Development of methionyl-tRNA synthetase inhibitors for Gram positive bacterial infections

The objective of this research is to develop a novel antibiotic targeting Gram positive bacteriawith an initial clinical indication of acute bacterial skin and skin structure infectionsABSSSIThe research will address the urgent problem of antibiotic resistant bacteria that are spreading around the worldThe new antibiotic is being designed to inhibit a novel targetthe bacterial methionyltRNA synthetase enzyme that is required for protein synthesisThe type of enzyme found in Gram positive bacteria is different from the comparable enzyme in the human cytoplasmthus making it possible to design selective and safe inhibitorsIn preliminary studies we have identified highly potent compounds against serious pathogens such as methicillin resistant Staphylococcus aureusMRSAvancomycin resistant Enterococcus faeciumVREStreptococcus speciesand othersThe minimum inhibitory concentrationsMICsare below those of widely used drugs such as vancomycin and linezolidThe compounds have minimal toxicity on mammalian cellsare well tolerated in miceare orally available and show efficacy in two mouse model of Staphylococcus infection comparable to linezolidSpecific Aimwill be to optimize the antibacterialpharmacologicaland safety properties of the compound in order to select a preclinical candidateApproximatelynew compounds will be synthesized and tested according to a screening cascadeThe selected compound will pass safety tests such as Ames and hERG inhibitionand will demonstrate potent activity in the murine model of Staphylococcus infectionSpecific Aimwill involve PK ADMEin vivo efficacy testing in mice and in vitro toxicology studies to allow for identification of a lead candidateThis will be followed by definitive PK and exploratory toxicology studies in rats and evaluation of the lead candidate in additional efficacy studiesAimThe scientific teams at University of Washington and TSRL have the combined expertise in chemistrymicrobiologypharmacologyand preclinical drug development to execute the proposed research planA successful project will bring forward a candidate drug in a novel antibiotic class to address the critical public health issue of bacterial drug resistance Infections due to antibiotic resistant bacteria are spreading throughout the world and represent a major threat to public healthThe goal of this project is to develop a new antibiotic acting by a novel mechanism that will provide a new option for treating drug resistant bacterial infections