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

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 ofPaenibacillaceaebacteria. Our culture-independent approach led to the discovery of paenimycin, a novel 11-merdepsi-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 pathogensin vitroandin vivomodels. Remarkably, paenimycin demonstrates no detectable resistance, favorable pharmacokinetics and low nephrotoxicity, positioning it as a promising candidate for treating serve and urgent MDR infections.