RRC ID 29436
Author Ishizaki Y, Hayashi C, Inoue K, Igarashi M, Takahashi Y, Pujari V, Crick DC, Brennan PJ, Nomoto A.
Title Inhibition of the first step in synthesis of the mycobacterial cell wall core, catalyzed by the GlcNAc-1-phosphate transferase WecA, by the novel caprazamycin derivative CPZEN-45.
Journal J Biol Chem
Abstract Because tuberculosis is one of the most prevalent and serious infections, countermeasures against it are urgently required. We isolated the antitubercular agents caprazamycins from the culture of an actinomycete strain and created CPZEN-45 as the most promising derivative of the caprazamycins. Herein, we describe the mode of action of CPZEN-45 first against Bacillus subtilis. Unlike the caprazamycins, CPZEN-45 strongly inhibited incorporation of radiolabeled glycerol into growing cultures and showed antibacterial activity against caprazamycin-resistant strains, including a strain overexpressing translocase-I (MraY, involved in the biosynthesis of peptidoglycan), the target of the caprazamycins. By contrast, CPZEN-45 was not effective against a strain overexpressing undecaprenyl-phosphate-GlcNAc-1-phosphate transferase (TagO, involved in the biosynthesis of teichoic acid), and a mutation was found in the tagO gene of the spontaneous CPZEN-45-resistant strain. This suggested that the primary target of CPZEN-45 in B. subtilis is TagO, which is a different target from that of the parent caprazamycins. This suggestion was confirmed by evaluation of the activities of these enzymes. Finally, we showed that CPZEN-45 was effective against WecA (Rv1302, also called Rfe) of Mycobacterium tuberculosis, the ortholog of TagO and involved in the biosynthesis of the mycolylarabinogalactan of the cell wall of M. tuberculosis. The outlook for WecA as a promising target for the development of antituberculous drugs as a countermeasure of drug resistant tuberculosis is discussed.
Volume 288(42)
Pages 30309-30319
Published 2013-10-18
DOI 10.1074/jbc.M113.492173
PII S0021-9258(20)85704-4
PMID 23986448
PMC PMC3798496
MeSH Antitubercular Agents / pharmacology* Azepines / pharmacokinetics* Bacillus subtilis / enzymology Bacillus subtilis / genetics Bacterial Proteins / antagonists & inhibitors Bacterial Proteins / genetics Bacterial Proteins / metabolism Cell Wall / enzymology* Cell Wall / genetics Galactans / biosynthesis Galactans / genetics Mycobacterium tuberculosis / enzymology* Mycobacterium tuberculosis / genetics Transferases / antagonists & inhibitors Transferases / genetics Transferases / metabolism Transferases (Other Substituted Phosphate Groups) / antagonists & inhibitors* Transferases (Other Substituted Phosphate Groups) / genetics Transferases (Other Substituted Phosphate Groups) / metabolism Tuberculosis, Multidrug-Resistant / drug therapy Tuberculosis, Multidrug-Resistant / enzymology Tuberculosis, Multidrug-Resistant / genetics
IF 4.238
Times Cited 85
General Microbes JCM 5803 JCM 6384