Lipidomic Analysis Links Mycobactin Synthase K to Iron Uptake and Virulence in M. tuberculosis

View/ Open
Author
Madigan, Cressida A.
Martinot, Amanda Jezek
Wei, Jun-Rong
Madduri, Ashoka
Cheng, Tan-Yun
Young, David C.
Layre, Emilie
Murry, Jeffrey P.
Published Version
https://doi.org/10.1371/journal.ppat.1004792Metadata
Show full item recordCitation
Madigan, Cressida A., Amanda Jezek Martinot, Jun-Rong Wei, Ashoka Madduri, Tan-Yun Cheng, David C. Young, Emilie Layre, Jeffrey P. Murry, Eric J. Rubin, and D. Branch Moody. 2015. “Lipidomic Analysis Links Mycobactin Synthase K to Iron Uptake and Virulence in M. tuberculosis.” PLoS Pathogens 11 (3): e1004792. doi:10.1371/journal.ppat.1004792. http://dx.doi.org/10.1371/journal.ppat.1004792.Abstract
The prolonged survival of Mycobacterium tuberculosis (M. tb) in the host fundamentally depends on scavenging essential nutrients from host sources. M. tb scavenges non-heme iron using mycobactin and carboxymycobactin siderophores, synthesized by mycobactin synthases (Mbt). Although a general mechanism for mycobactin biosynthesis has been proposed, the biological functions of individual mbt genes remain largely untested. Through targeted gene deletion and global lipidomic profiling of intact bacteria, we identify the essential biochemical functions of two mycobactin synthases, MbtK and MbtN, in siderophore biosynthesis and their effects on bacterial growth in vitro and in vivo. The deletion mutant, ΔmbtN, produces only saturated mycobactin and carboxymycobactin, demonstrating an essential function of MbtN as the mycobactin dehydrogenase, which affects antigenicity but not iron uptake or M. tb growth. In contrast, deletion of mbtK ablated all known forms of mycobactin and its deoxy precursors, defining MbtK as the essential acyl transferase. The mbtK mutant showed markedly reduced iron scavenging and growth in vitro. Further, ΔmbtK was attenuated for growth in mice, demonstrating a non-redundant role of hydroxamate siderophores in virulence, even when other M. tb iron scavenging mechanisms are operative. The unbiased lipidomic approach also revealed unexpected consequences of perturbing mycobactin biosynthesis, including extreme depletion of mycobacterial phospholipids. Thus, lipidomic profiling highlights connections among iron acquisition, phospholipid homeostasis, and virulence, and identifies MbtK as a lynchpin at the crossroads of these phenotypes.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376628/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:15034804
Collections
- HMS Scholarly Articles [18278]
- SPH Scholarly Articles [6399]
Contact administrator regarding this item (to report mistakes or request changes)