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journal article·2024-10Open access

CRISPR Screening and Comparative LC‐MS Analysis Identify Genes Mediating Efficacy of Delamanid and Pretomanid against Mycobacterium tuberculosis

Mei‐Yi Yan, Haifeng Li, Yun‐Mo Qu, Si‐Shang Li, Dandan Zheng, Xiao‐Peng Guo, Zhaojun Wu, Jie Lu, Yu Pang, Weimin Li, Jian Yang, Lingjun Zhan, Yi‐Cheng Sun

Advanced Science· Volume 11· Issue 39
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Source abstract

Abstract

Abstract Tuberculosis (TB), the leading cause of death from bacterial infections worldwide, results from infection with Mycobacterium tuberculosis (Mtb). The antitubercular agents delamanid (DLM) and pretomanid (PMD) are nitroimidazole prodrugs that require activation by an enzyme intrinsic to Mtb; however, the mechanism(s) of action and the associated metabolic pathways are largely unclear. Profiling of the chemical‐genetic interactions of PMD and DLM in Mtb using combined CRISPR screening reveals that the mutation of rv2073c increases susceptibility of Mtb to these nitroimidazole drugs both in vitro and in infected mice, whereas mutation of rv0078 increases drug resistance. Further assays show that Rv2073c might confer intrinsic resistance to DLM/PMD by interfering with inhibition of the drug target, decaprenylphophoryl‐2‐keto‐b‐D‐erythro‐pentose reductase (DprE2), by active nicotinamide adenine dinucleotide (NAD) adducts. Characterization of the metabolic pathways of DLM/PMD in Mtb using a combination of chemical genetics and comparative liquid chromatography‐mass spectrometry (LC‐MS) analysis of DLM/PMD metabolites reveals that Rv0077c, which is negatively regulated by Rv0078, mediates drug resistance by metabolizing activated DLM/PMD. These results might guide development of new nitroimidazole prodrugs and new regimens for TB treatment.
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Research context

OpenAlex topics: Tuberculosis Research and Epidemiology · Mycobacterium research and diagnosis · Cancer therapeutics and mechanisms

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

NHC Key Laboratory of Systems Biology of Pathogens, State Key Laboratory of Respiratory Health and Multimorbidity National Institute of Pathogen Biology and Center for Tuberculosis Research Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100730 P. R. China

NHC Key Laboratory of Human Disease Comparative Medicine, and National Center of Technology Innovation for Animal Model Institute of Laboratory Animal Sciences Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100021 P. R. China

Beijing Tuberculosis and Thoracic Tumor Research Institute Beijing Chest Hospital Capital Medical University Beijing P. R. China

Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery Beijing Pediatric Research Institute Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing P. R. China

Department of Bacteriology and Immunology Beijing Chest Hospital Capital Medical University Beijing P. R. China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China

References (44)

Show source-provided references
1. W. H. Organisation Global Tuberculosis Report 2023 https://www.who.int/publications/i/item/9789240083851(accessed: November2023).
2. W. H. Organization WHO consolidated guidelines on drug‐resistant tuberculosis treatment https://www.who.int/publications/i/item/9789241550529(accessed: March2019).
3. 10.3390/antibiotics303031710.3390/antibiotics3030317 ↗
4. 10.1016/j.tim.2016.03.00710.1016/j.tim.2016.03.007 ↗
5. 10.1111/febs.1558210.1111/febs.15582 ↗
6. 10.3389/fcimb.2022.99728310.3389/fcimb.2022.997283 ↗
7. 10.1038/s41570-023-00472-310.1038/s41570-023-00472-3 ↗
8. 10.1038/3501610310.1038/35016103 ↗
9. 10.1371/journal.pmed.003046610.1371/journal.pmed.0030466 ↗
10. 10.1016/j.tube.2018.04.00810.1016/j.tube.2018.04.008 ↗
11. 10.1056/NEJMoa190181410.1056/NEJMoa1901814 ↗
12. 10.1093/jac/dkab50510.1093/jac/dkab505 ↗
13. 10.1126/science.116457110.1126/science.1164571 ↗
14. 10.4161/cib.2.3.792610.4161/cib.2.3.7926 ↗
15. 10.1016/j.tube.2019.05.00210.1016/j.tube.2019.05.002 ↗
16. 10.2147/DDDT.S28163910.2147/DDDT.S281639 ↗
17. 10.1038/s41467-023-39300-z10.1038/s41467-023-39300-z ↗
18. 10.1128/JB.187.23.8020-8025.200510.1128/JB.187.23.8020-8025.2005 ↗
19. 10.1111/mmi.1254610.1111/mmi.12546 ↗
20. 10.1128/AAC.01755-1910.1128/AAC.01755-19 ↗
21. Zeng S. · Antimicrob. Agents Chemother. · 2021 · 6510.1128/AAC.00956-21 ↗
22. 10.1016/j.febslet.2011.07.03510.1016/j.febslet.2011.07.035 ↗
23. 10.1074/jbc.M40679620010.1074/jbc.M406796200 ↗
24. 10.1038/s41467-022-29832-110.1038/s41467-022-29832-1 ↗
25. Liu Y. · Antimicrob. Agents Chemother. · 2022 · 6610.1128/aac.00531-22 ↗
26. 10.1073/pnas.050839210310.1073/pnas.0508392103 ↗
27. 10.1128/AAC.00308-1510.1128/AAC.00308-15 ↗
28. 10.1016/j.tube.2017.12.00610.1016/j.tube.2017.12.006 ↗
29. 10.1128/AAC.01948-2010.1128/AAC.01948-20 ↗
30. 10.1126/sciadv.add590710.1126/sciadv.add5907 ↗
31. Xu W. · Antimicrob. Agents Chemother. · 2017 · 6110.1128/AAC.01334-17 ↗
32. 10.1038/s41564-022-01130-y10.1038/s41564-022-01130-y ↗
33. 10.1084/jem.2003020510.1084/jem.20030205 ↗
34. 10.1021/acsomega.1c0592310.1021/acsomega.1c05923 ↗
35. 10.1021/ar500250710.1021/ar5002507 ↗
36. 10.1128/mBio.00989-1810.1128/mBio.00989-18 ↗
37. 10.1099/mic.0.2008/016378-010.1099/mic.0.2008/016378-0 ↗
38. 10.1038/s42003-020-0941-110.1038/s42003-020-0941-1 ↗
39. 10.1002/9780471729259.mc10a02s610.1002/9780471729259.mc10a02s6 ↗
40. 10.1186/s13059-014-0554-410.1186/s13059-014-0554-4 ↗
41. 10.1194/jlr.D700041-JLR20010.1194/jlr.D700041-JLR200 ↗
42. 10.1016/j.chembiol.2011.10.01310.1016/j.chembiol.2011.10.013 ↗
43. 10.1126/science.abq278710.1126/science.abq2787 ↗
44. 10.1038/s41559-018-0680-610.1038/s41559-018-0680-6 ↗