A novel broad-spectrum antibiotic targets multiple-drug-resistant bacteria with dual binding targets and no detectable resistance

He, W.; Huan, X.; Li, Y.; Deng, Q.; Chen, T.; Xiao, W.; Chen, Y.; Ma, L.; Liu, N.; shang, z.; Wang, Z.

doi:10.1101/2025.01.11.632532

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bioRxiv · 10.1101/2025.01.11.632532

A novel broad-spectrum antibiotic targets multiple-drug-resistant bacteria with dual binding targets and no detectable resistance

He, W.·Huan, X.·Li, Y.·Deng, Q.·Chen, T.·Xiao, W.·Chen, Y.·Ma, L.·Liu, N.·shang, z.·Wang, Z.

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Abstract

The rapid emergence of difficult-to-treat multidrug-resistant pathogens, combined with the scarcity of antibiotics possessing novel mechanisms, poses a significant threat to global public health. Here, we integrated the synthetic-bioinformatic natural product approach with peptide optimization to unveil the antibiotic-producing potential of Paenibacillaceae bacteria. Our culture-independent approach led to the discovery of paenimycin, a novel 11-mer depsi-lipopeptide featuring an unprecedented dual-binding mechanism. By sequestering the phosphate and hydroxyl groups of lipid A in Gram-negative bacteria, as well as the phosphate groups of teichoic acids in Gram-positive bacteria, paenimycin exhibited potent and broad-spectrum efficacy against MDR pathogens in vitro and in vivo models. Remarkably, paenimycin demonstrates no detectable resistance, favorable pharmacokinetics and low nephrotoxicity, positioning it as a promising candidate for treating serve and urgent MDR infections.

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He, W., Huan, X., Li, Y., Deng, Q., Chen, T., Xiao, W., Chen, Y., Ma, L., Liu, N., shang, z., Wang, Z.. 2025-01-12. A novel broad-spectrum antibiotic targets multiple-drug-resistant bacteria with dual binding targets and no detectable resistance. https://doi.org/10.1101/2025.01.11.632532

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