Thiadiazolidinones: A new class of alanine racemase inhibitors with antimicrobial activity against methicillin-resistant Staphylococcus aureus

Mihai Ciustea, Sara Mootien, Adriana E. Rosato, Oriana Perez, Pier Cirillo, Kacheong R. Yeung, Michel Ledizet, Michael H. Cynamon, Paul A. Aristoff, Raymond A. Koski, Paul A. Kaplan, Karen G. Anthony

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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 (IC 50) 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.

Original languageEnglish (US)
Pages (from-to)368-377
Number of pages10
JournalBiochemical pharmacology
Volume83
Issue number3
DOIs
StatePublished - Feb 1 2012

Keywords

  • Alanine racemase
  • d-Alanine
  • MRSA
  • Peptidoglycan

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

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