Capsule modulation enhances immunity and delays resistance in MDR Acinetobacter baumannii

Multidrug-resistant Acinetobacter baumannii (MDRAB) is a serious clinical threat. Although bacteriophages provide pathogen-specific therapy, the rapid emergence of phage resistance limits clinical durability. Here, we isolated a lytic phage, WYF231108.1, from hospital wastewater targeting the clinical isolate AHMU_SF230901.1 (SF). Through serial passage, we generated phage-resistant derivatives (SF_R1, SF_R2, SF_R3) and host-range-adapted phages (WYF_V1, WYF_V2, WYF_V3). Genomic and phenotypic profiling showed that resistance coincided with capsule attenuation and downregulation of capsule-biosynthesis genes, accompanied by reduced virulence and enhanced recognition by innate immune cells. Adapted phages restored lytic activity against resistant strains and, when combined with antibiotics, suppressed resistant outgrowth in vitro and improved survival in murine infection models. Collectively, our results define an evolutionary trade-off in which phage resistance associated with capsule attenuation reduces pathogenicity while exposing a therapeutic vulnerability. This vulnerability may be exploited using an adapted phage-antibiotic combination regimen.