Telacebec Interferes with Virulence Lipid Biosynthesis Protein Expression and Sensitizes to Other Antibiotics
Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (Mtb), remains a public health issue, particularly due to multi-drug-resistant Mtb. The bacillus is wrapped in a waxy envelope containing lipids acting as essential virulence factors, accounting for the natural antibiotic res...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-09-01
|
| Series: | Microorganisms |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-2607/11/10/2469 |
| _version_ | 1797572858090618880 |
|---|---|
| author | Zhiyu Zhou Ruddy Wattiez Patricia Constant Hedia Marrakchi Karine Soetaert Vanessa Mathys Véronique Fontaine Sheng Zeng |
| author_facet | Zhiyu Zhou Ruddy Wattiez Patricia Constant Hedia Marrakchi Karine Soetaert Vanessa Mathys Véronique Fontaine Sheng Zeng |
| author_sort | Zhiyu Zhou |
| collection | DOAJ |
| description | Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (Mtb), remains a public health issue, particularly due to multi-drug-resistant Mtb. The bacillus is wrapped in a waxy envelope containing lipids acting as essential virulence factors, accounting for the natural antibiotic resistance of mycobacteria. Telacebec (previously known as Q203) is a promising new anti-TB agent inhibiting the cytochrome <i>bc</i><sub>1</sub> complex of a mycobacterial electron transport chain (ETC). Here, we show that the telacebec-challenged <i>M. bovis</i> BCG exhibited a reduced expression of proteins involved in the synthesis of phthiocerol dimycocerosates (PDIMs)/phenolic glycolipids (PGLs), lipid virulence factors associated with cell envelope impermeability. Consistently, telacebec, at concentrations lower than its MIC, downregulated the transcription of a PDIM/PGL-synthesizing operon, suggesting a metabolic vulnerability triggered by the drug. The drug was able to synergize on BCG with rifampicin or vancomycin, the latter being a drug exerting a marginal effect on PDIM-bearing bacilli. Telacebec at a concentration higher than its MIC had no detectable effect on cell wall PDIMs, as shown by TLC analysis, a finding potentially explained by the retaining of previously synthesized PDIMs due to the inhibition of growth. The study extends the potential of telacebec, demonstrating an effect on mycobacterial virulence lipids, allowing for the development of new anti-TB strategies. |
| first_indexed | 2024-03-10T21:01:44Z |
| format | Article |
| id | doaj.art-884c49f0ab4d4299b93d4b551b4bfbf8 |
| institution | Directory Open Access Journal |
| issn | 2076-2607 |
| language | English |
| last_indexed | 2024-03-10T21:01:44Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Microorganisms |
| spelling | doaj.art-884c49f0ab4d4299b93d4b551b4bfbf82023-11-19T17:27:13ZengMDPI AGMicroorganisms2076-26072023-09-011110246910.3390/microorganisms11102469Telacebec Interferes with Virulence Lipid Biosynthesis Protein Expression and Sensitizes to Other AntibioticsZhiyu Zhou0Ruddy Wattiez1Patricia Constant2Hedia Marrakchi3Karine Soetaert4Vanessa Mathys5Véronique Fontaine6Sheng Zeng7Microbiology, Bioorganic & Macromolecular Chemistry Research Unit, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, BelgiumLaboratory of Proteomics and Microbiology, Research Institute for Biosciences, University of Mons, Place du Parc 23, 7000 Mons, BelgiumInstitut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III—Paul Sabatier (UT3), 31077 Toulouse, FranceInstitut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III—Paul Sabatier (UT3), 31077 Toulouse, FranceNational Reference Laboratory “Mycobacterium”, Sciensano, 1180 Uccle, BelgiumNational Reference Laboratory “Mycobacterium”, Sciensano, 1180 Uccle, BelgiumMicrobiology, Bioorganic & Macromolecular Chemistry Research Unit, Faculté de Pharmacie, Université libre de Bruxelles (ULB), Boulevard du Triomphe, 1050 Brussels, BelgiumSchool of Nursing and Health, Nanfang College Guangzhou, Guangzhou 510970, ChinaTuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (Mtb), remains a public health issue, particularly due to multi-drug-resistant Mtb. The bacillus is wrapped in a waxy envelope containing lipids acting as essential virulence factors, accounting for the natural antibiotic resistance of mycobacteria. Telacebec (previously known as Q203) is a promising new anti-TB agent inhibiting the cytochrome <i>bc</i><sub>1</sub> complex of a mycobacterial electron transport chain (ETC). Here, we show that the telacebec-challenged <i>M. bovis</i> BCG exhibited a reduced expression of proteins involved in the synthesis of phthiocerol dimycocerosates (PDIMs)/phenolic glycolipids (PGLs), lipid virulence factors associated with cell envelope impermeability. Consistently, telacebec, at concentrations lower than its MIC, downregulated the transcription of a PDIM/PGL-synthesizing operon, suggesting a metabolic vulnerability triggered by the drug. The drug was able to synergize on BCG with rifampicin or vancomycin, the latter being a drug exerting a marginal effect on PDIM-bearing bacilli. Telacebec at a concentration higher than its MIC had no detectable effect on cell wall PDIMs, as shown by TLC analysis, a finding potentially explained by the retaining of previously synthesized PDIMs due to the inhibition of growth. The study extends the potential of telacebec, demonstrating an effect on mycobacterial virulence lipids, allowing for the development of new anti-TB strategies.https://www.mdpi.com/2076-2607/11/10/2469<i>Mycobacterium bovis</i> BCGtelacebecvancomycinPDIMsvirulence lipids |
| spellingShingle | Zhiyu Zhou Ruddy Wattiez Patricia Constant Hedia Marrakchi Karine Soetaert Vanessa Mathys Véronique Fontaine Sheng Zeng Telacebec Interferes with Virulence Lipid Biosynthesis Protein Expression and Sensitizes to Other Antibiotics Microorganisms <i>Mycobacterium bovis</i> BCG telacebec vancomycin PDIMs virulence lipids |
| title | Telacebec Interferes with Virulence Lipid Biosynthesis Protein Expression and Sensitizes to Other Antibiotics |
| title_full | Telacebec Interferes with Virulence Lipid Biosynthesis Protein Expression and Sensitizes to Other Antibiotics |
| title_fullStr | Telacebec Interferes with Virulence Lipid Biosynthesis Protein Expression and Sensitizes to Other Antibiotics |
| title_full_unstemmed | Telacebec Interferes with Virulence Lipid Biosynthesis Protein Expression and Sensitizes to Other Antibiotics |
| title_short | Telacebec Interferes with Virulence Lipid Biosynthesis Protein Expression and Sensitizes to Other Antibiotics |
| title_sort | telacebec interferes with virulence lipid biosynthesis protein expression and sensitizes to other antibiotics |
| topic | <i>Mycobacterium bovis</i> BCG telacebec vancomycin PDIMs virulence lipids |
| url | https://www.mdpi.com/2076-2607/11/10/2469 |
| work_keys_str_mv | AT zhiyuzhou telacebecinterfereswithvirulencelipidbiosynthesisproteinexpressionandsensitizestootherantibiotics AT ruddywattiez telacebecinterfereswithvirulencelipidbiosynthesisproteinexpressionandsensitizestootherantibiotics AT patriciaconstant telacebecinterfereswithvirulencelipidbiosynthesisproteinexpressionandsensitizestootherantibiotics AT hediamarrakchi telacebecinterfereswithvirulencelipidbiosynthesisproteinexpressionandsensitizestootherantibiotics AT karinesoetaert telacebecinterfereswithvirulencelipidbiosynthesisproteinexpressionandsensitizestootherantibiotics AT vanessamathys telacebecinterfereswithvirulencelipidbiosynthesisproteinexpressionandsensitizestootherantibiotics AT veroniquefontaine telacebecinterfereswithvirulencelipidbiosynthesisproteinexpressionandsensitizestootherantibiotics AT shengzeng telacebecinterfereswithvirulencelipidbiosynthesisproteinexpressionandsensitizestootherantibiotics |