Telacebec Interferes with Virulence Lipid Biosynthesis Protein Expression and Sensitizes to Other Antibiotics.
Zhiyu ZhouRuddy WattiezPatricia ConstantHedia MarrakchiKarine SoetaertVanessa MathysVéronique FontaineSheng ZengPublished in: Microorganisms (2023)
Tuberculosis (TB), caused by Mycobacterium tuberculosis (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 bc 1 complex of a mycobacterial electron transport chain (ETC). Here, we show that the telacebec-challenged M. bovis 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.
Keyphrases
- mycobacterium tuberculosis
- pulmonary tuberculosis
- drug resistant
- escherichia coli
- pseudomonas aeruginosa
- staphylococcus aureus
- public health
- cell wall
- antimicrobial resistance
- biofilm formation
- multidrug resistant
- acinetobacter baumannii
- fatty acid
- signaling pathway
- single cell
- emergency department
- risk assessment
- mesenchymal stem cells
- global health
- binding protein
- human immunodeficiency virus
- electronic health record