.2. U01 A108201 5-01 'Broad Spectrum Therapeutics Targeting Resolvase Enzymes"""""""" The goal of this project is to develop broad-spectrum antibiotics that are dual action inhibitors of gyrase B (GyrB) and histidine protein kinases (HPKs). GyrB is an established antibiotic drug target essential for bacterial viability and HPK5 are an emerging drug target involved in many virulence mechanisms. Though functionally distinct, these proteins are both members of the GHKL protein superfamily with the structurally defining feature of an unconventional ATP-binding fold. We will use a structure-based multi-target design strategy to identify low molecular weight 22o scaffolds with the potential to bind deeply into this conserved ATP-binding pocket. Based on the purchased from an American company, thereby advancing the goals of the ARRA. proiect will generate lobs for more than four people (4 FTE5) and one piece of equipment will be Perform Hit-to-Lead optimizations for new broad spectrum biodefense antibiotics. Funding of this Characterize the functional and antibiotic activities of the dual GyrB/QseC inhibitors;and 3. based, information-driven approach to identify dual GyrB/QseC inhibiting candidate scaffolds;2. N lAID Category A pathogen, Francisella tularensis.
The specific aims are to: 1. Use a structure- proposal is to develop lead candidate compounds targeting GyrB and the HPK, QseC, of the GHKL protein family inhibitors. Based on these observations, the experimental focus of this design strategy to identify low molecular weight scaffolds as starting points for the development of owing to the multi-target activity. Preliminary experiments have validated our structure-based dually active GyrB and HPK inhibitor would be a superior antibiotic with low resistance potential structural similarities of the adenine-binding pockets of these proteins, we hypothesize that a 0)_ BCD ?-o 0)+, 0>-0 (
Our primary focus will be to develop antibiotic lead compounds against F. fularensis, but with the intention of producing antibiotics with the broadest spectrum of activity possible. Since two of the three Category A and ten of the eleven Category B bacterial pathogens are gram-negative, the development of new gram-negative or broad-spectrum antibiotics is imperative to adequately protect civilian and military personnel from bioterrorist attacks. fl- D..-. m?' ='. ..r L_1
| Chopra, Sidharth; Matsuyama, Karen; Tran, Tran et al. (2012) Evaluation of gyrase B as a drug target in Mycobacterium tuberculosis. J Antimicrob Chemother 67:415-21 |
| Glaser, Bryan T; Malerich, Jeremiah P; Duellman, Sarah J et al. (2011) A high-throughput fluorescence polarization assay for inhibitors of gyrase B. J Biomol Screen 16:230-8 |
| Tambo-ong, Arlyn; Chopra, Sidharth; Glaser, Bryan T et al. (2011) Mannich reaction derivatives of novobiocin with modulated physiochemical properties and their antibacterial activities. Bioorg Med Chem Lett 21:5697-700 |
