Development of DksA-targeted Antibiotics for Treatment of Gram-negative Infections

Antibiotic resistant infections disproportionately affect veterans and their families. Antibiotic resistant Gram-negative bacterial infections are associated with high rates of morbidity and mortality around the globe, including the men and women actively serving in the armed forces, veterans, and patients in VA hospitals. Options for antibiotic usage are in dangerous decline. Despite this health crisis, only 24 new antibiotics have been approved since 1987. Most newer antibiotics are modifications or reformulations of existing drugs. None of the recently approved antibiotics have novel mechanisms of action, severely limiting mechanistic diversity among available drugs. The transcription factor DksA, an essential component of the stringent response that regulates the pathogenesis of diverse Gram-negative bacteria, is highly conserved among Gram-negative pathogens but is absent from humans. Informed by bioinformatic modeling and structure-activity relationship (SAR), we have generated new chemical entities (NCE) that bind to DksA and have antimicrobial activity against nontyphoidal Salmonella and several other Gram-negative pathogens. Our preliminary pharmacokinetic evaluations indicate that one of our DksA inhibitors is absorbed and distributed in rats, and exhibits excellent antibiotic activity in an acute murine model of Salmonella infection. The ultimate goal of the proposed investigations is to develop soluble compounds against the DksA transcriptional regulator that are endowed with potent antimicrobial activity against Gram-negative pathogens. Specifically, we propose to 1) synthesize new DksA inhibitors with improved antimicrobial activity, and 2) characterize ADME (absorption, distribution, metabolism and excretion) properties and therapeutic potential of DksA inhibitors in animals. Synthesis of DksA inhibitors will contribute to the rational development of novel antibiotics against Gram-negative bacteria that affect veterans and the general population.