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

Wenyan He, Xueting Huan, Yinchuan Li, Qisen Deng, Tao Chen, Wen Xiao, Yijun Chen, Lingman Ma, Nan Liu, Zhuo Shang and Zongqiang Wang ()
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Wenyan He: China Pharmaceutical University
Xueting Huan: China Pharmaceutical University
Yinchuan Li: China Pharmaceutical University
Qisen Deng: China Pharmaceutical University
Tao Chen: China Pharmaceutical University
Wen Xiao: China Pharmaceutical University
Yijun Chen: China Pharmaceutical University
Lingman Ma: China Pharmaceutical University
Nan Liu: China Pharmaceutical University
Zhuo Shang: Shandong University
Zongqiang Wang: China Pharmaceutical University

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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 integrate 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 paenimicin, 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, paenimicin exhibits potent and broad-spectrum efficacy against MDR pathogens in vitro and in vivo models. Paenimicin demonstrates no detectable resistance, favorable pharmacokinetics and low nephrotoxicity, positioning it as a promising candidate for treating severe and urgent MDR infections.

Date: 2025
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DOI: 10.1038/s41467-025-62407-4

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