title: Inhibition of mycobacterial alanine racemase activity and growth by thiadiazolidinones.
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.
authors.affiliation: L2 Diagnostics LLC, 300 George St., New Haven, CT 06511, USA.
authors.forename: Yashang
authors.initials: Y
authors.lastname: Lee
authors.forename: Sara
authors.initials: S
authors.lastname: Mootien
authors.forename: Carolyn
authors.initials: C
authors.lastname: Shoen
authors.forename: Michelle
authors.initials: M
authors.lastname: Destefano
authors.forename: Pier
authors.initials: P
authors.lastname: Cirillo
authors.forename: Oluwatoyin A
authors.initials: OA
authors.lastname: Asojo
authors.forename: Kacheong R
authors.initials: KR
authors.lastname: Yeung
authors.forename: Michel
authors.initials: M
authors.lastname: Ledizet
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cynamon
authors.forename: Paul A
authors.initials: PA
authors.lastname: Aristoff
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Koski
authors.forename: Paul A
authors.initials: PA
authors.lastname: Kaplan
authors.forename: Karen G
authors.initials: KG
authors.lastname: Anthony
mesh_terms: D000411:Alanine Racemase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D002384:Catalysis; D008969:Molecular Sequence Data; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D017386:Sequence Homology, Amino Acid; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013830:Thiadiazoles / Q000494:pharmacology*
chemical_list: D013830:Thiadiazoles; D000411:Alanine Racemase