Document Detail

Inhibition of mycobacterial alanine racemase activity and growth by thiadiazolidinones.
MedLine Citation:
PMID:  23680030     Owner:  NLM     Status:  MEDLINE    
The genus Mycobacterium includes non-pathogenic species such as M. smegmatis, and pathogenic species such as M. tuberculosis, the causative agent of tuberculosis (TB). Treatment of TB requires a lengthy regimen of several antibiotics, whose effectiveness has been compromised by the emergence of resistant strains. New antibiotics that can shorten the treatment course and those that have not been compromised by bacterial resistance are needed. In this study, we report that thiadiazolidinones, a relatively little-studied heterocyclic class, inhibit the activity of mycobacterial alanine racemase, an essential enzyme that converts l-alanine to d-alanine for peptidoglycan synthesis. Twelve members of the thiadiazolidinone family were evaluated for inhibition of M. tuberculosis and M. smegmatis alanine racemase activity and bacterial growth. Thiadiazolidinones inhibited M. tuberculosis and M. smegmatis alanine racemases to different extents with 50% inhibitory concentrations (IC50) ranging from <0.03 to 28μM and 23 to >150μM, respectively. The compounds also inhibited the growth of these bacteria, including multidrug resistant strains of M. tuberculosis. The minimal inhibitory concentrations (MIC) for drug-susceptible M. tuberculosis and M. smegmatis ranged from 6.25μg/ml to 100μg/ml, and from 1.56 to 6.25μg/ml for drug-resistant M. tuberculosis. The in vitro activities of thiadiazolidinones suggest that this family of compounds might represent starting points for medicinal chemistry efforts aimed at developing novel antimycobacterial agents.
Yashang Lee; Sara Mootien; Carolyn Shoen; Michelle Destefano; Pier Cirillo; Oluwatoyin A Asojo; Kacheong R Yeung; Michel Ledizet; Michael H Cynamon; Paul A Aristoff; Raymond A Koski; Paul A Kaplan; Karen G Anthony
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-05-13
Journal Detail:
Title:  Biochemical pharmacology     Volume:  86     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-06-21     Completed Date:  2013-09-03     Revised Date:  2014-07-21    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  222-30     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Elsevier Inc. All rights reserved.
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MeSH Terms
Alanine Racemase / antagonists & inhibitors*,  chemistry,  metabolism
Amino Acid Sequence
Molecular Sequence Data
Mycobacterium smegmatis / drug effects*,  enzymology
Mycobacterium tuberculosis / drug effects*,  enzymology
Sequence Homology, Amino Acid
Spectrometry, Mass, Electrospray Ionization
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Thiadiazoles / pharmacology*
Grant Support
Reg. No./Substance:
0/Thiadiazoles; EC Racemase

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