Abstract
FtsZ inhibitors represent a new drug class as no drugs using this mode of action (MOA) have been approved by regulators. 3-alkoxy substituted 2,6-difluorobenzamide scaffold is one of the most studied FtsZ inhibitors among which the most promising anti-MRSA candidate TXA709 is in clinical trial. In this paper, we present the screening and evaluation of a benzamide class that is functionalized at the alkoxy fragment targeting Gram-negative bacteria. The variations in 3-alkoxy substitutions, specifically the hydroxylated alkyl residues to the secondary and stereogenic pseudo-benzylic carbon of their methyleneoxy linker, are particularly active against K. pneumoniae ATCC 10031 in marked contrast to the derivatives related to PC190723, all of which were inactive against Gram-negative bacteria. The two lead molecules TXA6101 and TXY6129 inhibit the polymerization of E. coli FtsZ in a concentration-dependent manner and induce changes in the morphology of E. coli and K. pneumoniae consistent with inhibition of cell division. These classes of compounds, however, were found to be substrates for efflux pumps in Gram-negative bacteria.
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Acknowledgements
We are indebted to Prof. Edmond J. LaVoie for providing scientific inputs. We are also indebted to Prof. Daniel Pilch and Dr. Edgar Ferrer-González for providing us with the differential interference contrast (DIC) micrographs and with the E. coli W4573, N43 (acrA1), LZ2096 (∆norE), and LZ2310 (acrA1 ∆mdfA ∆norE) strains.
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Conceptualization, AP; methodology, AP and JR; investigation, JR; YS; AB; YC; PD; YZ, and YY; writing—original draft preparation, AP; writing—review and editing, YY; JR; supervision, AP; project administration, AP; JR; and YS; All authors have read and agreed to the published version of the manuscript.
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AP, JR, PD, and YZ are employees of TAXIS Pharmaceuticals, Inc. and, therefore, have a financial interest in the company.
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Rosado-Lugo, J.D., Sun, Y., Banerjee, A. et al. Evaluation of 2,6-difluoro-3-(oxazol-2-ylmethoxy)benzamide chemotypes as Gram-negative FtsZ inhibitors. J Antibiot 75, 385–395 (2022). https://doi.org/10.1038/s41429-022-00531-9
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DOI: https://doi.org/10.1038/s41429-022-00531-9
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