Inhibition of RND-type efflux pumps confers the FtsZ-directed prodrug TXY436 with activity against Gram-negative bacteria

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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.

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