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New classes of alanine racemase inhibitors identified by high-throughput screening show antimicrobial activity against Mycobacterium tuberculosis.
- Source :
-
PloS one [PLoS One] 2011; Vol. 6 (5), pp. e20374. Date of Electronic Publication: 2011 May 26. - Publication Year :
- 2011
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Abstract
- Background: In an effort to discover new drugs to treat tuberculosis (TB) we chose alanine racemase as the target of our drug discovery efforts. In Mycobacterium tuberculosis, the causative agent of TB, alanine racemase plays an essential role in cell wall synthesis as it racemizes L-alanine into D-alanine, a key building block in the biosynthesis of peptidoglycan. Good antimicrobial effects have been achieved by inhibition of this enzyme with suicide substrates, but the clinical utility of this class of inhibitors is limited due to their lack of target specificity and toxicity. Therefore, inhibitors that are not substrate analogs and that act through different mechanisms of enzyme inhibition are necessary for therapeutic development for this drug target.<br />Methodology/principal Findings: To obtain non-substrate alanine racemase inhibitors, we developed a high-throughput screening platform and screened 53,000 small molecule compounds for enzyme-specific inhibitors. We examined the 'hits' for structural novelty, antimicrobial activity against M. tuberculosis, general cellular cytotoxicity, and mechanism of enzyme inhibition. We identified seventeen novel non-substrate alanine racemase inhibitors that are structurally different than any currently known enzyme inhibitors. Seven of these are active against M. tuberculosis and minimally cytotoxic against mammalian cells.<br />Conclusions/significance: This study highlights the feasibility of obtaining novel alanine racemase inhibitor lead compounds by high-throughput screening for development of new anti-TB agents.
- Subjects :
- Alanine Dehydrogenase metabolism
Alanine Racemase chemistry
Alanine Racemase metabolism
Alanine Racemase pharmacology
Anti-Infective Agents analysis
Anti-Infective Agents chemistry
Anti-Infective Agents classification
Cell Death drug effects
Enzyme Inhibitors analysis
Enzyme Inhibitors chemistry
HeLa Cells
Humans
Inhibitory Concentration 50
Kinetics
Mass Spectrometry
Microbial Sensitivity Tests
Substrate Specificity drug effects
Alanine Racemase antagonists & inhibitors
Anti-Infective Agents pharmacology
Enzyme Inhibitors classification
Enzyme Inhibitors pharmacology
High-Throughput Screening Assays methods
Mycobacterium tuberculosis drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 6
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 21637807
- Full Text :
- https://doi.org/10.1371/journal.pone.0020374