Overexpression of the efflux pumps SmeVWX and SmeDEF is a major cause of resistance to cotrimoxazole in Stenotrophomonas maltophilia [PublishAheadOfPrint]

Cotrimoxazole is one of the antimicrobials of choice for treating Stenotrophomonas maltophilia infections. Most works on the molecular epidemiology of resistance to this drugs combination are based in the analysis of sul genes. Nevertheless, the existence of clinical cotrimoxazole resistant S. maltophilia isolates that do not harbor sul genes has been reported. To investigate potential mutations that can reduce the susceptibility of S. maltophilia to cotrimoxazole, spontaneous S. maltophilia cotrimoxazole resistant mutants isolated under different cotrimoxazole concentrations were studied. All mutants presented phenotypes compatible with the overexpression of either SmeVWX (94.6%) or SmeDEF (5.4%). Indeed, the analysis of a selected set of strains showed that overexpression of either one or another of these efflux pumps, which was due to mutations in their regulators smeRv and smeT respectively, was the cause of cotrimoxazole resistance. None other efflux pump was overexpressed in any of the studied mutants, indicating that they do not participate in the observed resistance phenotype. The analysis of mutants overexpressing or lacking SmeDEF or SmeVWX shows that SmeDEF contributes to intrinsic and acquired resistance to cotrimoxazole in S. maltophilia whereas SmeVWX only contributes to acquired resistance. It is important to highlight that all mutants were less susceptible to other antibiotics, including chloramphenicol and quinolones. Since both SmeVWX and SmeDEF are major determinants of quinolone resistance, the potential cross-selection of resistance to cotrimoxazole and quinolones, when either of the antimicrobial is used, is of particular concern for the treatment of S. maltophilia infections.

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