Analogs of the Antituberculous Agent Pyrazinamide Are Competitive Inhibitors of NADPH Binding to M. tuberculosis Fatty Acid Synthase I

Authors

  • Halimah Sayahi,

    1. Department of Chemistry, University at Albany, SUNY, 1400 Washington Ave, Albany, NY 12222, USA (phone: +1-518-442-4455; fax: +1-518-442-3462)
    Search for more papers by this author
  • Kaitlin M. Pugliese,

    1. Department of Chemistry, University at Albany, SUNY, 1400 Washington Ave, Albany, NY 12222, USA (phone: +1-518-442-4455; fax: +1-518-442-3462)
    Search for more papers by this author
  • Oren Zimhony,

    1. Infectious Diseases Division, Kaplan Medical Center, affiliated to the School of Medicine, Hebrew University and Hadassah Jerusalem, P.O. Box 1, Rehovot 76100, Israel
    Search for more papers by this author
  • William R. Jacobs Jr.,

    1. Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
    Search for more papers by this author
  • Alexander Shekhtman,

    1. Department of Chemistry, University at Albany, SUNY, 1400 Washington Ave, Albany, NY 12222, USA (phone: +1-518-442-4455; fax: +1-518-442-3462)
    Search for more papers by this author
  • John T. Welch

    Corresponding author
    1. Department of Chemistry, University at Albany, SUNY, 1400 Washington Ave, Albany, NY 12222, USA (phone: +1-518-442-4455; fax: +1-518-442-3462)
    • Department of Chemistry, University at Albany, SUNY, 1400 Washington Ave, Albany, NY 12222, USA (phone: +1-518-442-4455; fax: +1-518-442-3462)
    Search for more papers by this author

Abstract

Analogs of pyrazinamide (=pyrazine-2-carboxamide; PZA), an essential component of short-course antituberculous chemotherapy, such as 5-chloropyrazinamide (5-Cl-PZA) act as competitive inhibitors of NADPH binding to purified mycobacterial fatty acid synthase I (FAS I) as shown by Saturation Transfer Difference (STD) NMR studies. In addition, pyrazinoic acid esters (POE) and 5-Cl-POE reversibly bind to FAS I with the relatively greater affinity of longer-chain esters for FAS I, clear from the STD amplification factors. The competitive binding of PZA and 5-Cl-PZA clearly illustrates that both agents bind FAS. In contrast to PZA, at low NADPH concentrations 5-Cl-PZA is a cooperative inhibitor of NADPH binding.

Ancillary