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

Iron-withdrawing anti-infectives for new host-directed therapies based on iron dependence, the Achilles’ heel of antibiotic-resistant microbes

“…1. More detailed reviews on the range of siderophores produced by different microbes can be found elsewhere (Ellermann and Arthur 2017;Holbein et al 2021;Holden and Bachman 2015;Johnstone and Nolan 2015;Wilson et al 2016).…”

“…Bacteria have developed various strategies to obtain heme iron from their host during infection by targeting heme, hemoglobin, or complexes containing these molecules (e.g., haptoglobin-hemoglobin, hemopexin-heme) as reviewed previously (Holbein et al 2021).…”

“…Various bacterial pathogens can utilize non-heme, iron-containing proteins as sources of iron, such as the transferrin class iron carrying proteins (transferrin in blood plasma and lactoferrin in exocrine secretions) as well as intracellular ferritins (Caza and Kronstad 2013;Chitambar 2010;Holbein 1981). Acquisition from transferrin and lactoferrin is typically through receptors for these proteins utilizing mechanisms as reviewed recently (Holbein et al 2021).…”

“…A more recent alternative approach is to target pathogens more broadly based on their irreplaceable and heightened requirements for a growth essential trace metal during infection (Holbein et al 2021). Iron requirements of pathogens stand out as the top candidate, given almost all bacterial and fungal pathogens have irreplaceable iron requirements for their growth and survival (Ganz 2018;Weinberg 2009).…”

“…Host-directed therapies, i.e., those that work with and enhance innate host defense mechanisms, offer broader and longer-term potential, i.e., as opposed to continued reliance on narrow-target microbe-directed antibiotic therapies. This article is an abridged and updated version of our recent more comprehensive review (Holbein et al 2021).…”