Targeting FtsZ for antituberculosis drug discovery: noncytotoxic taxanes as novel antituberculosis agents.
Huang Q, Kirikae F, Kirikae T, Pepe A, Amin A, Respicio L, Slayden RA, Tonge PJ, Ojima I.
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.