Gallium as an Antibacterial Agent: A DFT/SMD Study of the Ga3+/Fe3+ Competition for Binding Bacterial Siderophores.

The urgency of finding novel antibacterial drugs (not only antibiotics), exhibiting different mechanisms of therapeutic action, is significant and has served as a premise for recognizing bacteria's siderophores as a plausible drug target. Bacteria secrete siderophores in order to sequester iron(III) from the surrounding medium by binding the essential metal with high affinity. Gallium, on the other hand, is an "abiogenic" ion, known for its anticancer, antibacterial, and anti-inflammatory action. The rationale behind its therapeutic effect lies in its close mimicry of the ferric ion. Since both ions share various physicochemical characteristics, it is of particular interest to understand if gallium could compete with the native ferric ion for binding siderophores and to decipher which molecular characteristics favor Ga3+ binding over Fe3+ binding. It is also well-known that some bacteria are susceptible to gallium-based therapy, while others are not. Therefore, many questions arise such as the following: (1) Which main group/groups building the siderophores promote gallium's attack? (2) Does the combination of the building blocks affect the preference toward a metal? (3) Does the environment play a crucial role? (4) Could the pH of the medium influence the balance between the ions? We try to address these questions by evaluating the free energy of the competition between Ga3+ and Fe3+ ions for siderophore ligands of various structures, denticities, and charge states by employing the tools of the computational chemistry at the DFT/SMD level. Our results not only fall in line with recent experimental data but also complement our knowledge about "Trojan horse" gallium-based therapy.