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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.

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  • Authors

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    Source

    Biochemical pharmacology 83:3 2012 Feb 1 pg 368-77

    MeSH

    Alanine Racemase
    Anti-Bacterial Agents
    Drug Delivery Systems
    HeLa Cells
    Humans
    Methicillin-Resistant Staphylococcus aureus
    Microbial Sensitivity Tests
    Thiadiazoles

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    22146584

    Citation

    TY - JOUR T1 - Thiadiazolidinones: a new class of alanine racemase inhibitors with antimicrobial activity against methicillin-resistant Staphylococcus aureus. AU - Ciustea,Mihai, AU - Mootien,Sara, AU - Rosato,Adriana E, AU - Perez,Oriana, AU - Cirillo,Pier, AU - Yeung,Kacheong R, AU - Ledizet,Michel, AU - Cynamon,Michael H, AU - Aristoff,Paul A, AU - Koski,Raymond A, AU - Kaplan,Paul A, AU - Anthony,Karen G, Y1 - 2011/11/29/ PY - 2011/9/30/received PY - 2011/11/20/revised PY - 2011/11/21/accepted PY - 2011/11/29/aheadofprint PY - 2011/12/8/entrez PY - 2011/12/8/pubmed PY - 2012/2/15/medline SP - 368 EP - 77 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 83 IS - 3 N2 - 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. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/22146584/full_citation/Thiadiazolidinones:_a_new_class_of_alanine_racemase_inhibitors_with_antimicrobial_activity_against_methicillin_resistant_Staphylococcus_aureus_ L2 - http://linkinghub.elsevier.com/retrieve/pii/S0006-2952(11)00858-6 ER -