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Targeting a chink in TB bacterias armour

R. PRASAD

T ODAY'S PAPER FEAT URES SCI-T ECH & AGRI June 19, 2014

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The proof-of-concept study opens up new approaches to intervention; better moleculesare needed to take it beyond the lab

A novel approach adopted by a team ofresearchers based in Bangalore has opened awindow of opportunities to design newantimicrobials that could potentially be used tokill the tuberculosis-causing bacteria.

The nine-member team comprised of Ph.Dstudents and faculty/professors. The newantimicrobials have been tested only in drug-sensitive TB. But in principle, drug-resistant TBbacteria should be equally vulnerable.

The results of the study were published recently

Jun 2014

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Thinking differently:A nine-member team targeted a classof proteins never before studied so far in any bacteria asantimicrobial agents. From right to left: Tuhin Bhowmick,Prof. S. Ramakumar, Prof. V. Nagaraja and SoumitraGhosh from IISc are part of the team.-- Photo: SpecialArrangement

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in the journal Nature Communications. The teamwas 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 anantimicrobial], 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. (TheDNA is a long thread and has to be compacted and condensed into a ball-like structure.) By binding andcompacting the DNA, the HU protein is able to regulate the DNA expression.

HU plays a role in the expression of several genes (a few hundred genes). So it is called a globalregulator 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 genewould in effect kill the TB causing bacterium Mycobacterium tuberculosis . And that was preciselywhat the team ended up doing.

Since the HU protein binds to DNA and compacts it, they identified small molecules that can bind tothe 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, DNAcompaction is disrupted and gene expression goes haywire, explained Prof. Nagaraja. Since geneexpression is the hallmark of life, the small molecule causes the bacterias death.

To identify the small molecules that can bind to the HU protein, the researchers first cloned the HU-encoding gene. The protein that got expressed in large quantities was then purified. Prof. Ramakumarsteam went ahead and derived the 3D structure of the protein using X-ray crystallography. The nextstep involved the identification of the core of interaction in the HU protein. This was done for the firsttime, 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 theDNA. 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 inhibitthe binding of HU protein with DNA. This was done using computational method. Two small (withrespect 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.

The basis

In the case of E. coli , there are 12 genes encoding for histone-like proteins that play a key role in DNAcompaction, 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 notessential 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 noadditional gene that can do a function similar to that of HU protein. Hence, HU protein is vital forMtbs survival.

We realised that the under-representation of histone-like protein in Mtb means there is no backup forthe 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 studiedthoroughly in Mycobacterium tuberculosis the bacterium that causes TB.

Miles to go

Prof. Nagaraja is extremely cautious of the new molecules clinical potential. This kind of basicresearch opens up new approaches to intervention. But clearly more studies are required to take it tothe 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 falsehope 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 tofind better molecules [there is] no way you can use these molecules directly but can aim to developbetter molecules.

In the end, its a proof-of-concept study, and a novel way of targeting TB bacteria. Thats the keypoint, Prof. Nagaraja concluded.

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