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

作者：Wenyan He, Xueting Huan, Y. Li, Qisen Deng, Tao Chen, Wen Xiao, Yijun Chen, Lingman Ma, Nan Liu, Zhuo Shang, Zongqiang Wang · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.01.11.632532 · 研究领域：Antibiotic Resistance in Bacteria、Bacteriophages and microbial interactions、Biochemical and Structural Characterization

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.