Arenicolide Family Macrolides Provide a New Therapeutic Lead Combating Multidrug‐Resistant Tuberculosis
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.
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)
- 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
- Song-Jin Jo
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
- Published
- 2024-10-14
- DOI
- https://doi.org/10.1002/ange.202412994
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Korea Health Industry Development Institute
- National Research Foundation of Korea