Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a pathogen of global importance;9 million new cases of TB are reported annually, with 1-2 million deaths. There are half a million cases of drug resistant TB cases each year and the problem of antibiotic resistance is rising. TB treatment is a lengthy process (6-24 months) giving rise to an urgent need for newer, more effective antibiotics. In order to develop new drugs, we need to understand which metabolic processes are the most important for bacterial survival and pathogenesis. Chemical entities can be powerful probes for the identification of key cellular processes underpinning survival. However, most recent work has focused on genetic approaches to identifying essential genes and there has been little progress in identifying the pathways that effective anti-bacterial compounds target. Recently, a number of novel compounds with unknown targets have been identified with cidal or static activity against drug-resistant pathogens including M. tuberculosis. We propose to apply a combination of techniques in conjunction with several compound classes in order to identify vulnerable pathways, which can be thoroughly characterized using compounds as chemical probes. We will use three main approaches to characterize anti-tubercular agents. (1) We will isolate compound-resistant strains (spontaneous mutants or over-expressing recombinant strains) to identify the protein targets and mode of resistance. (2) We will use three methods (affinity chromatography, photoaffinity labeling, and yeast three hybrid system) to identify protein targets which bind to the compounds. (3) We will look at the effect of compound exposure on cell metabolites and the induction of reactive oxygen species. Together these methods will enable us to identify the pathways and specific proteins that are targeted by each compound;such targets will form the basis for future drug discovery and development.
Mycobacterium tuberculosis is the causative agent of human tuberculosis, a devastating infectious disease, which kills nearly 2 million and infects more than 8 million people each year;there is an increasing threat from multi-drug resistant and extremely drug resistant strains. We aim to determine how newly discovered compounds kill the TB bacilli and to use this information to find new drug targets.
|Melief, Eduard; Kokoczka, Rachel; Files, Megan et al. (2018) Construction of an overexpression library for Mycobacterium tuberculosis. Biol Methods Protoc 3:bpy009|
|Korkegian, Aaron; O'Malley, Theresa; Xia, Yi et al. (2018) The 7-phenyl benzoxaborole series is active against Mycobacterium tuberculosis. Tuberculosis (Edinb) 108:96-98|
|O'Malley, Theresa; Alling, Torey; Early, Julie V et al. (2018) Imidazopyridine Compounds Inhibit Mycobacterial Growth by Depleting ATP Levels. Antimicrob Agents Chemother 62:|
|McNeil, Matthew B; Dennison, Devon; Shelton, Catherine et al. (2018) Corrigendum to ""Mechanisms of resistance against NITD-916, a direct inhibitor of Mycobacterium tuberculosis InhA"" [Tuberculosis 107 (December 2017) 133-136]. Tuberculosis (Edinb) 110:123|
|Berube, Bryan J; Castro, Lina; Russell, Dara et al. (2018) Novel Screen to Assess Bactericidal Activity of Compounds Against Non-replicating Mycobacterium abscessus. Front Microbiol 9:2417|
|Wescott, Heather H; Zuniga, Edison S; Bajpai, Anumita et al. (2018) Identification of Enolase as the Target of 2-Aminothiazoles in Mycobacterium tuberculosis. Front Microbiol 9:2542|
|Melief, Eduard; Bonnett, Shilah A; Zuniga, Edison S et al. (2018) Activation of 2,4-diaminoquinazoline in Mycobacterium tuberculosis by Rv3161c, a putative dioxygenase. Antimicrob Agents Chemother :|
|Patel, Nipul; O'Malley, Theresa; Zhang, Yong-Kang et al. (2017) A Novel 6-Benzyl Ether Benzoxaborole Is Active against Mycobacterium tuberculosis In Vitro. Antimicrob Agents Chemother 61:|
|McNeil, Matthew B; Dennison, Devon D; Shelton, Catherine D et al. (2017) In Vitro Isolation and Characterization of Oxazolidinone-Resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 61:|
|Howell Wescott, Heather A; Roberts, David M; Allebach, Christian L et al. (2017) Imidazoles Induce Reactive Oxygen Species in Mycobacterium tuberculosis Which Is Not Associated with Cell Death. ACS Omega 2:41-51|
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