Up to now, antimicrobial resistance is one of the biggest public health challenges. Multi-resistance is particularly worrying in both Gram-negative bacteria, Pseudomonas aeruginosa and Escherichia coli for instance, and parasites such as Plasmodium falciparum.
Consequently, developing new compounds with original and selective antimicrobial modes of action is critical. Fatty acids are essential to maintain the vital integrity of the bacterial membrane. Their biosynthesis involves the fatty acid synthase-II (FAS-II) system which is exclusively found in germs. Furthermore, the amino-acid sequences of the FAS-II enzymes active site are well conserved in the microbial pathogens. As proves of concept, Isoniazid, a well-known antituberculous compound, and Afabicin – currently in clinical development to treat drug resistant staphylococci infections- target InhA or FabI, FAS‑II enzymes. In this work, we focus on another important FAS-II enzyme, FabZ, to design new antimicrobials with limited side effects and minimal chances of cross resistance with existing drugs targeting other pathways.
In the Protein Data Bank (PDB), several FabZ 3D structures from different organisms have been reported. Among known FabZ inhibitors, the NAS91 family, with a quinoline core, inhibits PfFabZ with IC50 in the micromolar range. Additionally, co-crystal NAS91 family-PfFabZ complex structures are described in the PDB. Based on these data, we have started a FabZ-based drug design study to develop novel quinoline structures. Herein, the in silico study, synthesis of new quinolines and biological results will be exposed.
