Abstract
Bacterial resistance to antibiotics makes previously manageable infections again disabling and lethal, highlighting the need for new antibacterial strategies. In this regard, inhibition of the bacterial division process by targeting key protein FtsZ has been recognized as an attractive approach for discovering new antibiotics. Binding of small molecules to the cleft between the N-terminal guanosine triphosphate (GTP)-binding and the C-terminal subdomains allosterically impairs the FtsZ function, eventually inhibiting bacterial division. Nonetheless, the lack of appropriate chemical tools to develop a binding screen against this site has hampered the discovery of FtsZ antibacterial inhibitors. Herein, we describe the first competitive binding assay to identify FtsZ allosteric ligands interacting with the interdomain cleft, based on the use of specific high-affinity fluorescent probes. This novel assay, together with phenotypic profiling and X-ray crystallographic insights, enables the identification and characterization of FtsZ inhibitors of bacterial division aiming at the discovery of more effective antibacterials.
Highlights
New antibiotics are urgently needed to cope with the global rise of bacterial pathogens resistant to antibiotics in use, which renders lethal infections that once were treatable and controllable.[1,2,3,4] In order to discover new antibiotics, processes essential for bacterial reproduction and spreading must be targeted, such as bacterial cell division, a clinically unexplored target
Specific medium affinity probes are required for the effective detection of weak but competing molecules during inhibitor screening, whereas high affinity probes are needed for measurement of the dissociation constant (KD) of high affinity compounds
The allosteric benzamide binding site at the cleft between the nucleotide-binding and GTPaseactivating domains of FtsZ has been explored in this work
Summary
New antibiotics are urgently needed to cope with the global rise of bacterial pathogens resistant to antibiotics in use, which renders lethal infections that once were treatable and controllable.[1,2,3,4] In order to discover new antibiotics, processes essential for bacterial reproduction and spreading must be targeted, such as bacterial cell division, a clinically unexplored target. While eukaryote mitosis has been vastly exploited for cancer treatments, targeting the bacterial cell division remains a clinical challenge. One prodrug analog of PC190723, TXA70917 (Chart S1) was designated a qualified infectious disease product for Staphylococcus aureus infections and has recently completed a phase I clinical trial.[18]
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