Lactobacilli-derived extracellular vesicles as synergistic biomolecules for colistin efficacy against Acinetobacter...

Acinetobacter baumannii (A. baumannii), a gram-negative bacterium resistant to antibiotics, presents substantial medical challenges, causing nosocomial infections with high fatality rates. Colistin (COL) is frequently employed as a last-line defense against these pathogens. Nevertheless, its therapeutic efficacy has been significantly reduced due to the emergence of COL-resistant strains. With the slow development of novel antibiotics, researchers have explored materials to boost the effectiveness of COL against such pathogens. Postbiotics, comprising bioactive compounds derived from probiotic microorganisms, have shown potential antibacterial properties and may work synergistically with certain antibiotics. This study aimed to confirm the role of extracellular vesicles (EVs) as a collection of bioactive molecules that could potentially synergize with COL. EVs from various Lactobacilli strains (LEVs) were evaluated for their effect on COL susceptibility. The findings indicated that, compared to COL treatment alone, LEVs enhanced 4- to 8-fold bactericidal efficacy of COL against A. baumannii strains in the level of minimum inhibitory concentrations (MIC). Additional mechanistic investigations into the synergistic effects of LEVs on established COL mechanisms, including lipopolysaccharide binding, reactive oxygen species (ROS) generation, and biofilm formation, showed that LEVs act as either ROS enhancers or biofilm inhibitors, depending on the bacterial strains. Finally, we demonstrated that repeated use of LEVs did not induce COL resistance in A. baumannii. These results provide the first evidence that LEVs can serve as effective postbiotics, enhancing the susceptibility of A. baumannii strains to COL.