The hypothesis of this program is that Fabl, the conserved enoyl reductase enzyme in the bacterial fatty acid biosynthesis pathway, is a target for the development of preclinical lead compounds with broad spectrum activity against priority pathogens, including F. tularensis, B. pseudomallei, and Y. pestis. Based on this approach, we have developed inhibitors with potent activity against the Fabl enzyme from F. tularensis and 8. 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 priority pathogens, we will extend our studies to include the development of potent in vivo antibacterial agents against 6. pseudomallei and Y. pestis. Our overall goal is to rapidly progress lead compounds into animal models of infection for efficacy testing with the following Specific Aims:
Aim 1 : Rational Optimization of Lead Compounds Against F. tularensis. We will design and synthesize subsequent 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 the current diphenyl ether compounds against 8. pseudomallei will be assessed by determining (i) the IC50 for inhibition 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. pseudomallei animal 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 activity will be evaluated in animal models of infection. This research project fits within the RMRCE Integrated Research Focus on Bacterial Therapeutics, and will interact 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.
This proposal is to develop novel and highly effective broad spectrum chemotherapeutics against F. tularensis, B. pseudomallei and Y. pestis infections. In addition, such novel broad spectrum inhibitors can be used against other hard to treat bacterial agents with significant health relevance, particularly Gram-positive pathogens, including MRSA and Gram-negative pathogens including 8. cenocepacia, Acinetobacter baumannii, and Pseudomonas aeruginosa.
|Webb, Jessica R; Price, Erin P; Somprasong, Nawarat et al. (2018) Development and validation of a triplex quantitative real-time PCR assay to detect efflux pump-mediated antibiotic resistance in Burkholderia pseudomallei. Future Microbiol 13:1403-1418|
|York, Joanne; Nunberg, Jack H (2018) A Cell-Cell Fusion Assay to Assess Arenavirus Envelope Glycoprotein Membrane-Fusion Activity. Methods Mol Biol 1604:157-167|
|Rhodes, Katherine A; Somprasong, Nawarat; Podnecky, Nicole L et al. (2018) Molecular determinants of Burkholderia pseudomallei BpeEF-OprC efflux pump expression. Microbiology 164:1156-1167|
|Cummings, Jason E; Slayden, Richard A (2017) Transient In Vivo Resistance Mechanisms of Burkholderia pseudomallei to Ceftazidime and Molecular Markers for Monitoring Treatment Response. PLoS Negl Trop Dis 11:e0005209|
|Pettey, W B P; Carter, M E; Toth, D J A et al. (2017) Constructing Ebola transmission chains from West Africa and estimating model parameters using internet sources. Epidemiol Infect 145:1993-2002|
|Furuta, Yousuke; Komeno, Takashi; Nakamura, Takaaki (2017) Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci 93:449-463|
|Skyberg, Jerod A; Lacey, Carolyn A (2017) Hematopoietic MyD88 and IL-18 are essential for IFN-?-dependent restriction of type A Francisella tularensis infection. J Leukoc Biol 102:1441-1450|
|Plumley, Brooke A; Martin, Kevin H; Borlee, Grace I et al. (2017) Thermoregulation of Biofilm Formation in Burkholderia pseudomallei Is Disrupted by Mutation of a Putative Diguanylate Cyclase. J Bacteriol 199:|
|Randall, Linnell B; Georgi, Enrico; Genzel, Gelimer H et al. (2017) Finafloxacin overcomes Burkholderia pseudomallei efflux-mediated fluoroquinolone resistance. J Antimicrob Chemother 72:1258-1260|
|Podnecky, Nicole L; Rhodes, Katherine A; Mima, Takehiko et al. (2017) Mechanisms of Resistance to Folate Pathway Inhibitors in Burkholderia pseudomallei: Deviation from the Norm. MBio 8:|
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