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Antimicrobial Agents and Chemotherapy, October 2004, p. 3697-3701, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3697-3701.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Antimicrobial Evaluation of Nocathiacins, a Thiazole Peptide Class of Antibiotics

Michael J. Pucci,1* Joanne J. Bronson,2 John F. Barrett,1,{dagger} Kenneth L. DenBleyker,1 Linda F. Discotto,1 Joan C. Fung-Tomc,1 and Yasutsugu Ueda2

Department of Microbiology,1 Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut2

Received 30 March 2004/ Returned for modification 1 May 2004/ Accepted 3 June 2004

Nocathiacins are cyclic thiazolyl peptides with inhibitory activity against gram-positive bacteria. BMS-249524 (nocathiacin I), identified from screening a library of compounds against a multiply antibiotic-resistant Enterococcus faecium strain, was used as a lead chemotype to obtain additional structurally related compounds. The MIC assay results of BMS-249524 and two more water-soluble derivatives, BMS-411886 and BMS-461996, revealed potent in vitro activities against a variety of gram-positive pathogens including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin intermediate-resistant S. aureus, vancomycin-resistant enterococci, Mycobacterium tuberculosis and Mycobacterium avium. Analysis of killing kinetics revealed that these compounds are bactericidal for S. aureus with at least a 3-log10 reduction of bacterial growth within 6 h of exposure to four times the MICs. Nocathiacin-resistant mutants were characterized by DNA sequence analyses. The mutations mapped to the rplK gene encoding the L11 ribosomal protein in the 50S subunit in a region previously shown to be involved in the binding of related thiazolyl peptide antibiotics. These compounds demonstrated potential for further development as a new class of antibacterial agents with activity against key antibiotic-resistant gram-positive bacterial pathogens.

* Corresponding author. Present address: Achillion Pharmaceuticals, 300 George St., New Haven, CT 06511. Phone: (203) 752-5421. Fax: (203) 624-7003. E-mail: mpucci{at}achillion.com.

{dagger} Present address: Merck Research Laboratories, Rahway, NJ 07065.

Antimicrobial Agents and Chemotherapy, October 2004, p. 3697-3701, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3697-3701.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Pucci, M. J., Cheng, J., Podos, S. D., Thoma, C. L., Thanassi, J. A., Buechter, D. D., Mushtaq, G., Vigliotti, G. A. Jr., Bradbury, B. J., Deshpande, M. (2007). In Vitro and In Vivo Antibacterial Activities of Heteroaryl Isothiazolones against Resistant Gram-Positive Pathogens. Antimicrob. Agents Chemother. 51: 1259-1267 [Abstract] [Full Text]  


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