Design and development of carbapenem- and cephalosporin-based monocyclic beta-lactam derivatives to address antibiotic-insensitive penicillin-binding proteins

01 January 2022 → 31 December 2025
Research Foundation - Flanders (FWO)
Research disciplines
  • Natural sciences
    • Characterisation of biologically active (macro)molecules
    • Organic chemical synthesis
small moecule drug development Antibacterial resistance Beta-lactam antibiotics
Project description

Antibiotic-resistant ‘superbugs’ represent one of the most alarming global health issues, causing 700.000 deaths a year. The development of resistance to even last-line antibiotics seriously challenges the treatment of bacterial infections and, if antibiotic resistance continues to expand at the same pace, a catastrophic scenario, in which the burden of deaths could rise to 10 million people a year by 2050, becomes realistic. This project intends to discover new inhibitors that will interfere with the formation of the bacterial cell wall (peptidoglycan). To identify potential antibiotics, penicillin-binding proteins (PBPs) - enzymes catalyzing the last step of peptidoglycan biosynthesis - will be targeted. Drug-insensitive PBPs lower the efficiency of classical bicyclic beta-lactam antibiotics through active site distortion and represent important, though extremely demanding, drug targets. This project will elaborate on previous in house studies concerning the development of monocyclic carbapenem and cephalosporin derivatives as novel antibacterial agents. Strategies for inhibitor discovery include computational techniques, chemical synthesis of potential inhibitors and their structural, biological, antimicrobial and toxicological evaluation. The UGent team and their colleagues from Ljubljana and Liège will combine their complementary skills to achieve the ultimate goal of discovering new monocyclic beta-lactam-based antibiotics.