Synergy and antagonism between iron chelators and antifungal drugs in Cryptococcus

Area of Science:

• Mycology
• Antimicrobial drug development
• Infectious diseases

Background:

• Fungal infections are difficult to treat, driving research into synergistic agents to improve existing antifungal therapies.
• Iron limitation can inhibit fungal growth, leading to the exploration of iron chelators as potential antifungal adjuvants.
• Understanding how iron homeostasis disruption impacts antifungal susceptibility is crucial for developing novel treatment strategies.

Purpose of the Study:

• To investigate the synergistic potential of combining various iron chelators with established antifungal agents against pathogenic Cryptococcus species.
• To determine the effect of disrupting iron homeostasis on the susceptibility of Cryptococcus to antifungal drugs.
• To identify specific combinations that enhance antifungal efficacy and potentially overcome resistance.

Main Methods:

• Chequerboard testing was employed to systematically evaluate combinations of six iron chelators (EDTA, DFO, DFP, DSX, ciclopirox olamine, LF) with five antifungal agents (AmB, fluconazole, itraconazole, voriconazole, caspofungin).
• Combinations were tested against pathogenic Cryptococcus spp. to assess synergistic, additive, or antagonistic effects.
• Experiments included assessing the impact of exogenous iron addition on drug efficacy.

Main Results:

• Most tested chelators, except deferoxamine (DFO), enhanced the efficacy of amphotericin B (AmB) against Cryptococcus.
• Significant synergy was observed between AmB and lactoferrin (LF) across all tested Cryptococcus strains.
• Lactoferrin's synergistic effect with AmB was not solely due to iron chelation, as exogenous iron did not prevent the combined inhibition.
• Other antifungal-chelator combinations did not consistently show synergy, and some chelators antagonized azole drugs.

Conclusions:

• The combination of amphotericin B and lactoferrin presents a promising synergistic antifungal strategy against Cryptococcus, operating through mechanisms beyond simple iron chelation.
• Iron limitation does not universally enhance antifungal drug activity in Cryptococcus, and some chelator-drug combinations can be antagonistic.
• Further research into the non-iron-related properties of lactoferrin is warranted to fully understand its potentiation with amphotericin B.