Analysis of the drug target of the anti-tuberculosis compound OCT313: phosphotransacetylase is a potential drug target for anti-mycobacterial agents

mSphere

卷:10

Research Article

Takemasa Takii^1,2,3  Tomohiro Hasegawa²  Saotomo Itoh^2,4  Shinji Maeda⁵  Takayuki Wada^6,7  Yasuhiro Horita⁸  Akihito Nishiyama⁹  Sohkichi Matsumoto^9,10,11,12  Naoya Ohara¹³  Aoi Kimishima¹⁴  Yukihiro Asami¹⁴  Shigeaki Hida²  Kikuo Onozaki² 

[1] Department of Clinical Pharmaceutics, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Aichi, Japan

[2] Department of Bacteriology, Niigata University School of Medicine, Niigata, Japan

[3] Department of Oral Microbiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

[4] Department of Hygienic Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan

[5] Graduate School of Pharmaceutical Sciences, Hokkaido University of Sciences, Sapporo, Hokkaido, Japan

[6] Department of Mycobacterium Reference and Research, the Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Kiyose, Tokyo, Japan

[7] Division of Research Aids, Hokkaido University Institute for Vaccine Research & Development, Sapporo, Hokkaido, Japan

[8] Laboratory of Tuberculosis, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia

[9] Department of Bacteriology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan

[10] Osaka International Research Center for Infectious Diseases, Osaka Metropolitan University, Osaka, Osaka, Japan

[11] Laboratory of Hygienic Chemistry, School of Pharmacy, Aichi Gakuin University, Nagoya, Aichi, Japan

[12] Laboratory of Applied Microbial Chemistry, Ōmura Satoshi Memorial Institute, Kitasato University, Minato-ku, Tokyo, Japan

[13] Ōmura Satoshi Memorial Institute, Kitasato University, Minato-ku, Tokyo, Japan

[14] Department of Microbiology, Graduate School of Human Life and Ecology, Osaka Metropolitan University, Osaka, Japan

关键词: phosphotransacetylase;    acetyl coenzyme A;    dithiocarbamate;    N;    anti-mycobacterial agents;    latent tuberculosis infection;   

DOI  :  10.1128/msphere.00463-25

 received in 2025-07-10, accepted in 2025-11-15,  发布年份 2025

来源: American Society for Microbiology

【 摘 要 】

ABSTRACTTuberculosis (TB) is one of the most common infectious diseases caused by bacteria worldwide. The increasing prevalence of multidrug-resistant TB (MDR-TB) and latent TB infection (LTBI) has intensified the global TB burden. Therefore, the development of new drugs for MDR-TB and LTBI is urgently required. We have reported that the derivative of dithiocarbamate sugar derivative, 2-acetamido-2-deoxy-β-D-glucopyranosyl N,N-dimethyldithiocarbamate (OCT313), exhibits anti-mycobacterial activity against MDR-MTB. Here, we identified the target of OCT313. In experimentally generated OCT313-resistant bacteria, adenine at position 1,092 in the metabolic enzyme phosphotransacetylase (PTA) gene was replaced with cytosine. This mutation is a nonsynonymous mutation that converts methionine to leucine at position 365 in the PTA protein. OCT313 inhibited the enzymatic activity of recombinant wild-type PTA, but not of the mutant PTA (M365L). PTA is an enzyme that produces acetyl-coenzyme A (acetyl-CoA) from acetyl phosphate and CoA and is involved in metabolic pathways; therefore, it was expected to also be active against dormant Mycobacterium tuberculosis bacilli. OCT313 exhibits antibacterial activity in the Wayne model of dormancy using Mycobacterium bovis BCG, and overexpression of PTA in OCT313-resistant bacilli restored sensitivity to OCT313. Collectively, the target of OCT313 is PTA, and OCT313 is a promising antimicrobial candidate for MDR-TB and LTBI.IMPORTANCEThrough this study, we propose a new target for the development of medicines to treat multidrug-resistant tuberculosis and latent tuberculosis infection. The target enzyme phosphotransacetylase (PTA) is a key enzyme that functions in major metabolic pathways, and the homologous structures of PTA enzymes vary greatly among bacterial species. Since the treatment of mycobacterial disease is long term, the development of antibiotics targeting PTA is useful for species-specific therapy.

【 授权许可】

CC BY   
Copyright © 2025 Takii et al.

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