An Inhibitor Class That Abrogates Antibiotic Resistance in Methicillin-Resistant Staphylococcus aureus

About This Grant

Project Summary Staphylococcus aureus, designated as a serious public health threat, causes >323,000 hospitalizations and kills >10,000 individuals annually in the United States alone. A number of antibiotic-resistant variants of S. aureus—the variants referred to as methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant S. aureus (VRSA)—are among the most serious bacterial pathogens. This grant application targets this nefarious pathogen for intervention by small molecules. We disclose that the integral-membrane protein BlaR is a suitable target for inhibition by small molecules, whereupon the b-lactam- resistant bacterium becomes sensitive to b-lactam antibiotics. The BlaR protein is a b-lactam sensor/signal transducer protein that serves as a sentinel for detection of b-lactam antibiotics in the growth medium. Once the sensing of the antibiotic takes place, signal transduction across the membrane initiates cytoplasmic events that culminate in derepression of the antibiotic-resistance gene, resulting in full-blown resistance response to b-lactam antibiotics. We document for the first time that a class of designer boronates covalently modify the sensor domain of BlaR. Compound 15, an advance lead, potentiates by 16- to 4096-fold the activity of oxacillin and of meropenem against a broad range of strains of MRSA (and variants) of distinct clonal origins, lowering the minimal-inhibitory concentrations (MICs) of the antibiotics to below their clinical breakpoint MICs. The combination of 15 with oxacillin or meropenem shows efficacy in MRSA-infected mice, validating the strategy. The grant application proposes to optimize the boron-based adjuvants imparted it with drug-like attributes both as a mechanistic tool in studies of S. aureus as well as a potential therapeutic agent (Specific Aims 1 and 2). Furthermore, we will explore how resistance to these agents could emerge (Specific Aim 3)