Targeting FtsZ for antituberculosis drug discovery: noncytotoxic taxanes as novel antituberculosis agents.
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.
Huang
Qing
Q
Department of Chemistry, State University of New York at Stony Brook, New York 11794-3400, USA.
Kirikae
Fumiko
F
Kirikae
Teruo
T
Pepe
Antonella
A
Amin
Amol
A
Respicio
Laurel
L
Slayden
Richard A
RA
Tonge
Peter J
PJ
Ojima
Iwao
I
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D000970:Antineoplastic Agents / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001704:Biopolymers; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000648:ultrastructure; D017239:Paclitaxel / Q000494:pharmacology; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001704:Biopolymers; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D043823:Taxoids; D017239:Paclitaxel