The Role of Iron and Chelators on Infections in Iron Overload and Non Iron Loaded Conditions: Prospects for the Design of New Antimicrobial Therapies

Abstract

Iron overload is known to exacerbate many infectious diseases. Infectious complications are considered to be the second main cause of morbidity and mortality in iron loaded thalassemia patients. Effective chelation therapy leading to the normalization of the iron stores could reduce the incidence of related infections. Microbial pathogens could obtain growth-essential iron from healthy hosts. Conversely, iron withholding and/or removal is an important defense strategy for mammalian hosts, which is primarily accomplished by the iron chelating proteins transferrin and lactoferrin. Chelating drugs could prevent microbial growth and play an essential role in antimicrobial therapeutic strategies. Specific mechanisms and interactions apply in the transfer or withholding of iron between the chelating drugs deferoxamine (DFO), deferiprone (L1) and deferasirox (DFRA) with microbial pathogens such as bacteria, fungi and protozoa. In some cases, chelators and in particular DFO, could act as a siderophore for the microbe and exacerbate infections such as yersiniasis and mucormycosis. Deferiprone appears to have the highest therapeutic index for long-term antimicrobial activity and the highest tissue penetration, including access to the brain. Selection of specific chelation therapy protocols could be considered in conditions where other antimicrobial therapies have failed or where resistance has developed to existing therapies.

Keywords:

• Iron
• Infection
• Thalassemia
• Antimicrobial
• Chelating drugs
• Deferoxamine (DFO)
• Deferiprone (L1)
• Deferasirox (DFRA)