MOLECULAR RECOGNITION OF DEFEROXAMINE COMPLEXES WITH ALUMINUM, GALLIUM, AND IRON IN THE FHUE RECEPTOR: AN IN SILICO STUDY

Abstract

The World Health Organization has categorized Acinetobacter baumannii in the high-priority category, due to the urgent need for pharmacological strategies to combat its antibiotic resistance. The bacterial machinery for iron acquisition has been successfully employed in previous studies with different Gram-negative bacteria to internalize abiotic metals coordinated to siderophores through the Trojan horse effect. However, there are no reports yet with A. baumannii. In this work, an in silico study was conducted to explore the possibilities of applying this effect in A. baumannii, specifically by analyzing its hydroxamate-type iron-siderophore receptor (FhuE), and the molecular recognition of aluminum-desferrioxamine (Al-DFO) and gallium-desferrioxamine (Ga-DFO) complexes. A structural and energetic analysis of the complexes was carried out, including the control iron-desferrioxamine (Fe-DFO). We found significant differences in the chemical reactivity of Fe-DFO, which seemed not to influence the molecular recognition in FhuE. The affinity energy and intermolecular interactions were largely replicated when exchanging the metal, as per the docking analysis. However, molecular dynamics simulations showed that Al-DFO was primarily stabilized by hydrogen bonds, while Ga-DFO did so to a lesser extent, resembling Fe-DFO more closely. These results confirm that FhuE exhibits a molecular recognition of Al-DFO and Ga-DFO analogous to Fe-DFO. Therefore, the design of new metal-siderophore complexes could be a successful via for applying the Trojan horse effect in A. baumannii.