Development of Gallium(III) as an Antimicrobial Drug Targeting Pathophysiologic Iron Metabolism of Human Pathogens.

Abstract

The treatment of infections is becoming more difficult due to emerging resistance of pathogens to existing drugs. As such, alternative druggable targets, particularly those that are essential for microbe viability and thus make it harder to develop resistance, are desperately needed. In turn, once identified, safe and effective agents that disrupt these targets must be developed. Microbial acquisition and use of iron is a promising novel target for antimicrobial drug development. In this Review we look at the various facets of iron metabolism critical to human infection with pathogenic microbes and the various ways in which it can be targeted, altered, disrupted, and taken advantage of to halt or eliminate microbial infections. Although a variety of agents will be touched upon, the primary focus will be on the potential use of one or more gallium complexes as a new class of antimicrobial agents. In vitro and in vivo data on the activity of gallium complexes against a variety of pathogens including ESKAPE pathogens, mycobacteria, emerging viruses, and fungi will be discussed in detail, as well as pharmacokinetics, novel formulations and delivery approaches, and early human clinical results.