Targeting Bacterial Cell Division: A Binding Site-Centered Approach to the Most Promising Inhibitors of the Essential Protein FtsZ

Abstract

Binary fission is the most common mode of bacterial cell division and is mediated by a multiprotein complex denominated the divisome. The constriction of the Z-ring splits the mother bacterial cell into two daughter cells of the same size. The Z-ring is formed by the polymerization of FtsZ, a bacterial protein homologue of eukaryotic tubulin, and it represents the first step of bacterial cytokinesis. The high grade of conservation of FtsZ in most prokaryotic organisms and its relevance in orchestrating the whole division system make this protein a fascinating target in antibiotic research. Indeed, FtsZ inhibition results in the complete blockage of the division system and, consequently, in a bacteriostatic or a bactericidal effect. Since many papers and reviews already discussed the physiology of FtsZ and its auxiliary proteins, as well as the molecular mechanisms in which they are involved, here, we focus on the discussion of the most compelling FtsZ inhibitors, classified by their main protein binding sites and following a medicinal chemistry approach.

Antimicrobial Action and Reversal of Resistance in MRSA by Difluorobenzamide Derivatives Targeted at FtsZ

“…The most dramatic effects were observed with MST C4 (5) on clinical strain 15 where the MIC dropped by 1024-fold from 512 to 0.5 µg/mL (Figure 2). Synergism with methicillin or partial reversal of resistance against different MRSA ATCC strains were also observed in other studies for derivatives of benzofuroquinolinium, quinoline and TXA709 [12][13][14]28,[31][32][33].…”

“…Various classes of small-molecule inhibitors of FtsZ have been identified such as derivatives of 3-methoxybenzamide (3-MBA, Figure 1), berberine derivatives, quinolinium compounds, polyphenolic derivatives, cinnamaldehyde, quinuclidines and quinazolines [4,[11][12][13]. Among these inhibitors, PC190723 (a 2,6-difluoro derivative of benzamide with a thiazolopyridine moiety attached through an ether linker, Figure 1), has been one of the most extensively studied.…”

Computational Design and Development of Benzodioxane-Benzamides as Potent Inhibitors of FtsZ by Exploring the Hydrophobic Subpocket

“…Moreover, FtsZ is highly conserved among bacterial species [ 12 ], and although it is a functional homolog of human tubulin, their sequences and structures are divergent [ 13 ]. Among all the FtsZ inhibitors developed so far, benzamide compounds are the most studied, thanks to their excellent anti-staphylococcal activity, low cytotoxicity, wide chemical accessibility, and the interesting results obtained in association with other antibiotic classes [ 14 , 15 , 16 , 17 ]. Along these lines, we recently developed a class of FtsZ inhibitors [ 18 , 19 , 20 , 21 , 22 ] that contain a 2,6-difluoro-benzamide scaffold linked to a differently substituted 1,4-benzodioxane ring.…”

Targeting the FtsZ Allosteric Binding Site with a Novel Fluorescence Polarization Screen, Cytological and Structural Approaches for Antibacterial Discovery

“…The promiscuous inhibitors resveratrol, 40 plumbagin 41 2, Figure 4A and B). Different types of structural modifications around the three main structural features of benzamide inhibitors 16 were explored: i) linear or branched alkylenamino or alkylenoxy linkers of different length as spacers, similarly to recent structure activity relationship studies; 43 ii) difluorination of the benzamide core; and iii) position and effects of substituents around the phenyl ring selected as the aromatic moiety.…”