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.
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.
authors.affiliation: From the Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23, Kamiosaki, Shinagawa-ku, Tokyo, Japan,. Electronic address: ishizakiy@bikaken.or.jp.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Ishizaki
authors.affiliation: From the Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23, Kamiosaki, Shinagawa-ku, Tokyo, Japan.
authors.forename: Chigusa
authors.initials: C
authors.lastname: Hayashi
authors.affiliation: From the Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23, Kamiosaki, Shinagawa-ku, Tokyo, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Inoue
authors.affiliation: From the Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23, Kamiosaki, Shinagawa-ku, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Igarashi
authors.affiliation: the Institute of Microbial Chemistry (BIKAKEN), Hiyoshi, 3-34-17, Ida, Nakahara-ku, Kawasaki, Kanagawa, Japan, and.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: the Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado 80523-1682.
authors.forename: Venugopal
authors.initials: V
authors.lastname: Pujari
authors.affiliation: the Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado 80523-1682.
authors.forename: Dean C
authors.initials: DC
authors.lastname: Crick
authors.affiliation: the Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado 80523-1682.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Brennan
authors.affiliation: From the Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23, Kamiosaki, Shinagawa-ku, Tokyo, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Nomoto
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001381:Azepines / Q000493:pharmacokinetics*; D001412:Bacillus subtilis / Q000201:enzymology / Q000235:genetics; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002473:Cell Wall / Q000201:enzymology* / Q000235:genetics; D005685:Galactans / Q000096:biosynthesis / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics; D014166:Transferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics
chemical_list: D000995:Antitubercular Agents; D001381:Azepines; D001426:Bacterial Proteins; C583520:CPZEN-45; D005685:Galactans; C549865:mycolylarabinogalactan; D014166:Transferases; D017855:Transferases (Other Substituted Phosphate Groups); C079803:mraY protein, Bacteria
keywords: Antibiotics Action; Bacillus; CPZEN-45; Caprazamycin B; Cell Wall; Mycolylarabinogalactan; TagO; Teichoic Acid; Tuberculosis; WecA