A reevaluation of iron binding by Mycobactin J
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The complex stability constant (log β110) and the free iron concentration (pM) are used to compare the relative strength of iron binding by siderophores. Direct measurements of these thermodynamic parameters are often not possible for siderophores due to very large log β110 values ranging from 30 to 50. Instead, siderophore iron(III)-binding constants are determined by competitive experiments with other strong chelators with known values, such as EDTA. Iron(III) binding constants of water-insoluble siderophores, such as the mycobactins produced by the mycobacterium family, have never been directly measured. Since mycobactins contain two hydroxamic acid binding motifs, their log β110 values have been assumed to be comparable to those of other hydroxamate-based siderophores like desferrioxamine B, at ~ 30. However, exochelin MN, another mycobacterial siderophore that contains two hydroxamic acid moieties, has a log β110 of 39.1 and a pM of 31.1, which makes it among the strongest siderophores known. We have found that mycobactin J, the amphiphilic siderophore of Mycobacterium paratuberculosis, can remove iron(III) from TrenCAM (log β110 = 43.6) within 1 min in methanol. This surprising result indicates that log β110 for mycobactin J is ~ 43 and the ligand exchange kinetics in methanol is fast. The results imply that mycobactins are capable of removing iron quickly from very strongly binding siderophores in a cellular milieu. We propose a model mechanism for iron acquisition by pathogenic mycobacteria in vivo. This model explains how the host iron captured by siderophores can be returned to the invading pathogen even in the absence of active uptake mechanisms.
KeywordsIron acquisition Carboxymycobactin Exochelin Bacterial microvesicles
This work was supported by the US National Science Foundation award CHE-1464578. This paper is dedicated, with congratulations, to Alison Butler on the occasion of her receipt of the ACS Alfred Bader Award in Bioinorganic or Bioorganic Chemistry for 2018.
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Conflict of interest
The authors declare no competing financial interests.
- 5.Global tuberculosis control: epidemiology, strategy, financing: WHO report 2009 (2009) World Health Organization. Switzerland, Geneva, pp 6–33Google Scholar
- 6.Vilcheze C, Kim J, Jacobs WR (2018) Antimicrob Agents Chemother 62(3). pii: e02165-17. https://doi.org/10.1128/AAC.02165-17
- 17.Juárez-Hernández RR, HZ H, Miller MJ (2013) Siderophore-mediated iron acquisition: Target for the development of selective antibiotics towards mycobacterium tuberculosis. Springer, HeidelbergGoogle Scholar
- 18.Ryan KJ, Ray CG (eds) (2003) Sherris medical microbiology: An introduction to infectious diseases sherris medical microbiology: an introduction to infectious diseases. McGraw-Hill, New YorkGoogle Scholar
- 32.Hardy CD, Butler A (2018) J Biol Inorg Chem 23. https://doi.org/10.1007/s00775-018-1584-2
- 56.McQueen TM (2004) A novel approach to the study of equilibrium phase behavior: theory and practice. Chemistry. Harvey Mudd College, ClaremontGoogle Scholar
- 59.Crumbliss AL and Harrington JM (2009) In: R. Van Eldik and C. D. Hubbard (eds) Advances in Inorganic Chemistry, vol 61: Metal Ion Controlled Reactivity, p 179–250, Elsevier Academic Press Inc, San DiegoGoogle Scholar
- 68.Ratledge C, Dale J (eds) (1999) Mycobacteria: molecular biology and virulence mycobacteria: molecular biology and virulence. Blackwell Science Ltd., OxfordGoogle Scholar
- 89.Lide DR (ed) (2010) CRC Handbook of Chemistry and Physics. CRC Press/Taylor and Francis, Boca RatonGoogle Scholar