How to fight antimicrobial resistance: design and synthesis of FTSZ inhibitors as novel potent gram-positive antibiotics

Nowadays, antimicrobial resistance is a global threat to public health. This well know plague only recently burst out, prompting to the urgent need of developing efficient antibiotics with innovative mechanisms of action. In this context, the bacterial divisome turned out to be an interesting and promising target (1). Cell division proteins are indeed crucial for bacteria viability, are widely conserved among several species and are completely absent in eukaryotic cells, thus strengthening the selectivity of the novel antimicrobics. FtsZ (Filamentous temperature sensitive Z) is one of the essential cell division proteins; FtsZ is a tubulin homologue (2) and is the first protein that localizes to the mid-point of the cell and undergoes polymerization in a GTP-dependent manner, bringing to the formation of the Z-ring. It recruits at least ten other cell division proteins, which enable cell constriction, the formation of mesosome and two daughter cells (3). Recently, we studied and developed FtsZ inhibitors, starting from the most significant results of other research groups and confirming that FtsZ inhibition results in a bactericidal effect. We prepared 3-Methoxybenzamide (3-MBA) derivatives, structurally similar to the FtsZ inhibitors lead compound: PC190723 (4-6). Our derivatives (which general structure is depicted above) were designed replacing the thiazolopyridine of PC190723 with differently substituted 1,4-benzodioxane or 1,4-benzoxathiane. We further assessed the Structure Activity Relationship (SAR) of this class, through a series of isosteric, positional or substituent modifications (7-9). These molecules proved to strongly inhibit S. aureus, E. faecalis and M. tuberculosis viability and to target FtsZ. We specifically performed two different biochemical assays, aimed at studying GTPase and polymerization activities of S. aureus FtsZ, when incubated with our compounds.