Staphylococcus aureus response and adaptation to vancomycin.

Antibiotic resistance is an increasing challenge for the human pathogen Staphylococcus aureus. Methicillin-resistant S. aureus (MRSA) clones have spread globally, and a growing number display decreased susceptibility to vancomycin, the favoured antibiotic for treatment of MRSA infections. These vancomycin-intermediate S. aureus (VISA) or heterogeneous vancomycin-intermediate S. aureus (hVISA) strains arise from accumulation of a variety of point mutations, leading to cell wall thickening and reduced vancomycin binding to the cell wall building block, Lipid II, at the septum. They display only minor changes in vancomycin susceptibility, with varying tolerance between cells in a population, and therefore, they can be difficult to detect. In this review, we summarize current knowledge of VISA and hVISA. We discuss the role of genetic strain background or epistasis for VISA development and the possibility of strains being 'transient' VISA with gene expression changes mediated by, for example, VraTSR, GraXSR, or WalRK signal transduction systems, leading to temporary vancomycin tolerance. Additionally, we address collateral susceptibility to other antibiotics than vancomycin. Specifically, we estimate how mutations in rpoB, encoding the ß-subunit of the RNA polymerase, affect overall protein structure and compare changes with rifampicin resistance. Ultimately, such in-depth analysis of VISA and hVISA strains in terms of genetic and transcriptional changes, as well as changes in protein structures, may pave the way for improved detection and guide antibiotic therapy by revealing strains at risk of VISA development. Such tools will be valuable for keeping vancomycin an asset also in the future.

Cross-species communication via agr controls phage susceptibility in Staphylococcus aureus.

Bacteria use quorum sensing (QS) to coordinate group behavior in response to cell density, and some bacterial viruses (phages) also respond to QS. In Staphylococcus aureus, the agr-encoded QS system relies on accumulation of auto-inducing cyclic peptides (AIPs). Other staphylococci also produce AIPs of which many inhibit S. aureus agr. We show that agr induction reduces expression of tarM, encoding a glycosyltransferase responsible for α-N-acetylglucosamine modification of the major S. aureus phage receptor, the wall teichoic acids. This allows lytic phage Stab20 and related phages to infect and kill S. aureus. However, in mixed communities, producers of inhibitory AIPs like S. haemolyticus, S. caprae, and S. pseudintermedius inhibit S. aureus agr, thereby impeding phage infection. Our results demonstrate that cross-species interactions dramatically impact phage susceptibility. These interactions likely influence microbial ecology and impact the efficacy of phages in medical and biotechnological applications such as phage therapy.