Implication de deux protéines de mycobactérium tuberculosis, InhA et MabA, dans un système d'élongation d'acides gras, cible de l'antituberculeux isoniazide

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Implication de deux protéines de mycobactérium tuberculosis, InhA et MabA, dans un système d'élongation d'acides gras, cible de l'antituberculeux isoniazide

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Unraveling the structure of the Mycobacterial Envelope

International audienc

Mycolic Acids: From Chemistry to Biology

International audienc

Caractérisation enzymatique de la protéine FadD32 de M.tuberculosis, impliquée dans la biosynthèse des acides mycoliques et cible potentielle d'antituberculeux, ainsi que d'autres enzymes paralogues

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Telacebec Interferes with Virulence Lipid Biosynthesis Protein Expression and Sensitizes to Other Antibiotics

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 bc1 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.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Delineation of the roles of FadD22, FadD26 and FadD29 in the biosynthesis of phthiocerol dimycocerosates and related compounds in Mycobacterium tuberculosis

International audiencePhthiocerol and phthiodiolone dimycocerosates (DIMs) and phenolic glycolipids (PGLs) are complex lipids located at the cell surface of Mycobacterium tuberculosis that play a key role in the pathogenicity of tuberculosis. Most of the genes involved in the biosynthesis of these compounds are clustered on a region of the M. tuberculosis chromosome, the so-called DIM + PGL locus. Among these genes, four ORFs encode FadD proteins, which activate and transfer biosynthetic intermediates onto various polyketide synthases that catalyze the formation of these lipids. In this study, we investigated the roles of FadD22, FadD26 and FadD29 in the biosynthesis of DIMs and related compounds. Biochemical characterization of the lipids produced by a spontaneous Mycobacterium bovis BCG mutant harboring a large deletion within fadD26 revealed that FadD26 is required for the production of DIMs but not of PGLs. Additionally, using allelic exchange recombination, we generated an unmarked M. tuberculosis mutant containing a deletion within fadD29. Biochemical analyses of this strain revealed that, like fadD22, this gene encodes a protein that is specifically involved in the biosynthesis of PGLs, indicating that both FadD22 and FadD29 are responsible for one particular reaction in the PGL biosynthetic pathway. These findings were also supported by in vitro enzymatic studies showing that these enzymes have different properties, FadD22 displaying a p-hydroxybenzoyl-AMP ligase activity, and FadD29 a fatty acyl-AMP ligase activity. Altogether, these data allowed us to precisely define the functions fulfilled by the various FadD proteins encoded by the DIM + PGL cluster

Apricot genetic resource management. New prospects offered by phylo-geographic and association genetic approaches. Application in the mediterranean basin germplasm

International audienceApricot (Prunus armeniaca L.) was introduced from China to the Mediterranean region through at least two majn routes and a large number of cultivars are here developed in the different countries. In order to characterize the actual Mediterranean genetic variability, 251 apricot accessions from France, Spain, Tunisia, and Turkey were investigated with a common set of markers. Twenty five SSR loci, covering the whole Prunus genome were chosen according to their expected polymorphism. Our results confirmed that SSR markers are efticient tools for fingerprinting cultivars and for determining the genetic structure of apricot Mediterranean populations as well. On the base of a Bayesian analysis four main phylogeograpbical groups have been identified: Tunisian, Enropean (Mediterranean & continental), Turkish and a diversification group joining accessions from central Asia to Europe

The protein kinase PknB negatively regulates biosynthesis and trafficking of mycolic acids in mycobacteria

International audienc