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June 19, 2014

T ODAY 'S PAPER FEAT URES SCI-T ECH & AGRI

Jun

Targeting a chink in TB bacterias armour

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2014
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The proof-of-concept study opens up new approaches to intervention; better molecules


are needed to take it beyond the lab
A novel approach adopted by a team of
researchers based in Bangalore has opened a
window of opportunities to design new
antimicrobials that could potentially be used to
kill the tuberculosis-causing bacteria.

Thinking differently:A nine-member team targeted a class


of proteins never before studied so far in any bacteria as
antimicrobial agents. From right to left: Tuhin Bhowmick,
Prof. S. Ramakumar, Prof. V. Nagaraja and Soumitra
Ghosh from IISc are part of the team.-- Photo: Special
Arrangement

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The nine-member team comprised of Ph.D


students and faculty/professors. The new
antimicrobials have been tested only in drugsensitive TB. But in principle, drug-resistant TB
bacteria should be equally vulnerable.
The results of the study were published recently

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in the journal Nature Communications. The team


was led by Prof. Valakunja Nagaraja, Department
of Microbiology and Cell Biology, Indian Institute of Science (IISc), Bangalore.
We targeted a class of proteins never targeted anywhere [in the world] and in any bacteria [as an
antimicrobial], said Prof. Nagaraja, highlighting the importance of the study.
The protein in question is HU, which is a histone-like protein that binds to DNA and compacts it. (The
DNA is a long thread and has to be compacted and condensed into a ball-like structure.) By binding and
compacting the DNA, the HU protein is able to regulate the DNA expression.

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HU plays a role in the expression of several genes (a few hundred genes). So it is called a global
regulator of gene expression, said Prof. Suryanarayanarao Ramakumar, Department of Physics, IISc,
Bangalore and a co-author of the paper.
Considering the predominant role played by the gene encoding for HU protein, knocking the gene
would in effect kill the TB causing bacterium Mycobacterium tuberculosis . And that was precisely
what the team ended up doing.
Since the HU protein binds to DNA and compacts it, they identified small molecules that can bind to
the surface of the HU protein and inhibit the binding.
In effect, the small molecules prevent HU-DNA interaction by binding to the protein. As a result, DNA
compaction is disrupted and gene expression goes haywire, explained Prof. Nagaraja. Since gene
expression is the hallmark of life, the small molecule causes the bacterias death.

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To identify the small molecules that can bind to the HU protein, the researchers first cloned the HUencoding gene. The protein that got expressed in large quantities was then purified. Prof. Ramakumars
team went ahead and derived the 3D structure of the protein using X-ray crystallography. The next
step involved the identification of the core of interaction in the HU protein. This was done for the first
time, said Prof. Ramakumar.
The DNA-binding protein has a large interface for interaction with the DNA. So in the large interface,
the researchers had to identify the core of interaction region the major part that interacts with the
DNA. Prof. Nagaraja likens the core of interaction to a cavity where something can go and fit in well.
Only one cavity which plays a role in the DNA binding was identified, said Prof. Nagaraja.
Following the identification of the core region, the researchers had to identify molecules that inhibit
the binding of HU protein with DNA. This was done using computational method. Two small (with
respect to proteins) chemical entities trans-stilbene derivatives were identified. Subsequently,

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did further studies to confirm the inhibitory action of stilbene derivatives, explained Prof.
Ramakumar.

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In the case of E. coli , there are 12 genes encoding for histone-like proteins that play a key role in DNA
compaction, and there are many genes that can act as a backup in case one gene is compromised.
Many of these genes in E. coli serve a redundant or backup function for HU. So HU protein is not
essential for cell survival in the case of E. coli , Prof. Nagaraja explained.
In contrast, in Mtb, only five histone-like proteins have been identified. But there seems to be no
additional gene that can do a function similar to that of HU protein. Hence, HU protein is vital for
Mtbs survival.
We realised that the under-representation of histone-like protein in Mtb means there is no backup for
the HU protein when it is knocked off. We realised the new approach to target the TB pathogen, Prof.
Nagaraja explained. Had a hunch wanted to study the HU protein in greater detail.
Quite surprisingly, while HU has been studied extensively in other organisms, it has not been studied
thoroughly in Mycobacterium tuberculosis the bacterium that causes TB.

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Prof. Nagaraja is extremely cautious of the new molecules clinical potential. This kind of basic
research opens up new approaches to intervention. But clearly more studies are required to take it to
the next level, he noted.
This is an important, breakthrough research, but there are caveats for translation [into clinical use].
We need better molecules and need to take it beyond the lab, he emphasised, snuffing out any false
hope of these molecules becoming the magic bullet to get rid of TB bacteria right away.
Inhibition [of binding] is inefficient The potency is not sufficient to go in for animal studies. Need to
find better molecules [there is] no way you can use these molecules directly but can aim to develop
better molecules.
In the end, its a proof-of-concept study, and a novel way of targeting TB bacteria. Thats the key
point, Prof. Nagaraja concluded.

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