2. Academic Validation
  3. Identification of a Potential Antimycobacterial Drug Sensitizer Targeting a Flavin-Independent Methylenetetrahydrofolate Reductase

Identification of a Potential Antimycobacterial Drug Sensitizer Targeting a Flavin-Independent Methylenetetrahydrofolate Reductase

  • ACS Omega. 2023 Oct 4;8(41):38406-38417. doi: 10.1021/acsomega.3c05021.
Jiacong Li 1 2 3,  Yong Nian 2,  Jian Liu 2,  Mingxia Yang 1 4,  Yuanling Jin 1,  Xiaoman Kang 5,  Haodong Xu 2,  Zhuo Shang 6,  Wei Lin 3 2 1 7
Affiliations

Affiliations

  • 1 Department of Pathogen Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, 210023 Nanjing, China.
  • 2 School of Pharmacy, Nanjing University of Chinese Medicine, 210023 Nanjing, China.
  • 3 State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 200237 Shanghai, China.
  • 4 The Center for Microbes, Development and Health, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 200031 Shanghai, China.
  • 5 CAS Key Laboratory of Synthetic Biology, Centre of Excellence for Molecular Plant Sciences, Chinese Academy of Sciences, 200032 Shanghai, China.
  • 6 School of Pharmaceutical Sciences, Shandong University, 250100 Jinan, China.
  • 7 Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, 210023 Nanjing, China.
PMID: 37867661 DOI: 10.1021/acsomega.3c05021
Abstract

The increasing Antibiotic resistance of Mycobacterium tuberculosis and pathogenic nontuberculosis mycobacteria highlights the urgent need for new prevention and treatment strategies. Recently, the cocrystal structure of a Mycobacterium smegmatis flavin-independent 5,10-methylenetetrahydrofolate reductase (MsmMTHFR) that binds with a reduced nicotinamide adenine dinucleotide (NADH) has been well-determined, providing a structural basis for the screening of antimycobacterial leads targeting MsmMTHFR, a new Enzyme involved in tetrahydrofolic acid (THF) biosynthesis. In this study, we identified compound AB131 as a promising candidate that fits well into the NADH binding pocket of MsmMTHFR through virtual screening. We discovered that AB131 and its derivatives (13 and 14) can sensitize the antimycobacterial activity of the antitubercular drug para-aminosalicyclic acid (PAS) by 2-5-fold against various species of mycobacteria. Although the compounds themselves do not exhibit any antimycobacterial activity, the high binding affinity of AB131 with MsmMTHFR or Rv2172c was evaluated by microscale thermophoresis analysis. Additionally, we predicted and validated the key residues (V115, V117, P118, and R163) of MsmMTHFR that are involved in the interaction with AB131 by using molecular docking and mutagenesis analysis. These findings offer a potential exploitable target for developing potent and specific antimycobacterial drug sensitizers.

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