Allosteric inhibitors of Mycobacterium tuberculosis tryptophan synthase

Michalska, Karolina; Chang, Changsoo; Maltseva, Natalia I.; Jedrzejczak, Robert; Robertson, Gregory T.; Gusovsky, Fabian; McCarren, Patrick; Schreiber, Stuart L.; Nag, Partha P.; Joachimiak, Andrzej

doi:10.1002/pro.3825

Title: Allosteric inhibitors of Mycobacterium tuberculosis tryptophan synthase

Journal Article · Sun Jan 12 00:00:00 EST 2020 · Protein Science

DOI:https://doi.org/10.1002/pro.3825· OSTI ID:1632153

Michalska, Karolina ^[1]; Chang, Changsoo ^[1]; Maltseva, Natalia I. ^[2]; Jedrzejczak, Robert ^[2]; Robertson, Gregory T. ^[3]; Gusovsky, Fabian ^[4]; McCarren, Patrick ^[5]; Schreiber, Stuart L. ^[5]; Nag, Partha P. ^[5];

^[1]

Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
Univ. of Chicago, IL (United States)
Colorado State Univ., Fort Collins, CO (United States)
Eisai Co. Ltd., Cambridge, MA (United States)
Broad Inst.of MIT and Harvard, Cambridge MA (United States)

Global dispersion of multidrug resistant bacteria is very common and evolution of antibiotic-resistance is occurring at an alarming rate, presenting a formidable challenge for humanity. The development of new therapeuthics with novel molecular targets is urgently needed. Current drugs primarily affect protein, nucleic acid, and cell wall synthesis. Metabolic pathways, including those involved in amino acid biosynthesis, have recently sparked interest in the drug discovery community as potential reservoirs of such novel targets. Tryptophan biosynthesis, utilized by bacteria but absent in humans, represents one of the currently studied processes with a therapeutic focus. It has been shown that tryptophan synthase (TrpAB) is required for survival of Mycobacterium tuberculosis in macrophages and for evading host defense, and therefore is a promising drug target. In this paper we present crystal structures of TrpAB with two allosteric inhibitors of M. tuberculosis tryptophan synthase that belong to sulfolane and indole-5-sulfonamide chemical scaffolds. We compare our results with previously reported structural and biochemical studies of another, azetidine-containing M. tuberculosis tryptophan synthase inhibitor. This work shows how structurally distinct ligands can occupy the same allosteric site and make specific interactions. It also highlights the potential benefit of targeting more variable allosteric sites of important metabolic enzymes.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357; G2017-101; GM115586; HHSN272201200026C; HHSN272201700060C; AC02‐06CH11357

OSTI ID:: 1632153

Alternate ID(s):: OSTI ID: 1592520

Journal Information:: Protein Science, Vol. 29, Issue 3; ISSN 0961-8368

Publisher:: The Protein SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 18 works

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