The introduction of antibiotics in the medical practice has drastically reduced illness and death from infectious diseases. However, bacteria have exhibited a remarkable capacity to become resistant to commonly used antibacterial compounds. In parallel to efforts aimed at better understanding the strikingly diverse mechanisms they use, it is important to design strategies which will allow to counteract them and to search for new targets, ideally essential and specific to bacterial physiology. Our approach is based on the well established facts that peptidoglycan biosynthesis and cell morphogenesis are related phenomena and that they are totally specific to bacterial cells, without even remotely equivalent processes in eukaryotic cells. By attempting to interfere with these processes by inhibiting enzyme activities or perturbing protein-protein interactions, one should be able to design new antibacterial compounds active against pathogenic organisms such as streptococci, staphylococci, enterococci or chlamydiae. Five workpackages will provide converging approaches to the same general goal. 1 The study and the design of inhibitors for penicillin-resistant transpeptidases. 2 The development of inhibitors of the glycosyltransferase domain of class A penicillin-binding proteins. 3 The study and the design of inhibitors for the synthesis and transport steps of cell wall subunits located at the plasma membrane. 4 The study and the design of inhibitors for the synthesis of soluble peptidoglycan precursors. 5 The study of cell morphogenesis and of its regulation and the design of compounds which might interfere with these processes. This ambitious project will lead to new insights into bacterial physiology and might have a pronounced impact in other areas including biotechnology, and bacterial pathogenesis. Indeed, this project will create renewed interest in these key areas and pave the way to innovative for fighting resistance to antibiotics.
Keywords:
Antibiotic resistance, new targets, peptidoglycan, drug design, drug chemistry, morphogenesis
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