He Wenyan, Huan Xueting, Li Yinchuan, Deng Qisen, Chen Tao, Xiao Wen, Chen Yijun, Ma Lingman, Liu Nan, Shang Zhuo, Wang Zongqiang
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
Nat Commun. 2025 Jul 31;16(1):7048. doi: 10.1038/s41467-025-62407-4.
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.
难以治疗的多重耐药病原体迅速出现，加上具有新机制的抗生素稀缺，对全球公共卫生构成了重大威胁。在此，我们将合成生物信息学天然产物方法与肽优化相结合，以揭示芽孢杆菌科细菌产生抗生素的潜力。我们的非培养方法导致发现了paenimicin，这是一种新型的11聚体去甲脂肽，具有前所未有的双重结合机制。通过螯合革兰氏阴性菌中脂多糖的磷酸和羟基基团以及革兰氏阳性菌中磷壁酸的磷酸基团，paenimicin在体外和体内模型中对多重耐药病原体表现出强大的广谱疗效。Paenimicin未表现出可检测到的耐药性，具有良好的药代动力学和低肾毒性，使其成为治疗严重和紧急多重耐药感染的有希望的候选药物。
