Broad spectrum antimicrobials interacting with membrane lipid metabolism – ALASMEL

The development of resistance to current antibiotics and antiparasitics is a real public health issue. Multi-resistance is particularly worrying in Gram-negative bacteria isolated from nosocomial infections such as P. aeruginosa, enterobacteria (E. coli, K. pneumoniae). Resistance to highly virulent bacteria such as Y. pestis and B. pseudomallei, which could be used as a bioterrorist weapon, is also of concern. The decreasing effectiveness of antimalarial treatments is also a public health problem. P. falciparum, the most virulent species, is responsible for most malaria deaths. Therefore, there is an urgent need to identify and develop new effective treatments targeting new vital biological processes not targeted by current anti-infective agents to avoid cross-resistance. Membrane lipid metabolism is one of them, as it is essential for the maintenance of cellular integrity. Thus, blocking the proper functioning of enzymes involved in membrane lipid metabolism is a promising therapeutic approach. The FabZ and PfACBP enzymes are particularly interesting because (i) they are not or only slightly expressed in humans, (ii) they are found in P. aeruginosa, enterobacteria and P. falciparum, pathogens that we are targeting in this project. The objective of this research program is to synthesize and study selective inhibitors of FabZ and/or PfACBP enzymes which are involved in the metabolism of membrane lipids of these pathogens. This work will be the subject of a collaboration between the AGIR laboratory (P1) and three AID teams (P2: Parasitology and Entomology unit, IRBA, Marseille; P3: Analytical Development and Bioanalysis unit, IRBA, Brétigny-sur-Orge and P4: Bacteriology unit, IRBA, Brétigny-sur-Orge) in order to propose, for civilians as well as for the armed forces, new broad-spectrum anti-microbial treatments against Gram-negative bacteria such as E. coli and P. aeruginosa, bacteria classified as A and B by the CDC such as Y. pestis and B. pseudomallei and P. falciparum.