Allosteric inhibitors of <scp><i>Mycobacterium tuberculosis</i></scp> tryptophan synthase

Michalska, K.; Chang, Changsoo; Maltseva, Natalia; Jedrzejczak, R.; Robertson, Gregory T.; Gusovsky, Fabián; McCarren, Patrick; Schreiber, Stuart L.; Nag, Partha P.; Joachimiak, A.

doi:10.1002/pro.3825

Cited by 26 publications

(25 citation statements)

References 42 publications

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“…Two phenotypic screens of high-diversity chemical libraries independently identified inhibitors of M. tuberculosis tryptophan synthase that are active against the bacterium in culture (MIC 50 values in the 0.5-3 μM range) and also show moderate in vivo efficacy in both zebrafish and mouse models of TB [20,21,56]. Tryptophan synthase is a remarkable and complex enzyme.…”

Section: Inhibitors Targeting Tryptophan Biosynthesis In M Tuberculosismentioning

confidence: 99%

The tryptophan biosynthetic pathway is essential forMycobacterium tuberculosisto cause disease

Lott

2020

Biochemical Society Transactions

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Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is the most significant cause of death from a single infectious agent worldwide. Antibiotic-resistant strains of M. tuberculosis represent a threat to effective treatment, and the long duration, toxicity and complexity of current chemotherapy for antibiotic-resistant disease presents a need for new therapeutic approaches with novel modes of action. M. tuberculosis is an intracellular pathogen that must survive phagocytosis by macrophages, dendritic cells or neutrophils to establish an infection. The tryptophan biosynthetic pathway is required for bacterial survival in the phagosome, presenting a target for new classes of antitubercular compound. The enzymes responsible for the six catalytic steps that produce tryptophan from chorismate have all been characterised in M. tuberculosis, and inhibitors have been described for some of the steps. The innate immune system depletes cellular tryptophan in response to infection in order to inhibit microbial growth, and this effect is likely to be important for the efficacy of tryptophan biosynthesis inhibitors as new antibiotics. Allosteric inhibitors of both the first and final enzymes in the pathway have proven effective, including by a metabolite produced by the gut biota, raising the intriguing possibility that the modulation of tryptophan biosynthesis may be a natural inter-bacterial competition strategy.

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Section: Inhibitors Targeting Tryptophan Biosynthesis In M Tuberculosismentioning

confidence: 99%

The tryptophan biosynthetic pathway is essential forMycobacterium tuberculosisto cause disease

Lott

2020

Biochemical Society Transactions

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“…The crystallographic structure of TrpAB was described for the first time in 2017 by Wellington and co-workers, who analyzed both the apo form and the complex with the azetidine inhibitor BRD4592 (93, MIC = 1.6-3 µM, Figure 43) [42]. Later, in 2020, the same group investigated the cocrystal structures of the enzyme with GSK1 (94, MIC = 0.76 µM vs Mtb H37Rv) and GSK2 (95, MIC = 1.1 µM vs Mtb H37Rv), two inhibitors developed by the University of Birmingham and GlaxoSmithKline (Figure 43) [40,43]. The switch between open and closed conformations is pivotal to the activity of the enzyme and is coordinated by the so-called communication domain (COMM) [40].…”

Section: Tryptophan Synthase (Trpab)mentioning

confidence: 99%

An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis

et al. 2021

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The elucidation of the structure of enzymes and their complexes with ligands continues to provide invaluable insights for the development of drugs against many diseases, including bacterial infections. After nearly three decades since the World Health Organization’s (WHO) declaration of tuberculosis (TB) as a global health emergency, Mycobacterium tuberculosis (Mtb) continues to claim millions of lives, remaining among the leading causes of death worldwide. In the last years, several efforts have been devoted to shortening and improving treatment outcomes, and to overcoming the increasing resistance phenomenon. The structural elucidation of enzyme-ligand complexes is fundamental to identify hot-spots, define possible interaction sites, and elaborate strategies to develop optimized molecules with high affinity. This review offers a critical and comprehensive overview of the most recent structural information on traditional and emerging mycobacterial enzymatic targets. A selection of more than twenty enzymes is here discussed, with a special emphasis on the analysis of their binding sites, the definition of the structure–activity relationships (SARs) of their inhibitors, and the study of their main intermolecular interactions. This work corroborates the potential of structural studies, substantiating their relevance in future anti-mycobacterial drug discovery and development efforts.

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“…TS expression is required for the survival of M. tuberculosis to counteract the adaptive immune response, and of other Gram-positive and Gram-negative bacteria [ 38 ]. In this regard, some active site ligands behaving as allosteric inhibitors of the M. tuberculosis enzyme have been identified through high-throughput screening and crystallographic studies [ 41 , 42 ]. The key role of Trp synthesis in M. tuberculosis is also demonstrated by the ability of microbiota-derived indole-propionic acid to inhibit bacterial growth in both in vitro and in vivo models [ 43 , 44 ].…”

Section: A Biochemical Overview Of Microbial and Host Trp-metabolimentioning

confidence: 99%

Pyridoxal 5′-Phosphate-Dependent Enzymes at the Crossroads of Host–Microbe Tryptophan Metabolism

Cellini

Zelante

Dindo

et al. 2020

IJMS

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The chemical processes taking place in humans intersects the myriad of metabolic pathways occurring in commensal microorganisms that colonize the body to generate a complex biochemical network that regulates multiple aspects of human life. The role of tryptophan (Trp) metabolism at the intersection between the host and microbes is increasingly being recognized, and multiple pathways of Trp utilization in either direction have been identified with the production of a wide range of bioactive products. It comes that a dysregulation of Trp metabolism in either the host or the microbes may unbalance the production of metabolites with potential pathological consequences. The ability to redirect the Trp flux to restore a homeostatic production of Trp metabolites may represent a valid therapeutic strategy for a variety of pathological conditions, but identifying metabolic checkpoints that could be exploited to manipulate the Trp metabolic network is still an unmet need. In this review, we put forward the hypothesis that pyridoxal 5′-phosphate (PLP)-dependent enzymes, which regulate multiple pathways of Trp metabolism in both the host and in microbes, might represent critical nodes and that modulating the levels of vitamin B6, from which PLP is derived, might represent a metabolic checkpoint to re-orienteer Trp flux for therapeutic purposes.

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Allosteric inhibitors of Mycobacterium tuberculosis tryptophan synthase

Cited by 26 publications

References 42 publications

The tryptophan biosynthetic pathway is essential forMycobacterium tuberculosisto cause disease

The tryptophan biosynthetic pathway is essential forMycobacterium tuberculosisto cause disease

An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis

Pyridoxal 5′-Phosphate-Dependent Enzymes at the Crossroads of Host–Microbe Tryptophan Metabolism

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