Antibacterial peptides, Host Defence Peptides, Cathelicidins, Bactenecins, Pro-rich peptides, LL-37, BMAP, beta-defensins, helical peptides, innate immunity, mode-of-action.

Research description

The main focus of our research is the molecular characterization of the biological activities of antimicrobial peptides (AMPs) in general and of mammalian Host Defence Peptides, in particular. Our laboratory is currently pursuing a number of questions concerning the mechanism of action of different structural classes of animal-derived AMPs.

Understanding the antibiotic properties of these molecules has taken on increased importance in recent years due to the alarming spread of antibiotic resistance among nosocomial strains of bacteria. There is consequently a pressing need to develop novel effective classes of antimicrobial drugs with mechanisms of action based on cellular targets different from those on which existing antibiotics act.

Our laboratory concentrates principally on the study of cathelicidin-derived AMPS and beta-defensins. Cathelicidins are a family of peptide precursors isolated from mammalian leukocytes. Their C-terminal sequences correspond to a number of structurally quite diverse antimicrobial peptides such as Alfa-helical peptides, Pro-rich peptides, and Cys-rich peptides, that all display a direct, potent and broad spectrum antimicrobial activity

beta-Defensins are a large family of small proteins (about 30 genes have been identified in humans so far) with a cystine stabilized antiparallel beta-sheet core. They have several putative biological roles in host defence and some display a direct, but salt sensitive, antimicrobial activity.

Members of both the defensins and cathelicidins have also been reported to have indirect antimicrobial activities, including immunomodulatory effects on innate and adaptive immune cells (acting as signal molecules in chemotaxis or activation), anti-endotoxin effects and roles in wound healing and angiogenesis. These molecules might thus lead to multi-functional anti-infective drugs.

Main research topics

• Investigation of the mechanisms of antimicrobial activity of cathelicidin-derived Pro-rich antimicrobial peptides :
  
  
  • mode of action of Pro-rich peptides, determination of their mechanisms of membrane translocation and identification of their molecular target(s)
    
    
  • selection of resistant-mutants to PR-rich AMPs and genetic analysis to identify gene(s) involved in the peptides' action
    
    
  • cell-penetrating and drug delivery features of this group of peptides

• Investigation of the mechanisms of antimicrobial activity of the cathelicidin-derived alpha-helical peptides :
  
  
  • mode of action of helical peptides, determination of their mechanisms of membrane lysis and identification of their molecular target(s)
  • structure-activity studies to improve the antimicrobial activity and target selectivity of helical peptides
  • cytotoxic and immunomodulatory effects on host cells.

• Investigation of the mechanisms of antimicrobial activity of primate beta-defensins :
  
  
  • mode of action of helical peptides, determination of their mechanisms of membrane interaction and identification of their molecular target(s)
  • structure-activity studies to disect structural determinants necessary for antimimicrobial activities
  • cytotoxic and immunomodulatory effects on host cells.

• Investigation of evolutionary mechanisms of mammalian HDPs:
  
  
  • evolution of primate beta-defensins
  • evolution of the primate cathelicidin
  • effect of evolutionary variations on antimicrobial and immunomodulatory activities

• SAR and de novo design:
  
  
  • Develoment of bioinformatic methods for analysing AMP sequences
  • Development and use of sequence templates for de novo AMP design
  • SAR studies on designed model antimicrobial peptides

• Antimicrobial activity assays :
  
  
  • In vitro activity assays against reference bacteria and multi-resistant pathogens
  • In vivo efficacy assays using mouse acute infection models