Frontier Leaders: The Human-Bacterial arms race for iron

Frontier Leaders Seminar

Title: The Human-Bacterial arms race for iron

Speaker: Kenneth N. Raymond

Affiliation: Department of Chemistry, University of California, Berkeley

Host: Ricardo Louro

Abstract

Transferrin maintains free human serum ferric ion concentration at 10-24 M. Pathogenic bacteria compete against this thermodynamic limit through clever coordination chemistry to obtain iron from their human host. It is difficult to overestimate the significance of iron as a limiting nutrient in microbial growth: enhancement of pathogenicity of 4 to 7 orders of magnitude are seen when iron is supplemented. Powerful and selective iron chelators (siderophores) are produced and secreted in response to iron deficiency. These are taken up by membrane transporters.

Spectacular advances have taken place in recent years in understanding the recognition and transport processes involved in siderophore-mediated iron acquisition. In the last few years siderocalin, a protein of the human innate immune system has been found to interrupt siderophore mediated iron transport of pathogenic bacteria.¹ Pathogens such as Bacillus anthracis (anthrax) produce “stealth” siderophores that are designed to evade this protein.² The production of different types of siderophores correlates with the different life cycles of B. anthracis. This seems part of a general pattern in which the more pathogenic type or stage of a bacterium correlates with the production of a stealth siderophore. Furthermore, there is recent evidence of a human siderophore,³ which will be discussed, along with recent other work. ⁴

1 D. Goetz, M. Holms, N. Borregaard, M. Bluhm, K. Raymond and R. Strong, “The Neutrophil Lipocalin NGAL is a Bacteriostatic Agent that Interferes with Siderophore-Mediated Iron Acquisition.” Mol. Cell 2002, 10, 1033-1043.
2 A. Zawadzka, R. Abergel, R. Nichiporuk, U. Andersen and K. Raymond, “Siderophore-mediated iron acquisition systems in Bacillus cereus: identification of receptors for anthrax virulence-associated petrobactin,” Biochemistry 2009, 48, 3645–3657.
3 G. Bao, M. Clifton, T. Hoette, K. Mori, S. Deng, A. Qiu, M. Viltard, D. Williams, N. Paragas, T. Leete, R. Kulkarni, X. Li, B. Lee, A. Kalandadze, A. Ratner, J. Pizarro, K. Schmidt-Ott, D. Landry, K. Raymond, R. Strong and Jonathan Barasch, “Iron traffics in circulation bound to a siderocalin (Ngal)–catechol complex,” Nature Chemical Biology, 2010, 6, 602-609.
4 Tatsuya Fukushima, Rita Nichiporuk, Allyson K. Sia, Benjamin E. Allred, Zhongrui Zhou, Ulla N. Andersen, and Kenneth N. Raymond, “New Bacillus cereus ferric citrate-binding protein FctC selectively binds diferric dicitrate and unusual triferric tricitrate”, to be submitted.