atypical pathogens.

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Efflux Pump-Mediated Quinolone Resistance in Staphylococcus aureus Strains Wild Type for gyrA , gyrB , grlA , and norA

Cited by 44 publications

References 16 publications

Genome-Wide Identification of Antimicrobial Intrinsic Resistance Determinants in Staphylococcus aureus

Genome-Wide Identification of Antimicrobial Intrinsic Resistance Determinants in Staphylococcus aureus

Mechanisms of Action and Resistance of Older and Newer Fluoroquinolones

Delafloxacin, A Non-Zwitterionic Fluoroquinolone in Phase III of Clinical Development: Evaluation of its Pharmacology, Pharmacokinetics, Pharmacodynamics and Clinical Efficacy

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