Linking oxidative stress defense to biofilm architecture: Ohr mediates strain-dependent persistence in Acinetobacter baumannii

Biofilm formation is critical for the persistence of Acinetobacter baumannii, yet its directional correlation with antimicrobial resistance remains paradoxical. Here, we confirmed our prior finding that drug-sensitive and multidrug-resistant (MDR) strains employ distinct, temporally regulated biofilm developmental programs: susceptible strains excel at rapid biomass accumulation but undergo early collapse, while MDR strains delay biofilm initiation and optimize for the maintenance and reinforcement of mature biofilms. Transcriptomic profiling identified the organic hydroperoxide resistance protein (Ohr) as a crucial contributor mediating this strain-specific biofilm divergence, with its deletion resulting in severe biofilm defects. Metabolomics analyses further revealed that Ohr maintains biofilm integrity through dual mechanisms: by modulating redox homeostasis and regulating extracellular polymeric substance (EPS) production through control of AdeAB and AdeFG efflux pumps. Moreover, we identified indole-3-lactic acid as a potent biofilm inhibitor. Our findings suggest Ohr as a linchpin in A. baumannii biofilm development, elucidate the basis of temporal phenotypic divergence, and unveil promising therapeutic targets against biofilm-associated infections.