ArticleAntimicrobial agents and chemotherapy2016
Glutamate Racemase Is the Primary Target of β-Chloro-d-Alanine in Mycobacterium tuberculosis.
Article in Antimicrobial agents and chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed, 38 citations in OpenAlex.
- Dual transcriptional inhibition of glutamate and alanine racemase is synergistic inMicrobiology (Reading, England) · 2024Article
- A prototrophic suppressor of aJournal of bacteriology · 2024Article
- Development of a Chemogenetic Approach to Manipulate Intracellular pH.Journal of the American Chemical Society · 2023Article
- The Conserved Family of the Pyridoxal Phosphate-Binding Protein (PLPBP) and Its Cyanobacterial Paradigm PipY.Life (Basel, Switzerland) · 2022Review
- Metabolic bifunctionality of Rv0812 couples folate and peptidoglycan biosynthesis in Mycobacterium tuberculosis.The Journal of experimental medicine · 2021Article
- Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition.Chemical Society reviews · 2021Review
- Synthesis of the Hexahydropyrrolo-[3,2-c]-quinoline Core Structure and Strategies for Further Elaboration to Martinelline, Martinellic Acid, Incargranine B, and Seneciobipyrrolidine.Molecules (Basel, Switzerland) · 2021Review
- Tuberculosis Drug Discovery: A Decade of Hit Assessment for Defined Targets.Frontiers in cellular and infection microbiology · 2021Review
- Article
- Impaired Alanine Transport or Exposure to d-Cycloserine Increases the Susceptibility of MRSA to β-lactam Antibiotics.The Journal of infectious diseases · 2020Article
- Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes.Nature communications · 2019Article
- Cell wall peptidoglycan in Mycobacterium tuberculosis: An Achilles' heel for the TB-causing pathogen.FEMS microbiology reviews · 2019Review
- Construction and Use of TransposonFrontiers in microbiology · 2019Article
- Heterologous expression, purification and biochemical characterization of a glutamate racemase (MurI) fromPeerJ · 2019Article
- D-fining DarR: a LysR-type transcriptional regulator that responds to D-aspartate.Journal of bacteriology · 2018Article
- Article
- Identification of Highly Specific Diversity-Oriented Synthesis-Derived Inhibitors of Clostridium difficile.ACS infectious diseases · 2017Article
- Emerging Approaches to Tuberculosis Drug Development: At Home in the Metabolome.Trends in pharmacological sciences · 2017Review
- Learning from the past for TB drug discovery in the future.Drug discovery today · 2017Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
The increasing global prevalence of drug resistance among many leading human pathogens necessitates both the development of antibiotics with novel mechanisms of action and a better understanding of the physiological activities of preexisting clinically effective drugs. Inhibition of peptidoglycan (PG) biosynthesis and cross-linking has traditionally enjoyed immense success as an antibiotic target in multiple bacterial pathogens, except in Mycobacterium tuberculosis, where it has so far been underexploited. d-Cycloserine, a clinically approved antituberculosis therapeutic, inhibits enzymes within the d-alanine subbranch of the PG-biosynthetic pathway and has been a focus in our laboratory for understanding peptidoglycan biosynthesis inhibition and for drug development in studies of M. tuberculosis During our studies on alternative inhibitors of the d-alanine pathway, we discovered that the canonical alanine racemase (Alr) inhibitor β-chloro-d-alanine (BCDA) is a very poor inhibitor of recombinant M. tuberculosis Alr, despite having potent antituberculosis activity. Through a combination of enzymology, microbiology, metabolomics, and proteomics, we show here that BCDA does not inhibit the d-alanine pathway in intact cells, consistent with its poor in vitro activity, and that it is instead a mechanism-based inactivator of glutamate racemase (MurI), an upstream enzyme in the same early stage of PG biosynthesis. This is the first report to our knowledge of inhibition of MurI in M. tuberculosis and thus provides a valuable tool for studying this essential and enigmatic enzyme and a starting point for future MurI-targeted antibacterial development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.