Targeting Bacterial Cell Division with Benzodioxane–Benzamide FtsZ Inhibitors as a Novel Strategy to Fight Gram-Positive Ovococcal Pathogens

The widespread emergence of antimicrobial resistance (AMR) is a serious threat to global public health and among Gram-positive cocci, <i>Streptococcus pneumoniae</i> constitutes a priority in the list of AMR-threatening pathogens. To counteract this fundamental problem, the bacterial cell division cycle and the crucial proteins involved in this process emerged as novel attractive targets. FtsZ is an essential cell division protein, and FtsZ inhibitors, especially the benzamide derivatives, have been exploited in the last decade. In this work, we identified, for the first time, some benzodioxane-benzamide inhibitors capable of targeting FtsZ in <i>Streptococcus pneumoniae</i>, in addition to their previously demonstrated activity against other bacteria. These promising benzamides, with minimal inhibitory concentrations (MICs) ranging from 25 to 80 µg/mL, demonstrated bactericidal activity against <i>S. pneumoniae</i>. This was evidenced by their ability to dramatically affect growth and viability, further supported by the morphological changes observed through microscopy. Moreover, the compounds were characterized in vitro, combining turbidity measurements and confocal imaging, and significant alteration of a GTP-induced FtsZ assembly was found, in line with our previous data from other microorganisms.