Grant: Project Grant

Staphylococcus aureus causes many of the common hospital- and community-acquired infections. Historically, it has been managed using antibiotics such as penicillin or vancomycin however strains that are resistant to those antibiotics have emerged around the world and this is confounding therapy. We have been investigating the way S. aureus interacts with antibiotics for many years. For example, we previously elucidated the mechanisms of action of two antibiotics (siamycin I and actinorhodin) in the biosynthesis of the S. aureus cell wall. Along the way have discovered a very interesting situation in which resistance to some antibiotics is accompanied by very high sensitivity to others. We have demonstrated that at least part of this phenomenon results from down-regulation of a mechanism that recycles components of the cell wall. However, more recent data suggests that this is only part of the story. Our goals in this project grant are to understand how these mutations confer resistance to most antibiotics and how that resistance can, paradoxically, come pre-packed with enhanced sensitivity to a small number of other antibiotics. This work is important because it will shed light on the interplay between biochemical pathways that were previously thought to be unrelated. This in turn might help reveal new ways that S. aureus can be targeted for antibiotic therapy. This would be of considerable relevance to several antibiotic resistant forms of S.aureus including Vancomycin resistant S. aureus (VISA) and, more importantly, methicillin resistant S. aureus (MRSA). Indeed, given that there are now forms of the pathogen having characteristics of both VISA and MRSA, this work is potentially of broad significance to our understanding of, and ability to control infectious disease.