The traditional approach to antibacterial discovery is to target a specific antibacterial target with a single compound. This single agent/single target approach often suffers from significant drawbacks including the rapid emergence of resistance and limited bacterial spectrum. In contrast, the development of an antibacterial agent that targets two proteins within a cell provides advantages of greater potency and reduced resistance frequency. Trius has invented a novel class of Tricyclic pyrimidoindoles that inhibit GyrB and ParE (TriBE inhibitors). Previously discovered GyrB/ParE inhibitors were limited to Gram-positive profiles. 1 Many small molecule programs targeting gyrase generated lead compounds with significant lipophilicity, and were hampered by significant protein binding, limiting their utility in vivo.2 However, our current molecules demonstrate broad spectrum antimicrobial activity against key biodefense and clinically important pathogens including B. anthracis, Y. pestis, F. tularensis and B. pseudomallei as well as MRSA, E. coli, A. baumannii, K. pneumoniae and P. aeruginosa. We have successfully demonstrated in vivo efficacy in several animal models of lung infections including MRSA, A. baumannii and B. pseudomallei. The TriBE inhibitor program has several key compounds at different stages of development. Multiple intravenous (IV)-only compounds are currently being evaluated for selection as an IND candidate. In addition, progress has been made on earlier stage TriBE compounds that have the potential for oral (PO) administration, as demonstrated by efficacy in a Streptococcus pneumoniae lung infection model. Finally, we are developing TriBE prodrugs that can be delivered IV or PO. The goal ofthe current proposal is to evaluate several TriBE inhibitors (IV-only, PO and prodrugs) to determine the antimicrobial spectrum (MIC90) against important ESKAPE and biodefense pathogens, to evaluate efficacy in animal models, and to identify the PK/PD parameters that drive efficacy. These data will be used to select the final candidates for preclinical development for both IV and PO treatment.
The testing and selection of compounds described in this proposal will contribute to the development of this novel mechanism antibiotic class and provide an important new antibiotic efficacious against multi-drug resistant bacterial pathogens and biodefense pathogens.
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