Implementation\nof Three Gallium-Based Complexes in\nthe “Trojan Horse” Antibacterial Strategy against A. baumannii: A DFT Approach

Microorganisms of the ESKAPE group pose an enormous threat\nto human\nwell-being, thus requiring a multidisciplinary approach for discovering\nnovel drugs that are not only effective but utilize an innovative\nmechanism of action in order to decrease fast developing resistance.\nA promising but still hardly explored implementation in the “Trojan\nhorse” antibacterial strategy has been recognized in gallium,\nan iron mimicry species with no known function but exerting a bacteriostatic/bactericidal\neffect against some representatives of the group. The study herewith\nfocuses on the bacterium A. baumannii and its siderophore acinetobactin in its two isomeric forms depending\non the acidity of the medium. By applying the powerful tools of the\nDFT approach, we aim to delineate those physicochemical characteristics\nthat are of great importance for potentiating gallium’s ability\nto compete with the native ferric cation for binding acinetobactin\nsuch as pH, solvent exposure (dielectric constant of the environment),\ndifferent metal/siderophore ratios, and complex composition. Hence,\nthe provided results not only furnish some explanation of the positive\neffect of three Ga<sup>3+</sup>-based anti-infectives in terms of\nmetal cation competition but also shed light on reported in vitro\nand in vivo observations at a molecular level in regard to gallium’s\nantibacterial effect against A. baumannii.