Invasive methicillin resistant Staphylococcus aureus (MRSA) infections are responsible for significant morbidity and mortality worldwide. MRSA infections are particularly frightening since they are readily transmitted both in hospital settings and in the community, and they are typically resistant not only to beta lactams, but to other major classes of antibiotics as well. Clinical resistance has already been observed to several compounds introduced recently to treat MRSA. Moreover, there have been several well-documented cases involving mixed infections in which MRSA acquired genes conferring vancomycin resistance from VRE. This Harvard-wide Program Project on antibiotic resistance, led by Michael Gilmore, was established to foster collaborative research aimed at addressing the problem of antibiotic resistance in MRSA. It brings together scientists with expertise in relevant areas of infectious disease, animal models of infection, bacterial pathogenesis, bacterial physiology, the evolution of resistance, the discovery of novel antibiotics, and the exploration of new approaches to overcome antibiotic resistant infections. This subproject is focused on the discovery and exploration of novel compounds and strategies to combat MRSA. Three different approaches, each involving different compound classes and sets of targets, will be investigated.
Aim 1 will evaluate a potent and promising new structural class of wall teichoic acid inhibitors as anti-MRSA agents.
Aim II will address the potential of inhibitors of teichoic acid D-alanylation as anti-MRSA agents.
Aim III will provide a comprehensive list of beta lactam potentiator targets that are shared among MRSA strains, and will explore a new strategy to identify targets of previously discovered beta lactam potentiators to enable further development.

Public Health Relevance

Half of all deaths due to antibiotic-resistant infections in the United States are due to methicillin-resistant Staphylococcus aureus, or MRSA. MRSA is highly virulent and can infect healthy individuals in the community as well as ?at-risk? hospital patients. Clinical resistance has already emerged to several compounds recently introduced to treat MRSA, highlighting the importance of maintaining a pipeline of possible anti-MRSA agents. The work proposed is aimed at the discovery and evaluation of new compounds and compound combinations for overcoming MRSA infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Massachusetts Eye and Ear Infirmary
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