MRNA Interferases from Mycobacterium tuberculosis

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'''mRNA Interferases from Mycobacterium tuberculosis  :  a drug candidate for tuberculosis therapy'''
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                    '''Where are we standing?????????????????????'''
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Tuberculosis, an airborne infection that mainly affects the lungs, is classified as a “global health emergency” by the World Health Organisation. It is the most deadly and widespread major infectious disease, claiming the lives of two to three million people a year – one person every 15 seconds.
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The bacterium’s ability to lie dormant allows it to evade antibiotic treatment because most antibiotics target growing cells. Added to this, there has been a dramatic increase in multi-drug resistant strains of Mycobacterium tuberculosis and increased susceptibility to the disease of HIV-infected individuals. Effective treatment for TB currently requires combinations of expensive drugs for sustained periods of six to 12 months.
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Toxin targets are also of practical interest because they could be potential new drug targets in pathogenic bacteria
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Prokaryotic chromosomes code for toxin–antitoxin (TA) loci, often in multiple copies. Experimental evidence  indicates that TA loci are stress-response elements that help cells survive unfavorable growth conditions. The first gene in a TA operon codes for an antitoxin that combines with and neutralizes a regulatory ‘toxin’, encoded by the second gene.
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Mycobacterium tuberculosis has 65 chromosomal toxin–antitoxin loci, including 3 relBE and 9 mazEF loci
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The toxin component of TA operon MazF proteins involved in RNA interferase. These proteins chop up RNA in a sequence specific manner, which potentially arrests the growth of Mycobacterium tuberculosis.
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It has been proved that mRNA interferases target longer RNA sequences may alter protein expression through differential mRNA degradation, a regulatory mechanism that may allow adaptation to environmental conditions, including those encountered by M. tuberculosis during infection.
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One of the most compelling reasons to look at these proteins is that antibiotics in general work by seeking out and killing actively growing bacteria. It has been found that these proteins are responsible for arresting the growth of TB bacteria and enabling them to lie dormant. If we can get dormant TB bacteria to grow, this may make TB more susceptible to current antibiotic treatment.”
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After 126 years, the etiological agent of deadly tuberculosis (http://en.wikipedia.org/wiki/Tuberculosis) has been discovered by Robert Koch, we have only one vaccine and few countable antibiotics against tuberculosis. Is this justifiable?
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Because MazF proteins are present in a range of mycobacteria, the research findings will be applicable to other diseases, including bovine tuberculosis and Johne’s disease in cattle, caused by Mycobacterium avium subspecies paratuberculosis.
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Recent estimates of Tuberculosis disease is approximately 1.86 billion people with 16.2 million cases of active diseases. (Dye etal.,1999). It’s a fact and I also support that not a single treatment but a combinatorial approach is required against this culprit. We are living in the age of biotechnology and Nanotechnology so we should look for molecular medicine which may be some involve synthetic  molecules mimicking that in system approaches.  Through this article I have tried to make people think about the computers, biomolecules and some naturally occurring compounds as a combinatorial approach to fight the evil like tuberculosis.  
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“The future success in searching for new TB drug treatments will be based on understanding of the biology, dormancy and persistence of the tuberculosis bacterium, In targeting research towards the toxin-antitoxin proteins and the regulation of their genes.
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In my this report I am suggesting one of my idea although its very older approach which has been discovered in 20th century that is Antisense DNA technology (http://en.wikipedia.org/wiki/Antisense_therapy). I have targeted the dna N gene (Gene ID 887092) (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=57116681 from 2052 to 3260) of Mycobacterium tuberculosis H37Rv strain which is a DNA Polymerase III and is a complex, multi-chain enzyme responsible for most of the replicative process in bacteria. This DNA polymerase also exhibits 3' to 5' exonuclease activity.  
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A brief description of the method is as follows:
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•The sequence of the dna N gene has been analyzed for GC rich region which is from 2152 to 2172 of coding region (Total length of dna N gene in the genome of Mycobacterium 2052 to 3260).
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•The sequence was aligned with both the human genome (host of Mycobacterium tuberculosis) and Mycobacterium genome itself using the BLAST tool.
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•It was found that there was no significant homology between the genome of human and the oligonucleotide we are going to use for Antisense against dna N gene. This shows that the oligo would act specifically against Mycobacterium.
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•It was also observed that the oligo has homology with other gene of Mycobacterium tuberculosis H37Rv strain.
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•Then an expression vector (eg:  pCS 105 vector modified by Duve Turner’s) has been designed that will produce the antisense against the transcribed portion of dna N gene.
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•This vector has been transfected into the cell.
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•The vector would transcribe the antisense and this antisense result in DNA/RNA hybrid and RNase H degrade that hybrid resulting in no translation and killing of our target.
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This report is just an idea how we can utilize the molecular medicine and the drugs which are available to treat nasty tuberculosis. Although people have tried such approaches so I think computational biology alongwith our knowledge of disease can help in knocking out deadly pathogens.
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Courtesy: http://venturebeat.com/wp-content/uploads/2007/11/ .This picture is showing how  antisense therapy woks to inhibit expression of particular gene.
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References:
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Dye,C., Scheele,S., Dolin,P., Pathania,V., and Raviglione,R.C. (1999). Global burden of tuberculosis—estimated incidence, prevalence, and mortality by country. J. Am. Med. Assn. 282,677–686

Revision as of 09:48, 9 September 2008

                   Where are we standing?????????????????????

After 126 years, the etiological agent of deadly tuberculosis (http://en.wikipedia.org/wiki/Tuberculosis) has been discovered by Robert Koch, we have only one vaccine and few countable antibiotics against tuberculosis. Is this justifiable? Recent estimates of Tuberculosis disease is approximately 1.86 billion people with 16.2 million cases of active diseases. (Dye etal.,1999). It’s a fact and I also support that not a single treatment but a combinatorial approach is required against this culprit. We are living in the age of biotechnology and Nanotechnology so we should look for molecular medicine which may be some involve synthetic molecules mimicking that in system approaches. Through this article I have tried to make people think about the computers, biomolecules and some naturally occurring compounds as a combinatorial approach to fight the evil like tuberculosis. In my this report I am suggesting one of my idea although its very older approach which has been discovered in 20th century that is Antisense DNA technology (http://en.wikipedia.org/wiki/Antisense_therapy). I have targeted the dna N gene (Gene ID 887092) (http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=57116681 from 2052 to 3260) of Mycobacterium tuberculosis H37Rv strain which is a DNA Polymerase III and is a complex, multi-chain enzyme responsible for most of the replicative process in bacteria. This DNA polymerase also exhibits 3' to 5' exonuclease activity.

A brief description of the method is as follows:

•The sequence of the dna N gene has been analyzed for GC rich region which is from 2152 to 2172 of coding region (Total length of dna N gene in the genome of Mycobacterium 2052 to 3260). •The sequence was aligned with both the human genome (host of Mycobacterium tuberculosis) and Mycobacterium genome itself using the BLAST tool. •It was found that there was no significant homology between the genome of human and the oligonucleotide we are going to use for Antisense against dna N gene. This shows that the oligo would act specifically against Mycobacterium. •It was also observed that the oligo has homology with other gene of Mycobacterium tuberculosis H37Rv strain. •Then an expression vector (eg: pCS 105 vector modified by Duve Turner’s) has been designed that will produce the antisense against the transcribed portion of dna N gene. •This vector has been transfected into the cell. •The vector would transcribe the antisense and this antisense result in DNA/RNA hybrid and RNase H degrade that hybrid resulting in no translation and killing of our target. This report is just an idea how we can utilize the molecular medicine and the drugs which are available to treat nasty tuberculosis. Although people have tried such approaches so I think computational biology alongwith our knowledge of disease can help in knocking out deadly pathogens.

Courtesy: http://venturebeat.com/wp-content/uploads/2007/11/ .This picture is showing how antisense therapy woks to inhibit expression of particular gene.

References:

Dye,C., Scheele,S., Dolin,P., Pathania,V., and Raviglione,R.C. (1999). Global burden of tuberculosis—estimated incidence, prevalence, and mortality by country. J. Am. Med. Assn. 282,677–686

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