This project is focused on defining new mechanistic paradigms for Mycobacterium tuberculosis (Mtb) cell wall. biosynthesis and remodeling, which are essential for cell growth and division. Cell-wall biosynthesis is the target of well-known, critical anti-tuberculars, including isoniazid, cycloserine and ethambutol. We will concentrate on the pepfidoglycan (PG) layer of the cell wall, which serves as a meshwork for the structural integrity of the bacillus. Recent progress has identified proteins involved in PG homeostasis either enzymatically (PG hydrolases) or in regulatory roles (PknB, FhaA, and the lipid II flippase). These, along with other cell-wall biosynthetic enzymes, represent potential vulnerabilities that could be exploited for design of new TB drugs. We will take a multidisciplinary, multi-investigator approach enabled by our Core capabilities to address major questions about Mtb cell-wall biogenesis and its regulation.
In Aim 1, we will define new molecular mechanisms of auto-inhibition of PG hydrolases to discover how their toxicity is mitigated.
In Aim 2, we will structurally characterize complexes of active PG hydrolases. To uncover indirect cell-wall vulnerabilities, we also will determine the structures of complexes of regulatory factors that control PG biosynthesis in diverse environments. These studies will uncover for the first time activation mechanisms that control PG integrity.
Aim 3 focuses on determining structures of small-molecule complexes of PG hydrolases and other cell-wall targets to define the basis for subrate- and inhibitor-binding specificty. By testtng fundamental hypotheses about cell-wall biosynthettc pathways and regulatory networks, this project sets the stage to develop potent, selective inhibitors of Mtb growth.
The biogenesis of the cell wall and its interaction with the environment are common themes in all of the P01 projects. The successful collaborations of the TBSGC members enable strong synergies with Projects 2 and 3 (which will establish the mechanisms of production of key cell wall lipids). Project 2 (which will investigate drug targets in the cell wall), and Project 4 (which is concerned with transport across the cell wall).
|Costa, Diego L; Namasivayam, Sivaranjani; Amaral, Eduardo P et al. (2016) Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses Mycobacterium tuberculosis Infection In Vivo by a Mechanism Dependent on T Lymphocytes. MBio 7:|
|Wagner, Jonathan M; Chan, Sum; Evans, Timothy J et al. (2016) Structures of EccB1 and EccD1 from the core complex of the mycobacterial ESX-1 type VII secretion system. BMC Struct Biol 16:5|
|Diaz-Ochoa, Vladimir E; Lam, Diana; Lee, Carlin S et al. (2016) Salmonella Mitigates Oxidative Stress and Thrives in the Inflamed Gut by Evading Calprotectin-Mediated Manganese Sequestration. Cell Host Microbe 19:814-25|
|Olive, Andrew J; Sassetti, Christopher M (2016) Metabolic crosstalk between host and pathogen: sensing, adapting and competing. Nat Rev Microbiol 14:221-34|
|Bajaj, R Alexandra; Arbing, Mark A; Shin, Annie et al. (2016) Crystal structure of the toxin Msmeg_6760, the structural homolog of Mycobacterium tuberculosis Rv2035, a novel type II toxin involved in the hypoxic response. Acta Crystallogr F Struct Biol Commun 72:863-869|
|Lovewell, Rustin R; Sassetti, Christopher M; VanderVen, Brian C (2016) Chewing the fat: lipid metabolism and homeostasis during M. tuberculosis infection. Curr Opin Microbiol 29:30-6|
|Cheng, Yu-Shan; Sacchettini, James C (2016) Structural Insights into Mycobacterium tuberculosis Rv2671 Protein as a Dihydrofolate Reductase Functional Analogue Contributing to para-Aminosalicylic Acid Resistance. Biochemistry 55:1107-19|
|Dragset, Marte S; Poce, Giovanna; Alfonso, Salvatore et al. (2015) A novel antimycobacterial compound acts as an intracellular iron chelator. Antimicrob Agents Chemother 59:2256-64|
|Kieser, Karen J; Boutte, Cara C; Kester, Jemila C et al. (2015) Phosphorylation of the Peptidoglycan Synthase PonA1 Governs the Rate of Polar Elongation in Mycobacteria. PLoS Pathog 11:e1005010|
|Long, Jarukit E; DeJesus, Michael; Ward, Doyle et al. (2015) Identifying essential genes in Mycobacterium tuberculosis by global phenotypic profiling. Methods Mol Biol 1279:79-95|
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