A broad-spectrum antibiotic targets multiple-drug-resistant bacteria with dual binding targets and no detectable resistance
Wenyan He, Xueting Huan, Y. Li, Qisen Deng, Tao Chen, Wen Xiao, Yijun Chen, Lingman Ma, Nan Liu, Zhuo Shang, Zongqiang Wang
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. Through a synthetic-bioinformatic natural product approach combined with peptide optimization, a nature inspired antibiotic, paenimicin, was identified from Paenibacillaceae family. Paenimicin features a dual-target mechanism of action and shows broad-spectrum activities against multi-drug-resistant pathogens both in vitro and in vivo.