Fluoroquinolones induce the expression of patA and patB, which encode ABC efflux pumps in Streptococcus pneumoniae
Farid El Garch1, Ann Lismond, Laura J V Piddock
1Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Background:
Active efflux is a common mechanism of resistance to fluoroquinolones in Streptococcus pneumoniae. Two efflux systems have been described so far in this species: PmrA, a member of the major facilitator superfamily; and the two ABC transporters PatA and PatB. We studied the inducibility of expression of pmrA, patA and patB by using subinhibitory concentrations of fluoroquinolones.
Methods:
A wild-type susceptible strain, two clinical isolates resistant to fluoroquinolones and two efflux mutants selected in vitro after exposure to ciprofloxacin were studied. MICs were determined for these strains and their mutants in which pmrA, patA or patB had been disrupted. Gene expression was determined after exposure to half the MIC of norfloxacin, ciprofloxacin, levofloxacin, moxifloxacin or gemifloxacin and quantified by real-time PCR.
Results:
Increased MICs of norfloxacin, ciprofloxacin and levofloxacin (to a lesser extent) and increased expression of patA and patB were seen for all resistant strains; these were reduced in patA or patB disruptants or in the presence of reserpine. Exposure to any of the five fluoroquinolones caused a reversible increase in expression of patA and patB, but not of pmrA. Mitomycin C, an inducer of the competence system in S. pneumoniae, also induced patA and patB expression in the two strains tested.
Conclusion:
The ABC efflux system PatA/PatB is induced upon exposure to subinhibitory concentrations of fluoroquinolones, whether substrates of the transporter or not. This effect, possibly resulting from the activation of the competence pathway, may contribute to resistance.
Insights
The ABC efflux system PatA/PatB in Streptococcus pneumoniae is induced by fluoroquinolones, potentially increasing resistance. This induction may involve the competence pathway, highlighting a new mechanism for antibiotic resistance.
Area of Science:
- Microbiology
- Molecular Biology
- Genetics
Background:
- Fluoroquinolone resistance in Streptococcus pneumoniae is often mediated by active efflux pumps.
- Two primary efflux systems identified are PmrA (major facilitator superfamily) and PatA/PatB (ABC transporters).
Purpose of the Study:
- To investigate the inducibility of pmrA, patA, and patB gene expression in response to subinhibitory fluoroquinolone concentrations.
- To understand the role of these efflux systems in fluoroquinolone resistance.
Main Methods:
- Studied wild-type, resistant clinical isolates, and efflux mutants of Streptococcus pneumoniae.
- Determined Minimum Inhibitory Concentrations (MICs) for various fluoroquinolones.
- Quantified gene expression of pmrA, patA, and patB using real-time PCR after exposure to sub-MIC fluoroquinolones.
Main Results:
- Resistant strains showed increased MICs and elevated patA/patB expression, which decreased upon disruption of these genes or addition of reserpine.
- Exposure to all tested fluoroquinolones reversibly induced patA and patB expression, but not pmrA.
- Mitomycin C, a known inducer of competence, also upregulated patA and patB expression.
Conclusions:
- The PatA/PatB ABC efflux system is induced by sub-minimum inhibitory concentrations of fluoroquinolones.
- This induction, potentially linked to competence pathway activation, contributes to fluoroquinolone resistance in Streptococcus pneumoniae.
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