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A potential therapeutic for septic shock

We sometimes hear of post-surgery infections, which can even result in untimely death. The life-saving surgery at times leads to a life threatening recovery. In the intensive care units of hospitals, microbial contamination induces massive inflammation leading to sepsis or septic shock. This has been a rising cause of mortality worldwide in the hospital intensive care unit admissions.

As the famous saying goes “the more the merrier” does not necessarily hold true with new drugs because “less is always more”. All we need is a single efficient drug to combat the sudden and rapid spread of sepsis in the intensive care units of hospitals.

Sepsis is caused by the uncontrolled expression of several inflammatory genes in the host, leading to irreparable damages. The sudden onset and excessive expression of these genes leads to accumulation of harmful metabolic end products, resulting in multiple organ failure. During such cellular stress, some proteins are activated. Development of inhibitors to these stress activated proteins can help devise treatment of such disorders.

The stress activated proteins are comprised of two main subsets- c-Jun N-terminal Kinase (JNK) and p38 Mitogen Activated Protein Kinase (MAPK). It is interesting to note that this work stems out of an extensive collaborative work by three groups from IISc, K. Durga Prasad and T. N. Guru Row from SSCU, J. Trinath and K. N. Balaji from MCBL and Anshuman Biswas and K. Sekar from Bioinformatics. Carefully planned chemical modifications on the commercially available and expensive JNK inhibitor SP600125  improve its ability to bind and inhibit JNK at very low concentrations. The inhibitor also reduces the expression of the inflammatory genes, which in turn cascade into septic shock.“Our study is among the first reports of the description and meticulous biochemical characterisation of selective JNK inhibitors” says Professor Balaji K. N.

This selective and more efficient inhibition activity of JNK inhibitors could facilitate the generation of novel therapeutics to treat sepsis and other inflammatory disorders. It can also pave the way to understand the essential biological function of signalling pathways related to JNK.

About the authors:

Tayur N Guru Row is a Professor at Solid State and Structural Chemistry Unit (SSCU), IISc, Bangalore, India. Karothu Durga Prasad works in Guru Row’s group. K N Balaji is a Professor at Department of Microbiology and Cell Biology (MCBL), IISc, Bangalore and Jamma Trinath works at Balaji’s lab. Professor Kanagaraj Sekar works at the Supercomputer Education and Research Centre, IISc, Bangalore and Anshuman Biswas is his student.

Contact: http://mcbl.iisc.ernet.in/balaji/, http://sscu.iisc.ernet.in/guru_rao.html

K N Balaji balaji@mcbl.iisc.ernet.in; 080-2293 3223

Tayur N Guru Row sctng@sscu.iisc.ernet.in; 080-22932796

The paper appeared in the journal Scientific Reports in end November 2015. http://www.nature.com/srep/2014/141127/srep07214/full/srep07214.html