Characterization of two siderophores produced by Bacillus megaterium: A preliminary investigation into their potential as therapeutic agents

• Published in: Biochimica et biophysica acta. General subjects Vol. 1864; no. 10; p. 129670
• Main Authors: Chuljerm, Hataichanok, Deeudom, Manu, Fucharoen, Suthat, Mazzacuva, Francesca, Hider, Robert C., Srichairatanakool, Somdet, Cilibrizzi, Agostino
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2020
• Subjects: Animals; antioxidant activity; Antioxidants - chemistry; Antioxidants - pharmacokinetics; Antioxidants - pharmacology; Bacillus megaterium; Bacillus megaterium - chemistry; bioavailability; Cell Line, Tumor; Cells, Cultured; chelating agents; chelation; deferoxamine; gallium; hepatoma; human diseases; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacokinetics; Hydroxamic Acids - pharmacology; iron; Iron Chelating Agents - chemistry; Iron Chelating Agents - pharmacokinetics; Iron Chelating Agents - pharmacology; Iron overload; liquid chromatography; Male; mass spectrometry; microorganisms; mononuclear leukocytes; nuclear magnetic resonance spectroscopy; pharmacokinetics; rats; Rats, Sprague-Dawley; Schizokinen; Siderophores; Siderophores - chemistry; Siderophores - pharmacokinetics; Siderophores - pharmacology; therapeutics; urine; Siderophores; MRM; DFO; MTT; DMEM; LC-MS/MS; FBS; SK; UHPLC; Huh 7; Iron overload; PBS; DPPH; FAC; PBMC; ES; dH2O; SKI; CA-D4; LIP; NMR; CAS; TEAC; ROS; Bacillus megaterium; ABTS; PET; Schizokinen
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2020.129670

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. 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). 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. 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. 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. [Display omitted] •Schizokinen (SK) and schizokinen imide (SKI) display antioxidant activity in cells.•SK and SKI possess a strong Fe(III) affinity decreasing labile iron levels in cells.•Free SK and Fe(III)-SK complex are found in plasma and urine after SK oral gavage.•SK has potential for the development of 68Ga-PET agents for diagnostic applications.