Small Molecule Antibiotic Potentiators for Drug-Resistant Bacteria

DESCRIPTION provided by applicant An estimated two million Americans suffer from infections caused by multi drug resistant MDR bacteria resulting in a substantial impact on patientsandapos lives and an extraordinary economic burden Due to the arsenal of antibiotic resistance mechanisms that these bacteria present traditional antibiotic therapies are often ineffective New strategies that use a novel mechanism of action are needed to augment the arsenal of therapeutic options to address the growing problem of MDR bacteria Agile Sciencesandapos co founders Drs Christian Melander and John Cavanagh of NC State University have developed a new class of aminoimidazole AI small molecules that act via a novel mode of action to inhibit the ability of the bacteria to respond to environmental stimuli thus rendering the bacteri more sensitive to antibiotics The AI molecules inhibit response regulator RR proteins of two component systems resulting in lower antibiotic MIC values against MDR strains of Gram positive and Gram negative bacteria In addition the AI compounds have favorable toxicity and metabolic stability profiles and so they represent promising scaffolds for evaluation as potential therapeutics to address problems associated with MDR bacteria The overarching goal of this proposal is to identify lead AI molecules against each of three target bacteria methicillin resistant Staphylococcus aureus Acinetobacter baumannii and Pseudomonas aeruginosa that substantially increase the efficacy of antibiotics and have pharmaceutically relevant attributes RR proteins are an untapped target therefore there are insufficient tools fo target binding studies For this reason the objective of Aim is to generate target binding assays against three RR proteins that have been implicated in antibiotic resistance S aureus VraR A baumannii PmrA and P aeruginosa CzcR These binding assays involving electrospray ionization mass spectrometry surface plasmon resonance and reporter strains will be used to direct medicinal chemistry efforts in Aim In addition to target binding AI derivatives synthesized in Aim will be evaluated for MIC lowering cytotoxicity metabolic stability and plasma protein binding properties This project will be overseen by Dr Angela Pollard Agile Sciencesandapos Director of Research who has successfully managed development programs at Agile Sciences Dr Cavanagh an expert in bacterial cell signaling processes will design and validate RR protein binding assays in Aim Dr David Jung a medicinal chemist with years of experience and Dr Steve Young former head of Medicinal Chemistry at Merck will be responsible for designing AI derivatives in Aim Dr Jeff Collins who has over years of drug development experience specializing in anti infectives will provide consulting expertise This project has the potential to significantly impact the field of antibiotic drug development This new strategy for disabling bacterial resistance mechanisms could lead to a novel therapeutic that will provide clinicians with an effective treatment option for infection caused by MDR bacterial pathogens PUBLIC HEALTH RELEVANCE Insufficient therapeutic options exist for the treatment of infections caused by multi drug resistant bacterial pathogens resulting in extraordinary economic and public health impacts This project addresses the inherent limitation of antibiotic therapies by identifying lead aminoimidazole compounds that are capable of enhancing the effectiveness of the antibiotics by striping bacteria of their defense mechanisms