title: Thiadiazolidinones: a new class of alanine racemase inhibitors with antimicrobial activity against methicillin-resistant Staphylococcus aureus.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is a human pathogen and a major cause of hospital-acquired infections. New antibacterial agents that have not been compromised by bacterial resistance are needed to treat MRSA-related infections. We chose the S. aureus cell wall synthesis enzyme, alanine racemase (Alr) as the target for a high-throughput screening effort to obtain novel enzyme inhibitors, which inhibit bacterial growth. Among the 'hits' identified was a thiadiazolidinone with chemical properties attractive for lead development. This study evaluated the mode of action, antimicrobial activities, and mammalian cell cytotoxicity of the thiadiazolidinone family in order to assess its potential for development as a therapeutic agent against MRSA. The thiadiazolidones inhibited Alr activity with 50% inhibitory concentrations (IC₅₀) ranging from 0.36 to 6.4 μM, and they appear to inhibit the enzyme irreversibly. The series inhibited the growth of S. aureus, including MRSA strains, with minimal inhibitory concentrations (MICs) ranging from 6.25 to 100 μg/ml. The antimicrobial activity showed selectivity against Gram-positive bacteria and fungi, but not Gram-negative bacteria. The series inhibited human HeLa cell proliferation. Lead development centering on the thiadiazolidinone series would require additional medicinal chemistry efforts to enhance the antibacterial activity and minimize mammalian cell toxicity.
authors.affiliation: L2 Diagnostics, LLC, 300 George St., New Haven, CT 06511, USA.
authors.forename: Mihai
authors.initials: M
authors.lastname: Ciustea
authors.forename: Sara
authors.initials: S
authors.lastname: Mootien
authors.forename: Adriana E
authors.initials: AE
authors.lastname: Rosato
authors.forename: Oriana
authors.initials: O
authors.lastname: Perez
authors.forename: Pier
authors.initials: P
authors.lastname: Cirillo
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* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*; D008826:Microbial Sensitivity Tests; D013830:Thiadiazoles / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D013830:Thiadiazoles; D000411:Alanine Racemase