Abstract
Vancomycin has been used as the last resort in the clinical treatment of serious Staphylococcus aureus infections. Vancomycin-intermediate S. aureus (VISA) was discovered almost two decades ago. Aside from the vancomycin-intermediate phenotype, VISA strains from the clinic or laboratory exhibited common characteristics, such as thickened cell walls, reduced autolysis, and attenuated virulence. However, the genetic mechanisms responsible for the reduced vancomycin susceptibility in VISA are varied. The comparative genomics of vancomycin-susceptible S. aureus (VSSA)/VISA pairs showed diverse genetic mutations in VISA; only a small number of these mutations have been experimentally verified. To connect the diversified genotypes and common phenotypes in VISA, we reviewed the genetic alterations in the relative determinants, including mutations in the vraTSR, graSR, walKR, stk1/stp1, rpoB, clpP, and cmk genes. Especially, we analyzed the mechanism through which diverse mutations mediate vancomycin resistance. We propose a unified model that integrates diverse gene functions and complex biochemical processes in VISA upon the action of vancomycin.
Highlights
Staphylococcus aureus is a successful human pathogen because of its metabolic versatility and its ability to adapt to host defensive stress (Didelot et al, 2016)
We reviewed and analyzed four categoris of genetic mutations occurred in Vancomycin-intermediate S. aureus (VISA), including mutations in cell wall synthesis, hydrolysis, or remodeling genes, in metabolic genes, in transcription regulatory genes, and in post-translational modification genes
We proposed a multiple-hit model for vancomycin resistance in VISA (Figure 3)
Summary
Staphylococcus aureus is a successful human pathogen because of its metabolic versatility and its ability to adapt to host defensive stress (Didelot et al, 2016). The diverse genetic mutations that contribute to the altered cell wall structures and increased vancomycin resistance in VISA need to be experimentally investigated. Loss-offunction mutations in cell wall hydrolysis genes, such as sle[1], can directly contribute to vancomycin resistance in VISA.
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