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Targeting FtsZ for Antituberculosis Drug Discovery: Noncytotoxic Taxanes as Novel Antituberculosis Agents
journal contribution
posted on 2006-01-26, 00:00 authored by Qing Huang, Fumiko Kirikae, Teruo Kirikae, Antonella Pepe, Amol Amin, Laurel Respicio, Richard A. Slayden, Peter J. Tonge, Iwao OjimaScreening 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 μM), while
maintaining MIC99 values of 1.25−2.5 μM 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.
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Mycobacterium tuberculosisreversal agentsdetectionstrainRational optimizationTaxanephenotypic responseTargeting FtsZNoncytotoxicFtsZ inactivationMDRTRA 3 aaNovel Antituberculosis Agents Screening120 taxanesnoncytotoxicantituberculosis activitysolubilitycompoundprolongationMIC 99 valuesfilamentationMTB cells
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