Restoring Beta-lactam efficacy against methicillin-resistant Staphylococci

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Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) are a major cause of bloodstream infections in the hospital and in the community. Indeed, MRSA remains the second leading cause of mortality by drug-resistant bacterial pathogens in the USA. Although two mechanistically novel antibiotic classes exist to treat such infections (Daptomycin; DAP and Linezolid; LZD), their use in the clinic for nearly two decades has not reversed this trend. Moreover, DAP and LZD possess significant limitations; the former is solely IV-administered in a clinical setting, which significantly increases health care costs, and the latter, although delivered by IV and PO, can cause serious adverse effects, including myelosuppression following extended use, and resistance has emerged. The introduction of tedizolid is not likely to thwart LZD resistance since it shares the LZD target. Conversely, β-lactam antibiotics have historically served as the most impactful class of antibiotics to treat bacterial infections but their efficacy has been eroded by the emergence of MRSA/E. Reestablishing β- lactams as a standard of care therapy for Gram-positive bacterial infections including MRSA/E would provide clinicians a new therapeutic option addressing these issues and offer an antibiotic stewardship strategy to mitigate resistance to DAP and LZD. In recently published work, we have demonstrated that the Wall Teichoic Acid (WTA) biosynthetic pathway is rich in β -lactam potentiation targets. Building upon a solid foundation of preliminary data, our Aims are: Aim 1 (Phase 1; Ph1). Focused discovery effort to identify compounds with potency and pharmacokinetics (PK) superior to tarocin A2, for oral combination with dicloxacillin (DCX) or IV combination with imipenem (IPM). Aim 2 (Phase 2; Ph2). Expansion of SAR and detailed characterization of hit compounds. Aim 3 (Ph2). Advancement of at least two compounds from Aim 2 through in vivo efficacy testing to identify lead candidates.