Down the synthetic route

Down the synthetic route
Considered as mankind’s greatest killer, Mycobacterium tuberculosis, the causative agent of tuberculosis, has challenged microbiologists and medical researchers for decades. Since the discovery of Mycobacterium tuberculosis in 1882, many scientists and researchers have employed different strategies to handle and treat mycobacterial infections. Long treatment regime, the emergence of multiple drug resistance strains and chronic infections are the serious challenges associated with tuberculosis control.

To find an effective strategy to handle these infections, researchers from different disciplines have started working together all over the globe. Two groups of scientists with different backgrounds from the Indian Institute of Science (IISc), Bengaluru, have tried out such an interdisciplinary approach for fighting these killer bacteria. Professor N Jayaraman and his group at the Department of Organic Chemistry and Professor Dipankar Chatterji and his group from the Molecular Biophysics Unit of IISc, have collaborated in designing a strategy to impede mycobacterial growth, its ‘sliding motility’ and its ‘biofilm’ structure. Sliding motility is a property by which bacteria spread on solid media surfaces. The survival of many pathogenic microbial species against antibiotics is dependent on their ability to grow as surface-associated multicellular communities called biofilm.

Protective covering
Several mycobacterial species, including M. tuberculosis, form drug-tolerant biofilms. Multiple drug resistance is attributed to its recalcitrance towards antibiotics. In simple terms, the bacterium becomes resistant to the antibiotics because of the strong biofilm layer formed around them into which drugs cannot penetrate posing a challenge to reducing or stopping the growth of this bacterium.

In a recently published paper, the researchers have successfully demonstrated the inhibition of mycobacterial growth and rupture of biofilms using synthetic glycolipids — a uniquely assembled synthetic sugar molecule. This synthetic molecule has shown a significant growth reduction and a higher biofilm inhibition in a model mycobacterium species called Mycobacterium smegmatis. “M. smegmatis is a widely accepted model organism for M. tuberculosis. They belong to the same genus, so, effects are expected to be similar”, says Dr Kirtimaan Syal, from the Molecular Biophysics Unit and also the lead author of this research. The researchers have chemically synthesised polysaccharides called straight and branched arabinomannan pentasaccharides with glycolipids and studied their effects on mycobacterial growth, biofilm rupture and sliding motility.

The results observed in this study are promising. The polysaccharide molecules have significantly reduced the mycobacterial growth and its sliding motility. The biofilm coat was observed to be ruptured by 80-85%, according to the results presented in the research paper. They have also tested the toxicity of these novel synthetic compounds on red blood cells and have found that they are non-toxic. This proves that these compounds have an effect on the pathogenic bacterium but does nothing to the healthy cells of the human body, thus making it safe.

Mycobacteria contains a chain of long fatty acids called mycolic acids in their cell walls, which forms the main component of their cell envelops. Previously, it has been proven that mycolic acids present in the cell envelope of mycobacteria are essential for biofilm formation. A difference in the mycolic acid profiles is found to be directly correlated to biofilm rupture. Interestingly, in this study, the researchers have shown a significant decrease in the mycolic acid profiles of these bacteria on treatment with the synthetic glycolipid, which explains its inhibitory effects.

Further analysis of the total lipid profiles through lipidomics — the large-scale study of pathways and networks of cellular lipids in biological systems, has shown a profound reduction or downregulation of different mycolic acids. This again substantiates the inhibitory effects of the compound on biofilms. “Although the mechanism of inhibition of the biofilm is unclear, it emerges that synthetic glycolipids are potent inhibitors of such phenotype function of a mycobacteria”, state the authors. 

When asked about how closer we are towards an effective drug against the infectious mycobacterium, Dr Kirtimaan Syal says, “The most interesting part of this concept is that sugars assembled in a unique design along with alkyl chain that is non-toxic to humans, can inhibit the biofilm formation and the growth of mycobacteria. The concentrations of the sugars required are high, but it represents a unique approach where sugars, which are nutrients to bacteria, can be assembled with alkyl chain to inhibit bacterial growth and biofilm formation. After many years of research, we have increased the inhibition of biofilm from 20-25% to 80-85% by such glycolipid compounds and we hope to improve further in coming years.”

It is evident from the study that synthetic compounds can have inhibitory effects against mycobacterial biofilms. With molecular biophysicists and organic chemists working hand in hand with microbiology and biophysics researchers, an effective cure for the deadly aftermaths of mycobacterial infections seems to be achievable in the near future.

(The author is with Gubbi Labs, a research collective, Bengaluru)
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