With drug-resistant gram-negative bacteria spreading faster than new antibiotics can be developed, a research team at Pusan National University in South Korea took a different approach: rather than inventing a new drug, they looked for a way to make bacteria more vulnerable to one that already exists.

Polymyxins remain among the few treatment options for severe, multidrug-resistant E. coli infections, but their use is limited by kidney and nerve toxicity. The researchers screened 91 bacterial small non-coding RNAs and found that one of them, which encodes a peptide called TimP, was chiefly responsible for boosting bacterial susceptibility to polymyxins. Structural modeling and lab experiments showed TimP binds an outer membrane protein called LamB, triggering higher membrane permeability, a surge in reactive oxygen species, and increased release of extracellular vesicles — tiny membrane-bound packets bacteria naturally shed.

The team then built its own extracellular vesicles, loaded with both TimP and the antibiotic polymyxin B, calling the combination PMB@TimP EVs — a kind of Trojan horse that delivers the drug directly to bacteria while simultaneously weakening their outer defenses. In lab tests, the engineered vesicles killed bacteria more effectively than free polymyxin B, remained stable across a wider range of pH levels, and were less toxic to mammalian cells. In a mouse model of sepsis caused by multidrug-resistant E. coli, the vesicles improved survival at doses where free polymyxin B alone provided no protection, and safety testing turned up no abnormal organ accumulation or abnormal inflammatory or liver markers. Because the LamB protein the approach targets is also found in Salmonella Typhimurium, the researchers believe the strategy could extend beyond E. coli to other multidrug-resistant gram-negative bacteria.

Study leader Kwang-sun Kim said that with new antibiotic development failing to keep pace with bacterial evolution, getting more out of the drugs already available is likely to become a primary strategy, and that the engineered vesicles could serve as a potent adjuvant therapy for patients battling sepsis, with the goal of improving recovery rates. Kim suggested the platform could realistically be integrated into standard treatment approaches for multidrug-resistant pathogens within five to ten years, though the work so far has been limited to mouse models, and questions of long-term safety, manufacturing, and broader efficacy remain before any human trials could begin.

Journal: Drug Resistance Updates
Article Title: The sRNA-encoded peptide TimP rewires the Escherichia coli envelope via LamB to sensitize bacteria to polymyxins
DOI: 10.1016/j.drup.2026.101406
Publication Date: July 1, 2026

Source: EurekAlert