Design, synthesis and antimicrobial activities of potential FabZ inhibitors

To date, antimicrobial resistance is one of the biggest public health challenges. Multi-drug-resistance is particularly worrying in both Gram-negative bacteria such as P. aeruginosa or E. coli and parasites such as P. falciparum. Therefore, it is urgent to propose novel treatments with original and selective antimicrobial modes of action. Lipids are crucial to maintain the bacterial membrane integrity. Their biosynthesis involves both fatty acid synthase-I (FAS-I) and fatty acid synthase-II (FAS-II) systems. While FAS-I is present in both humans and microbes, FAS-II is uniquely found in germs. Furthermore, the FAS-II enzyme sequences have a high level of conservation in the microbial pathogens. Targeting these enzymes, especially FabZ, a β-hydroxyacyl-acyl carrier protein (ACP) dehydratase, represents a promising strategy to design broad-spectrum antimicrobials with limited side effects and offers minimum chances of cross-resistance with existing drugs targeting others pathways. Few FabZ inhibitors were described while several FabZ 3D structures from different organisms such as P. aeruginosa, P. falciparum and H. pylori have been reported (Protein Data Bank: PDB). Among known FabZ inhibitors, the NAS91 family, with a quinoline core, inhibits PfFabZ with IC50 in a micromolar range. Additionally, co-crystal NAS91 family-PfFabZ complex structures are described in the PDB (3AZA, 3AZ9, 3AZB). Based on these data, we have started a FabZ-based drug design study to propose new quinoline structures. The in silico study, synthesis of some new quinolines and the first biological results will be exposed.