In Vitro Studies Indicate a High Resistance Potential for the Lantibiotic Nisin in Staphylococcus aureus and Define a Genetic Basis for Nisin Resistance

摘要: Lantibiotics such as nisin (NIS) are peptide antibiotics that may have a role in the chemotherapy of bacterial infections. A perceived benefit lantibiotics for clinical use is their low propensity to select resistance, although detailed resistance studies with relevant pathogens lacking. Here we examined development NIS Staphylococcus aureus, establishing mutants, including small-colony variants, exhibiting substantial (4- 32-fold) reductions susceptibility could be selected readily. Comparative genome sequencing single NISr mutant 32-fold increase MIC revealed presence only two mutations, leading substitutions V229G purine operon repressor, PurR, and A208E an uncharacterized protein encoded by SAOUHSC_02955. Independently mutants also harbored mutations genes encoding these products. Reintroduction into S. aureus chromosome alone combination SAOUHSC_02955(A208E) made primary contribution phenotype, conferring up 16-fold decrease susceptibility. Bioinformatic analyses suggested this gene encodes sensor histidine kinase, us designate it “nisin susceptibility-associated (nsaS).” Doubling-time determinations mixed-culture competition assays between NISs strains indicated had little impact on fitness, was stable absence selection. The apparent ease which can develop maintain vitro suggests other similar modes action would arise clinic if agents employed chemotherapeutic drugs.