Abstract：
: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.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Lee Y,Mootien S,Shoen C,Destefano M,Cirillo P,Asojo OA,Yeung KR,Ledizet M,Cynamon MH,Aristoff PA,Koski RA,Kaplan PA,Anthony KGdoi
10.1016/j.bcp.2013.05.004subject
Has Abstractpub_date
2013-07-15 00:00:00pages
222-30issue
2eissn
0006-2952issn
1873-2968pii
S0006-2952(13)00288-8journal_volume
86pub_type
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