Muramyl endopeptidase Spr contributes to intrinsic vancomycin resistance inSalmonella entericaserovar Typhimurium

Abstract

ABSTRACTThe impermeability barrier provided by the outer membrane of enteric bacteria, a feature lacking in Gram-positive bacteria, plays a major role in maintaining resistance to numerous antimicrobial compounds and antibiotics. Here we demonstrate that mutational inactivation ofspr, coding for a muramyl endopeptidase, significantly sensitizesSalmonella entericaserovar Typhimurium to vancomycin without any accompanying apparent growth defect or outer membrane destabilization. A similar phenotype was not achieved by deleting themepA, pbpG, nlpC, yebAoryhdOgenes coding for functional homologues to Spr. Thesprmutant revealed increased autolytic behavior in response to not only vancomycin, but also to penicillin G, an antibiotic for which the mutant displayed a wild-type MIC. A screen for suppressor mutations of thesprmutant phenotype revealed that deletion oftsp(prc), encoding a periplasmic carboxypeptidase involved in processing Spr and PBP3, restored intrinsic resistance to vancomycin and reversed the autolytic phenotype of ansprmutant. Our data suggest that Spr contributes to intrinsic antibiotic resistance in S. Typhimurium without directly affecting the outer membrane permeability barrier. Furthermore, our data suggests that compounds that target specific cell wall endopeptidases might have the potential to expand the activity spectrum of traditional Gram-positive antibiotics.