Small Molecule Inhibitors of trans-Translation with Broad Spectrum Antibacterial

DESCRIPTION provided by applicant Because of the emergence of resistance to known antibiotics there is a critical need for new antibacterial agents especially against Gram negative pathogens trans Translation is a biochemical pathway that is essential to many bacterial species including Neisseria gonorrhoeae Shigella flexneri and Mycoplasma spp A high throughput assay of trans translation produced a series of inhibitors based on a common scaffold that includes an oxadiazole amide core These compounds exhibited potent and selective inhibition of a series of representative bacterial pathogens The hypothesis of this proposal is that modifications of the inhibitor scaffold will provide optimized antibacterial agent with in vitro ADME T profile suitable for further development and demonstrated efficacy in a murine model of infection The overall goal of this proposal is to develop the triazole amide scaffold as a broad spectrum antibacterial therapeutic with activity against drug resistant pathogens The specific objective of this proposal is to optimize the structure of the hit compound KKL to increase the antibacterial potency and improve the predictive in vitro ADME T properties to produce an advanced lead compound suitable for additional development into an effective broad spectrum antibacterial for use against antibiotic resistant pathogens There is currently a critical need for such therapies especially against prevalent drug resistant strains The major milestone of this proposal will be the optimization of KKL to a potent MIC g mL selective CC andgt g mL antibacterial agent that is active in a murine model ED mg kg The compound will be further developed in a Phase II SBIR grant Subsequent development will ideally lead to the identification of a clinical development candidate PUBLIC HEALTH RELEVANCE The goal of this project is to optimize a series of bacterial trans translation inhibitors based on an oxadiazole amide scaffold into potent and selective antibacterial agents The optimization will produce a compound that is active in a murine model of infection and has an in vitro ADME T profile suitable for additional preclinical development