Comprehensive analysis of iron utilization by Mycobacterium tuberculosis

Iron is essential for nearly all bacterial pathogens, including Mycobacterium tuberculosis (Mtb), but is severely limited in the human host. To meet its iron needs, Mtb secretes siderophores, small molecules with high affinity for iron, and takes up iron-loaded mycobactins (MBT) and carboxymycobacti...

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Vydáno v:PLoS pathogens Ročník 16; číslo 2; s. e1008337
Hlavní autoři: Zhang, Lei, Hendrickson, R. Curtis, Meikle, Virginia, Lefkowitz, Elliot J., Ioerger, Thomas R., Niederweis, Michael
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Public Library of Science 18.02.2020
Public Library of Science (PLoS)
Témata:
Amide Synthases - metabolism
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
Biological Transport
Biology and Life Sciences
Chromosomes
Efflux
Genetic research
Glycosylated hemoglobin
Heme
Heme - metabolism
Hemoglobin
Hemoglobins
Hemoglobins - metabolism
Humans
Infections
Iron
Iron - metabolism
Medicine and Health Sciences
Membrane Transport Proteins - genetics
Membrane Transport Proteins - metabolism
Mutants
Mutation
Mycobacterium tuberculosis
Mycobacterium tuberculosis - genetics
Mycobacterium tuberculosis - metabolism
Novels
Oxazoles - metabolism
Pathogenic microorganisms
Physiological aspects
Proteins
Research and Analysis Methods
Secretion
Siderophores
Siderophores - metabolism
Software
Transcription
Transcription (Genetics)
Transposon mutagenesis
Transposons
Tuberculosis
Utilization
Virulence
Alabama
United States > US
Texas
ISSN:1553-7374, 1553-7366, 1553-7374
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Shrnutí:Iron is essential for nearly all bacterial pathogens, including Mycobacterium tuberculosis (Mtb), but is severely limited in the human host. To meet its iron needs, Mtb secretes siderophores, small molecules with high affinity for iron, and takes up iron-loaded mycobactins (MBT) and carboxymycobactins (cMBT), from the environment. Mtb is also capable of utilizing heme and hemoglobin which contain more than 70% of the iron in the human body. However, many components of these iron acquisition pathways are still unknown. In this study, a high-density transposon mutagenesis coupled with deep sequencing (TnSeq) showed that Mtb exhibits nearly opposite requirements for 165 genes in the presence of heme and hemoglobin versus MBT and cMBT as iron sources. The ESX-3 secretion system was assessed as essential for siderophore-mediated iron uptake and, surprisingly, also for heme utilization by Mtb. Predictions derived from the TnSeq analysis were validated by growth experiments with isogenic Mtb mutants. These results showed that (i) the efflux pump MmpL5 plays a dominant role in siderophore secretion, (ii) the Rv2047c protein is essential for growth of Mtb in the presence of mycobactin, and (iii) the transcriptional repressor Zur is required for heme utilization by Mtb. The novel genetic determinants of iron utilization revealed in this study will stimulate further experiments in this important area of Mtb physiology.
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The authors have declared that no competing interests exist.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1008337