Role of mexA-mexB-oprM in antibiotic efflux in Pseudomonas aeruginosa

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Abstract
We have earlier described mexA-mexB-oprK, an operon involved in pyoverdine export in Pseudomonas aeruginosa, and suggested that the products of these genes also contribute to the active efflux of several antibiotics (K. Poole, K. Krebes, C. McNally, and S. Neshat, J. Bacteriol. 175:7363-7372, 1993). Recently the outer membrane component of this efflux system was shown to be OprM, rather than OprK (N. Gotoh and K. Poole, unpublished results). In the present study, the conclusion concerning the efflux activity of this system was confirmed and extended by the measurement of drug accumulation in intact cells. Thus, the steady-state accumulation levels of tetracycline and norfloxacin were increased in mexA and oprM null mutants. mexA and oprM null mutants also showed an increase in susceptibility to a wide variety of beta-lactam antibiotics and an increase in the steady-state accumulation level of benzylpenicillin, indicating that the MexA-MexB-OprM pump also effluxes beta-lactams. Furthermore, deenergization of the cytoplasmic membrane with a proton conductor always produced a strong increase in the accumulation level. Finally, a single-step mutant over-producing MexAB-OprM accumulated less tetracycline and chloramphenicol than the parent strain and was more resistant to a wide range of antimicrobial compounds, including beta-lactams. These results support the notion that these proteins contribute to the intrinsic resistance of P. aeruginosa through the multidrug active efflux process.