Arenicolide Family Macrolides Provide a New Therapeutic Lead Combating Multidrug‐Resistant Tuberculosis
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.
Authors
- Dong‐Chan Oh (ORCID: https://orcid.org/0000-0001-6405-5535)
- Joonseok Oh (ORCID: https://orcid.org/0000-0002-7616-1949)
- Jichan Jang (ORCID: https://orcid.org/0000-0002-4598-5371)
- Minjeong Woo
- Thanh‐Hau Huynh (ORCID: https://orcid.org/0009-0002-5789-6621)
- Sung‐Gwon Lee (ORCID: https://orcid.org/0000-0002-0928-9950)
- Eunkyung Shin (ORCID: https://orcid.org/0009-0001-1525-2396)
- Chungoo Park (ORCID: https://orcid.org/0000-0002-9545-6654)
- Sung-Yoon Jo (ORCID: https://orcid.org/0000-0002-0163-5273)
- Yeo Joon Yoon (ORCID: https://orcid.org/0000-0002-3637-3103)
- Eun‐Kyeong Jo (ORCID: https://orcid.org/0000-0001-7191-0587)
- Bo Eun Heo
- Sungweon Ryoo (ORCID: https://orcid.org/0000-0002-5085-0068)
- Sunghoon Hwang (ORCID: https://orcid.org/0000-0001-9564-7293)
- Thanh Quang Nguyen (ORCID: https://orcid.org/0000-0003-3524-7700)
- Myungin Bæk (ORCID: https://orcid.org/0000-0001-8906-901X)
- Dae‐Duk Kim (ORCID: https://orcid.org/0000-0003-0093-3874)
- Seungwha Paik (ORCID: https://orcid.org/0000-0002-5015-1494)
- Da‐Gyum Lee (ORCID: https://orcid.org/0000-0003-3787-6455)
- Eunji Kim (ORCID: https://orcid.org/0000-0001-5484-803X)
- Kyung Tae Kim (ORCID: https://orcid.org/0000-0002-3032-8109)
- Young Jae Kim (ORCID: https://orcid.org/0000-0003-0035-037X)
- Eun Jin Park (ORCID: https://orcid.org/0000-0002-5478-2074)
- Connor Wood
Institutions
- Chonnam National University (KR)
- National Institutes of Health (US)
- Institut Pasteur Korea (KR)
- Seoul National University (KR)
- Gyeongsang National University (KR)
- Chungnam National University (KR)
- New Generation University College (ET)
- Yale University (US)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Gachon University Gil Hospital (KR)
- National University (SD)
- National University College (PR)
- Masan National Tuberculosis Hospital (KR)
Publication Details
- Journal
- Angewandte Chemie International Edition
- Published
- 2024-10-14
- DOI
- https://doi.org/10.1002/anie.202412994
- Citations
- 5
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 1.95
Funders
- National Research Foundation
- Korea Health Industry Development Institute
- National Research Foundation of Korea
- Ministry of Science and ICT, South Korea