Nutrient-driven small-colony variants as an adaptive outcome in Carbapenem-resistant Acinetobacter baumannii

Carbapenem-resistant Acinetobacter baumannii (CRAB) is a serious threat, and resistance is emerging to cefiderocol, one of the few remaining treatment options. However, how host micronutrients drive bacterial adaptation under antibiotic pressure is poorly defined. Using the AB5075 and CDC AR Bank #0033 (M27835) CRAB isolates, we combined time-kill assays, whole-genome sequencing, gene expression analysis, and phenotyping to test how vitamin B12 promotes small-colony variants (SCVs) -like adaptive derivatives and alters cefiderocol response. Vitamin B12 reproducibly selected slow-growing SCV-like adaptive derivatives that showed incomplete cefiderocol killing and frequent regrowth across drug concentrations in both genetic backgrounds. These derivatives carried genetic alterations affecting cell-surface structures, nutrient transport and TonB-dependent iron uptake, and energy balance, with capsule/biofilm remodeling and altered aminoglycoside killing. Co-exposure to vitamin B12 and cefiderocol further enriched SCV-like adaptive derivatives with changes in siderophore receptors and the BfmRS sensor BfmS. These findings identify vitamin B12 as an environmental cue that promotes the emergency of SCV-like adaptive derivatives and modulates cefiderocol response in CRAB, highlight nutrient availability as an underrecognized factor influencing antibiotic efficacy.