The efflux pump inhibitor reserpine selects multidrug-resistant Streptococcus pneumoniae strains that overexpress the ABC transporters PatA and PatB.
One way to combat multidrug-resistant microorganisms is the use of efflux pump inhibitors (EPIs). Spontaneous mutants resistant to the EPI reserpine selected from Streptococcus pneumoniae NCTC 7465 and R6 at a frequency suggestive of a single mutational event were also multidrug resistant. No mutations in pmrA (which encodes the efflux protein PmrA) were detected, and the expression of pmrA was unaltered in all mutants. In the reserpine-resistant multidrug-resistant mutants, the overexpression of both patA and patB, which encode ABC transporters, was associated with accumulation of low concentrations of antibiotics and dyes. The addition of sodium orthovanadate, an inhibitor of ABC efflux pumps, or the insertional inactivation of either gene restored wild-type antibiotic susceptibility and wild-type levels of accumulation. Only when patA was insertionally inactivated were both multidrug resistance and reserpine resistance lost. Strains in which patA was insertionally inactivated grew significantly more slowly than the wild type. These data indicate that the overexpression of both patA and patB confers multidrug resistance in S. pneumoniae but that only patA is involved in reserpine resistance. The selection of reserpine-resistant multidrug-resistant pneumococci has implications for analogous systems in other bacteria or in cancer.
Garvey
Mark I
MI
Antimicrobial Agents Research Group, Division of Immunity and Infection, The Medical School, University of Birmingham, Birmingham, United Kingdom B15 2TT.
Piddock
Laura J V
LJ
D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology; D001426:Bacterial Proteins / Q000235:genetics* / Q000502:physiology; D001692:Biological Transport / Q000187:drug effects; D002939:Ciprofloxacin / Q000378:metabolism / Q000493:pharmacokinetics; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D004996:Ethidium / Q000378:metabolism / Q000493:pharmacokinetics; D023061:Gene Order; D009154:Mutation; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D012110:Reserpine / Q000494:pharmacology*; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; D020033:Protein Isoforms; D014638:Vanadates; D002939:Ciprofloxacin; D012110:Reserpine; D004996:Ethidium