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-35 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-35 to a potent (MIC ?10 ?g/mL), selective (CC50>50 ?g/mL) antibacterial agent that is active in a murine model (ED50 ?50 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.
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.
|Alumasa, John N; Keiler, Kenneth C (2015) Clicking on trans-translation drug targets. Front Microbiol 6:498|