Gallium nitrate inhibits multidrug-resistant Acinetobacter baumannii isolated from bloodstream infection by disrupting multiple iron-dependent metabolic processes

Abstract

Background: Acinetobacter baumannii is a major pathogen in hospitals, causing a notable rise in bloodstream infections among inpatients. Its growing resistance to multiple drugs limits treatment options. This study aims to examine the antibacterial effects of gallium nitrate [Ga(NO3)3] against A. baumannii and elucidate the underlying molecular mechanism. Methods: 40 strains of A. baumannii with different antimicrobials susceptibility patterns were isolated from bloodstream infections. The in vitro antibacterial activity of Ga(NO3)3 was analyzed by micro-dilution method and time-kill assay. The influence of ferric chloride/hemin on the antibacterial efficacy of Ga(NO3)3 was investigated. Transcriptome sequencing was performed to elucidate the antibacterial mechanism of Ga(NO3)3. A mouse infection model was conducted to assess its in vivo performance. Results: Ga(NO3)3 exhibited a potent antibacterial effect in RPMI 1640 medium containing 10% human serum, with MICs ranging from 0.06 μg/mL to 0.125 μg/mL. The antibacterial activity of Ga(NO3)3 was found to be dose- and time- dependent. However, the antibacterial effect of Ga(NO3)3 was partially compromised in the presence of exogenous ferric chloride/hemin. Transcriptomics analysis revealed that Ga(NO3)3 exerted its antibacterial effect by up-regulating the expression of genes associated with siderophore biosynthesis and transport, while simultaneously disrupting multiple iron-dependent metabolic processes. Ga(NO3)3 treatment significantly reduced bacterial load in vivo using a neutropenic mouse thigh infection model. Conclusion: This study sheds light on the antibacterial mechanisms of Ga(NO3)3 against A. baumannii, suggesting its potential as a promising antibacterial drug for treating bloodstream infections caused by multidrug-resistant A. baumannii.