The hypothesis of this program is that Fabl, the conserved enoyl reductase enzyme in the bacterial fatty acidbiosynthesis pathway, is a target for the development of preclinical lead compounds with broad spectrumactivity against priority pathogens, including F. tularensis, B. pseudomallei, and Y. pestis. Based on thisapproach, we have developed inhibitors with potent activity against the Fabl enzyme from F. tularensis and8. pseudomallei. Significantly, we have demonstrated efficacy in an animal model of tularemia.Encouraged by this progress and due to the need to develop chemotherapeutics against other prioritypathogens, we will extend our studies to include the development of potent in vivo antibacterial agentsagainst 6. pseudomallei and Y. pestis. Our overall goal is to rapidly progress lead compounds into animalmodels of infection for efficacy testing with the following Specific Aims:
Aim 1 : Rational Optimization of Lead Compounds Against F. tularensis. We will design and synthesizesubsequent generations of our lead compounds using SAR information derived from molecular modeling,activity against whole bacteria and efficacy in animals and bioavailability studies.
Aim 2 : In Vitro and In Vivo Antibacterial Activity against B. pseudomallei. The in vitro activity of thecurrent diphenyl ether compounds against 8. pseudomallei will be assessed by determining (i) the IC50 forinhibition of the 8. pseudomallei Fabl enzyme (FablBpm), (ii) antibacterial activity (MIC and MBC) (iii) toxicity,PK/PD and deliverability. Selected compounds will be progressed to efficacy testing in the 8. pseudomalleianimal model of infection.
Aim 3 : Extension to Y. pestis. We will extend our antibacterial discovery efforts to include the pathogen Y.pestis. Testing will be conducted using the established approach and compounds with appropriate activitywill be evaluated in animal models of infection.This research project fits within the RMRCE Integrated Research Focus on Bacterial Therapeutics, and willinteract directly with RP 2.1, RP 2.2, RP 2.5 and RP 2.6, and utilize the resources of Core C and Core E.
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