Targeting the Heart of Mycobacterium: Advances in Anti-Tubercular Agents Disrupting Cell Wall Biosynthesis
<i>Mycobacterium tuberculosis</i> infections continue to pose a significant global health challenge, particularly due to the rise of multidrug-resistant strains, random mycobacterial mutations, and the complications associated with short-term antibiotic regimens. Currently, five approved...
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MDPI AG
2025-01-01
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| author | Ahmad Diab Henry Dickerson Othman Al Musaimi |
| author_facet | Ahmad Diab Henry Dickerson Othman Al Musaimi |
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| description | <i>Mycobacterium tuberculosis</i> infections continue to pose a significant global health challenge, particularly due to the rise of multidrug-resistant strains, random mycobacterial mutations, and the complications associated with short-term antibiotic regimens. Currently, five approved drugs target cell wall biosynthesis in <i>Mycobacterium tuberculosis</i>. This review provides a comprehensive analysis of these drugs and their molecular mechanisms. Isoniazid, thioamides, and delamanid primarily disrupt mycolic acid synthesis, with recent evidence indicating that delamanid also inhibits decaprenylphosphoryl-β-D-ribose-2-epimerase, thereby impairing arabinogalactan biosynthesis. Cycloserine remains the sole approved drug that inhibits peptidoglycan synthesis, the foundational layer of the mycobacterial cell wall. Furthermore, ethambutol interferes with arabinogalactan synthesis by targeting arabinosyl transferase enzymes, particularly embB- and embC-encoded variants. Beyond these, six promising molecules currently in Phase II clinical trials are designed to target arabinan synthesis pathways, sutezolid, TBA 7371, OPC-167832, SQ109, and both benzothiazinone derivatives BTZ043 and PBTZ169, highlighting advancements in the development of cell wall-targeting therapies. |
| format | Article |
| id | doaj-art-217b56e80a2348acbdfa63bed42774d7 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-217b56e80a2348acbdfa63bed42774d72025-01-24T13:45:16ZengMDPI AGPharmaceuticals1424-82472025-01-011817010.3390/ph18010070Targeting the Heart of Mycobacterium: Advances in Anti-Tubercular Agents Disrupting Cell Wall BiosynthesisAhmad Diab0Henry Dickerson1Othman Al Musaimi2School of Pharmacy, Newcastle University, Newcastle upon Tyne NE1 7RU, UKSchool of Pharmacy, Newcastle University, Newcastle upon Tyne NE1 7RU, UKSchool of Pharmacy, Newcastle University, Newcastle upon Tyne NE1 7RU, UK<i>Mycobacterium tuberculosis</i> infections continue to pose a significant global health challenge, particularly due to the rise of multidrug-resistant strains, random mycobacterial mutations, and the complications associated with short-term antibiotic regimens. Currently, five approved drugs target cell wall biosynthesis in <i>Mycobacterium tuberculosis</i>. This review provides a comprehensive analysis of these drugs and their molecular mechanisms. Isoniazid, thioamides, and delamanid primarily disrupt mycolic acid synthesis, with recent evidence indicating that delamanid also inhibits decaprenylphosphoryl-β-D-ribose-2-epimerase, thereby impairing arabinogalactan biosynthesis. Cycloserine remains the sole approved drug that inhibits peptidoglycan synthesis, the foundational layer of the mycobacterial cell wall. Furthermore, ethambutol interferes with arabinogalactan synthesis by targeting arabinosyl transferase enzymes, particularly embB- and embC-encoded variants. Beyond these, six promising molecules currently in Phase II clinical trials are designed to target arabinan synthesis pathways, sutezolid, TBA 7371, OPC-167832, SQ109, and both benzothiazinone derivatives BTZ043 and PBTZ169, highlighting advancements in the development of cell wall-targeting therapies.https://www.mdpi.com/1424-8247/18/1/70mycobacterium tuberculosisisoniaziddelamanidmycolic acidcycloserinepeptidoglycan |
| spellingShingle | Ahmad Diab Henry Dickerson Othman Al Musaimi Targeting the Heart of Mycobacterium: Advances in Anti-Tubercular Agents Disrupting Cell Wall Biosynthesis Pharmaceuticals mycobacterium tuberculosis isoniazid delamanid mycolic acid cycloserine peptidoglycan |
| title | Targeting the Heart of Mycobacterium: Advances in Anti-Tubercular Agents Disrupting Cell Wall Biosynthesis |
| title_full | Targeting the Heart of Mycobacterium: Advances in Anti-Tubercular Agents Disrupting Cell Wall Biosynthesis |
| title_fullStr | Targeting the Heart of Mycobacterium: Advances in Anti-Tubercular Agents Disrupting Cell Wall Biosynthesis |
| title_full_unstemmed | Targeting the Heart of Mycobacterium: Advances in Anti-Tubercular Agents Disrupting Cell Wall Biosynthesis |
| title_short | Targeting the Heart of Mycobacterium: Advances in Anti-Tubercular Agents Disrupting Cell Wall Biosynthesis |
| title_sort | targeting the heart of mycobacterium advances in anti tubercular agents disrupting cell wall biosynthesis |
| topic | mycobacterium tuberculosis isoniazid delamanid mycolic acid cycloserine peptidoglycan |
| url | https://www.mdpi.com/1424-8247/18/1/70 |
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