Restoring Beta-lactam efficacy against methicillin-resistant Staphylococci

Methicillin resistant Staphylococcus aureusMRSAand methicillin resistant Staphylococcus epidermidisMRSEare a major cause of bloodstream infections in the hospital and in the communityIndeedMRSA remains the second leading cause of mortality by drug resistant bacterial pathogens in the USAAlthough two mechanistically novel antibiotic classes exist to treat such infectionsDaptomycinDAP and LinezolidLZDtheir use in the clinic for nearly two decades has not reversed this trendMoreoverDAP and LZD possess significant limitationsthe former is solely IV administered in a clinical settingwhich significantly increases health care costsand the latteralthough delivered by IV and POcan cause serious adverse effectsincluding myelosuppression following extended useand resistance has emergedThe introduction of tedizolid is not likely to thwart LZD resistance since it shares the LZD targetConverselylactam 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 EReestablishinglactams 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 LZDIn recently published workwe have demonstrated that the Wall Teichoic AcidWTAbiosynthetic pathway is rich inlactam potentiation targetsBuilding upon a solid foundation of preliminary dataour Aims areAimPhasePhFocused discovery effort to identify compounds with potency and pharmacokineticsPKsuperior to tarocin Afor oral combination with dicloxacillinDCXor IV combination with imipenemIPMAimPhasePhExpansion of SAR and detailed characterization of hit compoundsAimPhAdvancement of at least two compounds from Aimthrough in vivo efficacy testing to identify lead candidates Narrative Methicillin resistant Staphylococcus aureusMRSAand methicillin resistant Staphylococcus epidermidisMRSEare a major cause of bloodstream infections in the hospital and in the communityIndeedMRSA has recently been reported as the second leading cause of mortality by drug resistant bacterial pathogens in the United StatesThis project will develop a new strategy to thwart these deadly infections