Advisory Committee Chair
Michael Niederweis
Advisory Committee Members
Charles L Turnbough, Jr
David M Bedwell
William H Benjamin, Jr
Hui Wu
Document Type
Dissertation
Date of Award
2012
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Iron is an essential nutrient for the vast majority of organisms; yet, the availability of iron is limited to microorganisms due to the insolubility of ferric hydroxides and to pathogens by iron withholding strategies of their hosts. Many bacteria produce small, high-affinity iron chelators called siderophores to scavenge iron from the environment. In addition, many bacterial pathogens have evolved mechanisms to steal host iron contained in heme, hemoglobin, or transferrin. Mycobacteria are unique genera of bacteria represented by the notorious pathogens Mycobacterium tuberculosis and Mycobacterium leprae, the causative agents of tuberculosis (TB) and leprosy, respectively. Tuberculosis remains a global health concern. 2010 witnessed nearly 2 million deaths from TB and a 47% increase in the number of multi-drug resistant TB cases. M. tuberculosis produces the siderophores mycobactin and carboxymycobactin. Even though mycobactin was one of the first siderophores characterized, little is known about siderophore transport in this organism. In this work, I illuminate the iron acquisition systems of M. tuberculosis, demonstrating for the first time that M. tuberculosis can utilize heme as an iron source independently of siderophores but not transferrin-bound iron nor iron salts. This is in contrast to the soil-dwelling M. smegmatis, which employs general porins in the mycobacterial outer membrane for the uptake of iron salts. This finding is the first demonstration of the long held assumption that general porins can mediate the uptake of iron salts. I also demonstrate that mycobactin and carboxymycobactin are recycled in M. tuberculosis by a process dependent on the M. tuberculosis siderophore secretion systems involving the membrane proteins MmpS4/MmpL4 and MmpS5/MmpL5. The addition of purified mycobactin or carboxymycobactin to a mutant deficient in siderophore secretion results in the intracellular accumulation of deferrated siderophores causing severe growth attenuation. This siderophore-dependent growth inhibition of the secretion mutant still occurs despite the presence of heme and could be reduced by eliminating de novo siderophore biosynthesis. Taken together, these results suggest that the buildup of intracellular siderophores due to lack of secretion and/or recycling decreases the fitness of M. tuberculosis by both iron-acquisition dependent and independent mechanisms. The same cannot be said about the fitness of an M. tuberculosis mutant deficient in siderophore biosynthesis. Thus, pharmacological intervention into the siderophore secretion and recycling systems of M. tuberculosis might make better drug targets than siderophore biosynthesis enzymes.
Recommended Citation
Jones, Christopher M., "Mycobacterial Iron Acquisition Systems" (2012). All ETDs from UAB. 2063.
https://digitalcommons.library.uab.edu/etd-collection/2063