Recently, Professor Wang Zongqiang's research team at our university published their latest research findings in Nature Communications, titled “A broad-spectrum antibiotic targets multiple-drug-resistant bacteria with dual binding targets and no detectable resistance.” The paper's co-first authors are He Wenyan, a 2022 master's student, and Xun Xueting, a 2023 doctoral student, both from our university. Professor Wang Zongqiang is the corresponding author, and China Pharmaceutical University is the sole corresponding institution.
In response to the increasingly severe global issue of multidrug-resistant bacterial infections, traditional antibiotic development has struggled to keep pace with the evolution of drug resistance. Discovering novel antibiotics with novel mechanisms of action, broad-spectrum antimicrobial activity, and low potential for inducing resistance has become a core challenge in current antimicrobial drug development. Professor Wang Zongqiang's team has long been dedicated to the discovery of antimicrobial drugs for infection control. In this study, they identified a highly coupled relationship between Bacillus-like bacteria and cyclopeptides, and utilized AI-assisted biomimetic synthesis of non-ribosomal peptide-like active natural products to discover and synthesize a novel broad-spectrum antibiotic, Paenimicin, from the genome of Bacillus-like bacteria.
The research team screened 1,256 Paenibacillaceae genomes through bioinformatics prediction and selection, identifying 901 novel non-ribosomal peptide synthesis gene clusters. Through similarity network analysis, they identified a previously unreported BNP37 gene cluster. Since this cluster was silent under conventional cultivation conditions, the team employed solid-phase chemical synthesis combined with structural optimization to obtain the cyclic lipopeptide-type broad-spectrum antibiotic Paenimicin. This molecule forms a unique structure by linking the N-terminal myristoyl chain to the cyclized skeleton, exhibiting dual-target binding capacity to both the phospho-hydroxy di-site of lipopolysaccharide lipid A in Gram-negative bacteria and the phospho group of teichoic acid in Gram-positive bacteria, thereby exerting dual bactericidal effects.
In vitro experiments showed that Paenimicin exhibits excellent antibacterial activity against multidrug-resistant strains such as carbapenem-resistant Acinetobacter baumannii, third-generation cephalosporin/carbapenem-resistant Enterobacteriaceae, and methicillin-resistant Staphylococcus aureus, all of which are listed as “critical” priorities by the WHO. It also maintains activity against natural or acquired polymyxin-resistant strains and is unlikely to develop resistance under laboratory conditions. In vivo studies further validate its therapeutic value: Paenimicin has a long half-life when administered subcutaneously, high bioavailability, and does not cause renal dysfunction even after seven days of continuous high-dose administration. In three mouse infection models, a single dose significantly reduced the bacterial load of multiple multidrug-resistant bacteria. This study offers new insights into addressing the current severe clinical situation of multidrug-resistant bacterial infections, where the last line of defense is increasingly threatened. Paenimicin holds promise as a lead drug for treating multidrug-resistant bacterial infections, providing patients with additional treatment options.
This research was supported by funding from the National Natural Science Foundation of China, the National Key Research and Development Program, and the Jiangsu Province Major Science and Technology Project.
Original article link: https://www.nature.com/articles/s41467-025-62407-4
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