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The widespread emergence of antimicrobial resistance (AMR) is a serious threat to global public health and among Gram-positive cocci, Streptococcus pneumoniae 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 Streptococcus pneumoniae , 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 S. pneumoniae . 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.

The conserved process of cell division in bacteria has been a long-standing target for antimicrobials, although there are few examples of potent broad-spectrum compounds that inhibit this process. Most currently available compounds acting on division are directed towards the FtsZ protein, a self-assembling GTPase that is a central element of the division machinery in most bacteria. Benzodioxane-benzamides are promising candidates, but poorly explored in Gram-negatives. We have tested a number of these compounds on E. coli FtsZ and found that many of them significantly stabilized the polymers against disassembly and reduced the GTPase activity. Reconstitution in crowded cell-like conditions showed that FtsZ bundles were also susceptible to these compounds, including some compounds that were inactive on protofilaments in dilute conditions. They efficiently killed E. coli cells defective in the AcrAB efflux pump. The activity of the compounds on cell growth and division generally showed a good correlation with their effect in vitro, and our experiments are consistent with FtsZ being the target in vivo. Our results uncover the detrimental effects of benzodioxane-benzamides on permeable E. coli cells via its central division protein, implying that lead compounds may be found within this class for the development of antibiotics against Gram-negative bacteria., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Silvia Zorrilla reports financial support was provided by Spanish Ministerio de Ciencia e Innovación. Marta Sobrinos-Sanguino reports financial support was provided by Agencia Estatal de Investigación and the European Social Fund. William Margolin reports financial support was provided by National Institutes of Health., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

FtsZ is a crucial prokaryotic protein involved in bacterial cell replication. It recently arose as a promising target in the search for antimicrobial agents able to fight antimicrobial resistance. In this work, going on with our structure-activity relationship (SAR) study, we developed variously 7-substituted 1,4-benzodioxane compounds, linked to the 2,6-difluorobenzamide by a methylenoxy bridge. Compounds exhibit promising antibacterial activities not only against multidrug-resistant Staphylococcus aureus, but also on mutated Escherichia coli strains, thus enlarging their spectrum of action toward Gram-negative bacteria as well. Computational studies elucidated, through a validated FtsZ binding protocol, the structural features of new promising derivatives as FtsZ inhibitors., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A wide variety of drug-resistant microorganisms are continuously emerging, restricting the therapeutic options for common bacterial infections. Antimicrobial agents that were originally potent are now no longer helpful, due to their weak or null activity toward these antibiotic-resistant bacteria. In addition, none of the recently approved antibiotics affect innovative targets, resulting in a need for novel drugs with innovative antibacterial mechanisms of action. The essential cell division protein filamentous temperature-sensitive Z (FtsZ) has emerged as a possible target, thanks to its ubiquitous expression and its homology to eukaryotic β-tubulin. In the latest years, several compounds were shown to interact with this prokaryotic protein and selectively inhibit bacterial cell division. Recently, our research group developed interesting derivatives displaying good antibacterial activities against methicillin-resistant Staphylococcus aureus, as well as vancomycin-resistant Enterococcus faecalis and Mycobacterium tuberculosis. The aim of the present study was to summarize the structure-activity relationships of differently substituted heterocycles, linked by a methylenoxy bridge to the 2,6-difluorobenzamide, and to validate FtsZ as the real target of this class of antimicrobials., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)