Metallotherapeutics development in the age of iron-clad bacteria

Drug-resistant infections pose a significant risk to global health as pathogenic bacteria become increasingly difficult to treat. The rapid selection of resistant strains through poor antibiotic stewardship has reduced the number of viable treatments and increased morbidity of infections, especially among the immunocompromised. To circumvent such challenges, new strategies are required to stay ahead of emerging resistance trends, yet research and funding for antibiotic development lags other classes of therapeutics. Though the use of metals in therapeutics has been around for centuries, recent strategies have devoted a great deal of effort into the pathways through which bacteria acquire and utilize iron, which is critical for the establishment of infection. To target iron uptake systems, siderophore-drug conjugates have been developed that hijack siderophore-based iron uptake for delivery of antibiotics. While this strategy has produced several potential leads, the use of siderophores in infection is diminished over time when bacteria adapt to utilize heme as an iron source, leading to a need for the development of porphyrin mimetics as therapeutics. The use of such strategies as well as the inclusion of gallium, a redox-inert iron mimic, are herein reviewed.