황성훈 (서울대학교, 현 Princeton University) | 한빛사논문 > 한빛사

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조회698

황성훈Sunghoon Hwang

서울대학교, 현 Princeton University

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Angew. Chem.-Int. Edit., Oct 14 2024, | https://doi.org/10.1002/anie.202412994 Arenicolide Family Macrolides Provide a New Therapeutic Lead Combating Multidrug-resistant Tuberculosis

Sunghoon Hwang ¹⁺, Bo Eun Heo²⁺, Thanh Quang Nguyen ²⁺, Young Jae Kim ³⁺, Sung-Gwon Lee ⁴, Thanh-Hau Huynh ¹, Eunji Kim ¹, Shin-Il Jo ⁵, Min-Jun Baek ¹, Eun-Kyung Shin¹, Joonseok Oh ⁶, Chungoo Park ⁷, Yeo Joon Yoon ¹, Eun-Jin Park ³, Kyung Tae Kim ³, Sungweon Ryoo ⁸, Da-Gyum Lee ⁸, Connor Wood ⁹, Minjeong Woo ⁹, Dae-Duk Kim ¹, Seungwha Paik ^3*, Eun-Kyeong Jo ^3*, Jichan Jang ^2*, Dong-Chan Oh ^10*

¹Seoul National University, College of Pharmacy, KOREA, REPUBLIC OF.

²Gyeongsang National University, Division of Life Science, KOREA, REPUBLIC OF.

³Chungnam National University College of Medicine and Graduate School of Medicine, Microbiology, KOREA, REPUBLIC OF.

⁴National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, UNITED STATES OF AMERICA.

⁵Institute of Korean Insect Life, Institute of Korean Insect Life, KOREA, REPUBLIC OF.

⁶Yale University, Chemistry, UNITED STATES OF AMERICA.

⁷Chonnam National University, School of Biological Sciences and Technology, KOREA, REPUBLIC OF.

⁸Masan National Tuberculosis Hospital, Clinical Research Center, KOREA, REPUBLIC OF.

⁹Pasteur Institute of Korea, Tuberculosis Research Laboratory, KOREA, REPUBLIC OF.

¹⁰Seoul National University, College of Pharmacy, Rm 525, Bldg 20, 1 Gwanak-ro, Gwanak-gu, 08826, Seoul, KOREA, REPUBLIC OF.

⁺These authors contributed equally to this work.

^*Corresponding authors: Seungwha Paik, Eun-Kyeong Jo, Jichan Jang, Dong-Chan Oh

Abstract

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (Mtb) poses a significant threat to health globally. During searching for new chemical entities regulating MDR- and XDR-Mtb, chemical investigation of the black oil beetle gut bacterium Micromonospora sp. GR10 led to the discovery of eight new members of arenicolides along with the identification of arenicolide A (Ar-A, 1), which was a previously reported macrolide with incomplete configuration. Genomic analysis of the bacterial strain GR10 revealed their putative biosynthetic pathway. Quantum mechanics-based computation, chemical derivatizations, and bioinformatic analysis established the absolute stereochemistry of Ar-A and arenicolides D-K (Ar-D-K, 2-9) completely for the first time. Biological studies of 1-9 revealed their antimicrobial activity against MDR and XDR strains of Mtb. Ar-A had the most potent in vitro antimicrobial efficacy against MDR- and XDR-Mtb. Mechanistically, Ar-A induced ATP depletion and destabilized Mtb cell wall, thereby inhibiting growth. Notably, Ar-A exerted a significant antimicrobial effect against Mtb in macrophages, was effective in the treatment of Mtb infections, and showed a synergistic effect with amikacin (AMK) in a mouse model of MDR-Mtb lung infection. Collectively, our findings indicate Ar-A to be a promising drug lead for drug-resistant tuberculosis.

논문정보

형식Research article
게재일2024년 10월 (BRIC 등록일 2024-10-17)
연구진국내(교신)+국외 연구진
분야 의약학 > 약학

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