Abstract
Capuramycin (1) and its analogs are strong translocase I (MurX/MraY) inhibitors. In our structure-activity relationship studies of capuramycin analogs against Mycobacterium tuberculosis (Mtb), we observed for the first time that a capuramycin analog, UT-01320 (3) killed nonreplicating (dormant) Mtb at low concentrations under low oxygen conditions, whereas selective MurX inhibitors killed only replicating Mtb under aerobic conditions. Interestingly, 3 did not exhibit MurX enzyme inhibitory activity even at high concentrations, however, 3 inhibited bacterial RNA polymerases with the IC50 values of 100-150 nM range. A new RNA polymerase inhibitor 3 displayed strong synergistic effects with a MurX inhibitor SQ 641 (2), a promising preclinical tuberculosis drug.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminoglycosides / administration & dosage
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Aminoglycosides / chemistry
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Aminoglycosides / pharmacology*
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Antitubercular Agents / administration & dosage
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Antitubercular Agents / chemistry
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Antitubercular Agents / pharmacology*
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Bacterial Proteins / antagonists & inhibitors
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Caprolactam / administration & dosage
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Caprolactam / analogs & derivatives*
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Caprolactam / pharmacology
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DNA-Directed RNA Polymerases / antagonists & inhibitors
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Drug Synergism
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacology*
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Inhibitory Concentration 50
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Microbial Sensitivity Tests
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Mycobacterium tuberculosis / drug effects*
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Oxygen / metabolism
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Structure-Activity Relationship
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Transferases (Other Substituted Phosphate Groups)
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Transferases / antagonists & inhibitors
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Uridine / administration & dosage
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Uridine / analogs & derivatives*
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Uridine / pharmacology
Substances
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Aminoglycosides
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Antitubercular Agents
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Bacterial Proteins
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Enzyme Inhibitors
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SQ-641
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UT-01320
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capuramycin
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Caprolactam
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Transferases
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DNA-Directed RNA Polymerases
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Transferases (Other Substituted Phosphate Groups)
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mraY protein, Bacteria
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Oxygen
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Uridine