Exploiting the Achilles’ Heel of Iron Dependence in Antibiotic Resistant Bacteria with New Antimicrobial Iron Withdrawal Agents

Abstract

Pathogenic microorganisms including bacteria and fungi have irreplaceable needs for iron as critically needed for the activities of a wide array of essential enzymes that are vital for energy production, metabolism, nucleic acid synthesis and cellular defense. Various virulence-associated iron acquisition mechanisms are deployed by microbes as iron availability in vertebrate hosts is quite limited and host innate defense mechanisms seek to further withdraw iron availability during infection. Antibiotic resistant microbes appear unaltered in their iron requirement, but iron withdrawal can enhance microbial sensitivity to various antibiotics and suppress outgrowth of antibiotic-exposed resistant survivors. Thus, iron dependence of antibiotic resistant microbes represents an Achilles’ heel that can be exploited as the basis of alternative therapeutic approaches to address infection. Three major therapeutic approaches can potentially exploit this susceptibility of antibiotic resistant microbes. Gallium, a non-functional iron analogue metal can be used to thwart microbes as it can substitute and effectively displace functional iron, resulting in loss of iron dependent enzymes critical for microbial growth. A second approach utilizes synthetic copies of microbial iron acquisition siderophores chemically linked to antibiotics resulting in Trojan-horse carriers that are imported into microbial cells utilizing their own siderophore uptake systems to thereby deliver antibiotics to their cytoplasmic targets. Thirdly, new generation iron chelators that have been purpose-designed as antimicrobials offer advantages over conventional hematologically used chelators for selective iron withdrawal from antibiotic sensitive or resistant pathogens. Importantly, these chelators also function to bolster innate iron withdrawal defenses of the infected host. To date, the 3-hydroxypyridin-4-one containing chelators appear to have the most promise. DIBI (developmental name) is an example of these new agents and it is a low molecular weight, water-soluble copolymer with strong antimicrobial activity yet it exhibits a very low toxicity profile for animals.