Targeting FtsZ for antituberculosis drug discovery: noncytotoxic taxanes as novel antituberculosis agents

  • J Med Chem. 2006 Jan 26;49(2):463-6. doi: 10.1021/jm050920y.
Qing Huang  1 ,  Fumiko Kirikae ,  Teruo Kirikae ,  Antonella Pepe ,  Amol Amin ,  Laurel Respicio ,  Richard A Slayden ,  Peter J Tonge ,  Iwao Ojima
Affiliations
  • 1. Department of Chemistry, State University of New York at Stony Brook, New York 11794-3400, USA.
PMID: 16420032 DOI: 10.1021/jm050920y
Abstract

Screening of 120 taxanes identified a number of compounds that exhibited significant antituberculosis activity. Rational optimization of selected compounds led to the discovery that the C-seco-taxane-multidrug-resistance (MDR) reversal agents (C-seco-TRAs) are noncytotoxic at the upper limit of solubility and detection (>80 microM), while maintaining MIC(99) values of 1.25-2.5 microM against drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis (MTB). Treatment of MTB cells with TRA 3aa and 10a at the MIC caused filamentation and prolongation of the cells, a phenotypic response to FtsZ inactivation.