The Development of FtsZ Inhibitors as Potential Antibacterial Agents
ABSTRACT The emergence and prevalence of bacterial resistance has resulted in a clear demand for novel antibacterial drugs. As a tubulin homologue, FtsZ is an essential cell-division protein in prokaryotic organisms and is showing increasing promise as a target for antibacterial drug discovery. This review describes the role of FtsZ in bacterial cytokinesis and various FtsZ inhibitors, with particular focus on their discovery, antibacterial activities, mechanisms of action, synthetic methods, and representative analogues.
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ABSTRACT: Natural product discovery arises through a unique interplay between chromatographic purification and biological assays. Currently, most techniques used for natural product purification deliver leads without a defined biological action. We now describe a technique, referred to herein as functional chromatography, that deploys biological affinity as the matrix for compound isolation.Organic & Biomolecular Chemistry 01/2015; 13(8). DOI:10.1039/c4ob02292k · 3.49 Impact Factor
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ABSTRACT: Infections caused by Gram-negative bacterial pathogens are often difficult to treat, with the emergence of multidrug-resistant strains further restricting clinical treatment options. As a result, there is an acute need for the development of new therapeutic agents active against Gram-negative bacteria. The bacterial protein FtsZ has recently been demonstrated to be a viable antibacterial target for treating infections caused by the Gram-positive bacteria Staphylococcus aureus in mouse model systems. Here, we investigate whether an FtsZ-directed prodrug (TXY436) that is effective against S. aureus can also target Gram-negative bacteria, such as Escherichia coli. We find that the conversion product of TXY436 (PC190723) can bind E. coli FtsZ and inhibit its polymerization/bundling in vitro. However, PC190723 is intrinsically inactive against wild-type E. coli, with this inactivity being derived from the actions of the efflux pump AcrAB. Mutations in E. coli AcrAB render the mutant bacteria susceptible to TXY436. We further show that chemical inhibition of AcrAB in E. coli, as well as its homologs in Klebsiella pneumoniae and Acinetobacter baumannii, confers all three Gram-negative pathogens with susceptibility to TXY436. We demonstrate that the activity of TXY436 against E. coli and K. pneumoniae is bactericidal in nature. Evidence for FtsZ-targeting and inhibition of cell division in Gram-negative bacteria by TXY436 is provided by the induction of a characteristic filamentous morphology when the efflux pump has been inhibited as well as by the lack of functional Z-rings upon TXY436 treatment.Biochemical pharmacology 03/2014; DOI:10.1016/j.bcp.2014.03.002 · 4.65 Impact Factor
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ABSTRACT: Naturally occurring phytochemicals with reported antibacterial activity were screened for their ability to inhibit the bacterial cell division protein Escherichia coli FtsZ. Among the representative compounds, coumarins inhibit the GTPase and polymerization activities of this protein effectively. Further screening with ten coumarin analogs we identified two promising candidates, scopoletin and daphnetin. The former is found to inhibit the GTPase activity of the protein in a noncompetitive manner. Docking of these coumarins with the modeled protein indicate that they bind to T7 loop, which is different from the GTP-binding site (active site), thereby supporting the experimental data. Lowest binding energy is obtained with scopoletin. 3D QSAR indicates the need for groups such as hydroxyl, diethyl, or dimethyl amino in the 7th carbon for enhanced activity. None of the coumarins exhibited cytotoxicity against NIH/3T3 and human embryonic kidney cell lines. The length of Bacillus subtilis increases in the presence of these compounds probably due to the lack of septum formation. Results of this study indicate the role of coumarins in halting the first step of bacterial cell division process.Applied Biochemistry and Biotechnology 07/2014; 174(1). DOI:10.1007/s12010-014-1056-2 · 1.69 Impact Factor