Battle against antimicrobial resistance: FtsZ inhibitors as novel potent Gram-positive antibiotics

Antimicrobial resistance is one of the major actual health plagues. Even if it started more than 70 years ago, the problem burst out only in the latest years, prompting to the urgent need of novel efficient antibiotics, showing innovative mechanisms of action. In this context, the bacterial cell division process turned to be an interesting and promising target, firstly because divisome components are crucial for the viability of bacteria. Moreover, the most important division proteins are widely conserved in bacteria and are absent in eukaryotic cells, strengthening the selectivity of the possible novel antimicrobics. Among the essential cell division proteins, FtsZ (Filamentous temperature sensitive Z), which is a tubulin homologue, became an attractive target. FtsZ is the first protein that localizes to the mid-point of the cell and it 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. In the last 10 years several research group studied and developed FtsZ inhibitors, confirming that protein inhibition results in a bactericidal effect. Interesting results were obtained with synthetic small molecules; specifically with 3-Methoxybenzamide (3-MBA) derivatives: the lead compound of this class of antimicrobics is PC190723. In the attempt to design potent novel antibacterial agents, in the latest years we designed and accomplished several derivatives, firstly replacing the thiazolopyridine of PC190723 with differently substituted 1,4-benzodioxane, bringing in particular to compounds I-III. These molecules proved to be strong inhibitors of S. aureus, E. faecalis and M. tuberculosis viability. Recently we consolidated the Structure Activity Relationship (SAR) of this class, designing a number of analogues of I and III, through a series of isosteric, positional or substituent modifications. Furthermore, we confirmed the target, performing two different biochemical assays, aimed at studying GTPase and polymerization activities of S. aureus FtsZ, when incubated with our compounds.