Novel antimicrobial 3-phenyl-4-phenoxypyrazole derivatives target cell wall lipid intermediates with low mammalian cytotoxicity

TL;DR

This paper introduces new antimicrobial compounds that target bacterial cell wall lipids with low toxicity to mammalian cells.

Contribution

The study introduces novel 3-phenyl-4-phenoxypyrazole derivatives that target cell wall lipid intermediates with low mammalian cytotoxicity.

Findings

PYO12 and PYO12a show bactericidal activity against gram-positive bacteria with low cytotoxicity to mammalian cells.

Gram-negative bacteria resist PYO12 via efflux pumps, and PYO12 induces resistance-related gene expression.

PYO12's activity is antagonized by undecaprenyl-pyrophosphate, suggesting it binds to lipid II.

Abstract

The growing crisis of antimicrobial resistance (AMR) underscores the critical need for innovative antimicrobial discoveries. Novel antibiotics targeting the bacterial cell wall remain an attractive area of research, due to their conservation and essentiality in bacteria and their absence in eukaryotic cells. Antibiotics targeting lipid II are of special interest due to the reduced potential for target modification of lipid components and their surface accessibility to inhibitors. In this study, we identified 3-phenyl-4-phenoxypyrazole analogues named PYO12 and PYO12a with bactericidal activity against gram-positive bacteria and low cytotoxicity for different types of mammalian cells. Gram-negative bacteria were resistant to PYO12 activity through extrusion of this compound via efflux pumps. Exposure to PYO12 induces expression of genes involved in resistance to antimicrobials targeting the cell wall, suggesting that PYO12 acts via binding to lipid II or other lipid intermediates involved in peptidoglycan or teichoic acid biosynthesis. Antagonism of PYO12 antibacterial activity by undecaprenyl-pyrophosphate supports the idea that PYO12 may bind to the lipid moiety of lipid II blocking the shuttling of peptidoglycan precursors across the cytoplasmic membrane. These findings open opportunities to further develop these compounds as antibiotics targeting bacterial cell wall synthesis.

The online version contains supplementary material available at 10.1038/s41598-025-19561-y.

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