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Source: Howard Hughes Medical Institute (HHMI) Released: Thu
02-Feb-2006, 20:40 ET

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Ironing Out New Details of Tuberculosis Infection
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TUBERCULOSIS TB RAJESH GOKHALE HOWARD HUGHES MEDICAL INSTITUTE HHMI MBT
SIDEROPHORE IRON INFECTION
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Description

Scientists in India, led by a Howard Hughes Medical Institute
international research scholar, have identified five key genes that
enable the bacterium that causes TB to acquire the iron it needs to
sustain growth and promote infection.

Newswise - Scientists in India, led by a Howard Hughes Medical
Institute (HHMI) international research scholar, have identified five
key genes that enable Mycobacterium tuberculosis to acquire the iron it
needs to sustain growth and promote infection.

"Targeting genes within this cluster represents a good strategy for
preventing tuberculosis and other mycobacterial infections," said
Rajesh S. Gokhale, an HHMI international research scholar at the
National Institute of Immunology in New Delhi, India, and lead
investigator on the study. "Because some of these genes are conserved
across a number of related bacterial families, they are promising
targets for drugs to treat TB and other bacterial diseases."

The tuberculosis bacterium, which infects more than one third of the
world's inhabitants, is a leading cause of death and disease
worldwide.

Gokhale and colleagues report their findings in early online
publication January 30, 2006, in the Proceedings of the National
Academy of Sciences.

When M. tuberculosis infects humans, it takes up residence in immune
cells called macrophages. To survive in this harsh environment,
mycobacteria, like many other types of bacteria, need iron to carry out
life-sustaining functions, such as creating proteins and synthesizing
nucleotides to form DNA. However, free iron is not easily found in an
intracellular environment. To obtain this rare element, most bacteria
manufacture and secrete chemical compounds called siderophores that
scavenge iron from the environment.

Researchers discovered siderophores-chemical compounds used by
bacteria to scavenge iron from their cellular environment-well over
50 years ago, but the genes involved in adding the long-chain lipid
anchor that enables M. tuberculosis to do so more efficiently, remained
a mystery until now.

Mycobacteria have evolved siderophores with lipid-chain tails that
enable them to exploit the macrophage's lipid-trafficking system to
capture iron more efficiently. Instead of using siderophores that
diffuse freely, mycobacteria anchor their siderophores to lipid
membranes by means of a long fatty acid tail. After these siderophores
bind to iron within the macrophage, the lipid tail makes the iron
"sticky" enough to permit delivery to the very compartment in
macrophages where the mycobacteria are lurking.

Using microarray data, the available literature, and intuition,
Gokhale's group identified the location of the four genes that
produce the lipid tail after observing that the expression of the genes
significantly increased in response to low iron concentrations. The
gene required for the synthesis of the siderophore core, called mbt-1,
functions the same way, so Gokhale's team named the new locus mbt-2
and the new genes mbtK, mbtL, mbtM, and mbtN.

"Now that the major siderophore genes and their functions have been
defined, understanding the biosynthetic pathway provides an opportunity
to develop small-molecule inhibitors with the potential for developing
anti-tuberculosis drugs," said Gokhale. His team has already
determined that some of genes from the mbt-2 cluster is conserved
across several other bacterial species that cause various pulmonary,
skin, and organ diseases. Since the mbt-1 genes are also conserved
across many bacterial families, the mbt genes appear to be ideal
antibacterial targets for treating tuberculosis and other bacterial
infections, he said.


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