Antimicrobial agents targeting complex III of mitochondrial respiratory chain : characterization of new inhibitors and study of the resistance development
type: Dataset
contact point: Organization
  fn: CCSD
keyword: inhibitors
keyword: sdvsalife-sciences-q-bioagricultural-sciences
keyword: mitochondria
keyword: theses
keyword: mitochondrie
keyword: resistance
keyword: cytochrome-b
keyword: complexe-bc1
keyword: infoeu-reposemanticsdoctoralthesis
keyword: bc1-complex
keyword: inhibiteurs
landing page: https://theses.hal.science/tel-00840029
description: Inhibitors of the mitochondrial respiratory chain bc1 complex are currently used against human and plant pathogens. These drugs bind to Qo and Qi pockets of the mitochondrially-encoded cytochrome b. Comparison of the cytochrome b sequences shows that the Qo and Qi sites are well conserved between organisms. However, there are variations that could explain the differential sensitivity to respiratory inhibitors. In order to investigate the determinants of resistance / sensitivity to the antimalarial compounds, atovaquone and RCQO6, we used S.cerevisiae as a model. We showed that residue 275 plays a central role in the sensitivity to these drugs. We are now using a similar approach to identify the determinants of sensitivity towards two drugs targeting the oomycete Qi site. Unfortunately, cases of acquired resistance to these antimicrobial agents have been reported. They are caused by mutations in the cytochrome b. Thus, new molecules are required to bypass resistance. During my PhD, we developed a test to screen chemical libraries and identify inhibitors of the respiratory function. We identified a novel inhibitor of bc1 complex: D12. We determined the binding mode of D12 as well as of HDQ, a compound capable of inhibiting the proliferation of Plasmodium. To do this, we used a collection of mutants with alterations of the catalytic pockets. We showed that HDQ targets the Qi site. This finding suggests that HDQ could be used with an inhibitor of the Qo site to limit the emergence of resistance mutations. D12 is an inhibitor of Qo site and fully active against the enzyme harbouring the fungicide resistance mutation G143A. This mutation has been reported in many plant pathogenic fungi but has not evolved in fungi that harbour an intron immediately after the codon for G143. Using yeast, we showed that the mutation hinders the splicing of this intron by altering the exon / intron structure needed for efficient intron excision. We also identified by-pass mechanisms that res…
identifier: NNT: 2012PA112180
issued: 2026-05-10T12:34:06.433493
language: fr
modified: 2026-05-10T12:34:06.433498

Antimicrobial agents targeting complex III of mitochondrial respiratory chain : characterization of new inhibitors and study of the resistance development
type: Distribution
access URL: https://theses.hal.science/tel-00840029
format: HTML
issued: 2026-05-10T12:34:06.438530
modified: 2026-05-10T12:34:06.421124

test_moissonnage_selune
type: Agent