Repurposing bleomycin against Acinetobacter baumannii HisG: computational, biophysical, and antibacterial evidence

Acinetobacter baumannii (A. baumannii) has become a serious clinical threat due to its increasing antibiotic resistance, particularly in hospital environments. As conventional treatments become less effective, there is an urgent need to explore alternative therapeutic strategies. One promising target is the histidine biosynthesis pathway, which is absent in humans but essential for bacterial survival. This study focuses on ATP phosphoribosyltransferase (HisG), the enzyme that catalyzes the first committed step in histidine biosynthesis. We investigated whether Bleomycin, a known anticancer drug, could interact with and potentially inhibit this enzyme in A. baumannii. Initial virtual screening identified Bleomycin as a top candidate based on its favorable docking score. Follow-up molecular interaction analysis revealed strong binding within the enzyme's active site, involving key residues critical for catalysis. To validate this computational prediction, surface plasmon resonance (SPR) was used to assess the binding kinetics of Bleomycin to recombinant HisG. The observed dissociation constant (KD = 270 nM) indicated moderate to strong affinity. Further, in vitro antibacterial assays demonstrated that Bleomycin significantly inhibited A. baumannii growth, with a minimum inhibitory concentration (MIC) of 7.8125 µg/mL. Time-dependent growth studies revealed strong bacteriostatic activity of Bleomycin at and above MIC concentrations. Overall, the results suggest that Bleomycin strongly interacts with the HisG active site and suppresses the growth of A. baumannii, highlighting its potential as a promising HisG-associated antibacterial agent. Further in vivo work is needed to assess safety and efficacy; this study opens the door to new therapeutic options using existing drugs to tackle multidrug-resistant pathogens.