Hataichanok Chuljerm1, Manu Deeudom2, Suthat Fucharoen3, Francesca Mazzacuva4, Robert C Hider5, Somdet Srichairatanakool6, Agostino Cilibrizzi7. 1. Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. 2. Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. 3. Thalassemia Research Center, Institute of Molecular Bioscience, Mahidol University, Salaya Campus, Nakornpathom 73710, Thailand. 4. Mass Spectrometry Facility, King's College London, London, UK. 5. Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom. 6. Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address: somdet.s@cmu.ac.th. 7. Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom. Electronic address: agostino.cilibrizzi@kcl.ac.uk.
Abstract
BACKGROUND: Microorganisms produce siderophores in order to scavenge iron from the environment and this study focuses on the characterization of the two siderophores secreted by Bacillus megaterium. The general biological properties and pharmacokinetics following oral application of these compounds are reported. METHODS: Under optimized culture conditions, the siderophores were harvested, purified by chromatography and identified using LC-MS and NMR. Two dihydroxamate siderophores were isolated, schizokinen (MW = 420) and schizokinen imide (MW = 402). RESULTS: Both compounds demonstrate strong antioxidant activity and were found to be relatively nontoxic to both human hepatocellular carcinoma (Huh7) and peripheral blood mononuclear cells. The siderophores possess a strong affinity for iron(III) and decrease the levels of the labile iron pool (LIP) in iron-loaded cells in a concentration-dependent manner. Schizokinen, was detected as both the free siderophore and the iron complex in the plasma and urine of rats after oral gavage. CONCLUSIONS: However, the bioavailability was low and thus schizokinen, like deferoxamine, has no potential as an orally active iron chelator for the treatment of systemic iron overload. GENERAL SIGNIFICANCE: By virtue of the high affinity of schizokinen for tribasic metals, this siderophore does have considerable potential for the chelation of gallium(III) and the development of clinical diagnostic reagents.
BACKGROUND: Microorganisms produce siderophores in order to scavenge iron from the environment and this study focuses on the characterization of the two siderophores secreted by Bacillus megaterium. The general biological properties and pharmacokinetics following oral application of these compounds are reported. METHODS: Under optimized culture conditions, the siderophores were harvested, purified by chromatography and identified using LC-MS and NMR. Two dihydroxamate siderophores were isolated, schizokinen (MW = 420) and schizokinen imide (MW = 402). RESULTS: Both compounds demonstrate strong antioxidant activity and were found to be relatively nontoxic to both humanhepatocellular carcinoma (Huh7) and peripheral blood mononuclear cells. The siderophores possess a strong affinity for iron(III) and decrease the levels of the labile iron pool (LIP) in iron-loaded cells in a concentration-dependent manner. Schizokinen, was detected as both the free siderophore and the iron complex in the plasma and urine of rats after oral gavage. CONCLUSIONS: However, the bioavailability was low and thus schizokinen, like deferoxamine, has no potential as an orally active iron chelator for the treatment of systemic iron overload. GENERAL SIGNIFICANCE: By virtue of the high affinity of schizokinen for tribasic metals, this siderophore does have considerable potential for the chelation of gallium(III) and the development of clinical diagnostic reagents.