Design, Synthesis and Antimicrobial Activities of Quinoline-Based FabZ Inhibitors as Promising Antimicrobial Drugs ^†

At present, antimicrobial resistance is one of the most significant public health challenges. Multi-resistance is particularly worrying in both Gram-negative bacteria, including Pseudomonas aeruginosa and Escherichia coli, and parasites, such as Plasmodium falciparum.

Consequently, the development of 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 microorganisms. Furthermore, the amino-acid sequences of the active sites of FAS-II enzymes are well-conserved in microbial pathogens. As a proof of concept, isoniazid, a well-known antituberculous compound, and afabicin, which is 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 that target other pathways.

In the Protein Data Bank (PDB), several FabZ 3D structures from different organisms have been reported. Among the known FabZ inhibitors, the NAS91 family, with a quinoline core, inhibits PfFabZ with an IC₅₀ value 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 presented.