ADVERTISEMENT

Synthetic Glycolipids As A New Class Of Antimicrobials To Down-regulate Cell Wall Functions

Microbial species constitute the most abundant and oldest life forms on earth among organisms.  Studies aimed at understanding the ability of microbes to withstand and survive harsh environmental conditions opens-up important learning on the complex, networked lifestyles of the microbes.  The lifestyle nature of many pathogenic bacteria is a primary concern for human welfare and healthcare, as the pathogen on-slaught leads to immuno-compromise of host cells and to their eventual pathogenesis.

Altered genomic and metabolic processes regulate the survival mechanisms of pathogenic bacteria under environmental stresses.  Colonization is a key survival strategy of many pathogens, it occurs readily when the cells attach onto surfaces and quorum sensing processes are initiated, leading to the cells adopting phenotype changes.  One such phenotype change onto surface-bound pathogenic mycobacterial cell colonies is the formation of an extra-cellular polymer matrix, known as a biofilm.  A biofilm of grown mycobacteria is well-protected from environmental stresses, including the inability of potent antimicrobials and antibiotics to be effective against the pathogen.

ADVERTISEMENT

Whereas the mycobacteria cell membrane exposes outer cell wall components composed of thick, waxy mixture of glycolipids, the biofilm is composed of a heterogeneous mixture that includes polysaccharides, proteins, and nucleic acids.  Synthetic glycolipids that mimic the constituent components of the cell-wall bound glycolipids might act as ligands for enzymes responsible for the biochemical assembly of such cell-wall bound glycolipids.  An important cell-wall bound glycolipid is the lipoarabinomannan, composed of arabinan, mannan and mycolic acids.  Further, the presence of mannan caps is essential in order to induce virulence in the case of pathogenic M. tuberculosis.

 

Armed with rich information on cell-wall bound glycolipids of pathogenic mycobacteria and biofilm, chemically synthesized glycolipids were developed as potent ligands to modulate the biochemical processes associated with the mycobacterial growth, motility and biofilm formation.  Using the fast-growing, acid-fast species M. smegmatis, synthetic glycolipids constituted with arabinan, mannan and lipid, are found to exhibit potent inhibitory activities against the mycobacterial growth.  As opposed to only arabinan containing glycolipids, oligosaccharide arabinomannan glycolipids are observed to inhibit the mycobacterial growth more effectively.  Heptasaccharide arabinomannan glycolipids show growth reduction to as much as 85% when M. smegmatis was treated with the ligand at 100 microgram/mL.

Further, such synthetic glycolipids exert profound inhibition activities on the sliding motility actions of the growing mycobacterium and on the biofilm.  Sliding motilities are disrupted and the biofilm coat is ruptured upon treating the cells with the synthetic glycolipids.  These phenotype functions of the mycobacterium are inhibited to as much as 90% by the glycolipids.  Critical events of mycolic acid and phosphatidylinositol mannoside biosynthesis are heavily down-regulated, along with moderate down-regulation of further components, when the bacterium is treated with the glycolipids.  The synthetic arabinomannan glycolipids are non-toxic to human red blood cells.

ADVERTISEMENT

Expanding the scope of the inhibitory potencies, further research has shown that the glycolipids could supplement the inhibitory activities of well-known M. tuberculosis antibiotic, namely, isoniazid.  This drug exhibits inhibition of mycolic acid biosynthesis in a growing mycobacterium.  A biofilm formed mycobacterium can acquire a drug tolerance, as the biofilm blocks the drug actions.

Combined with the observation of biofilm disruption by synthetic glycolipids, it is now established that a biofilm grown mycobacterium can be treated with a combination of isoniazid drug and synthetic glycolipid inhibitor (50 microgram/mL), so as to improve upon the drug action by more than three-fold.  Development of the new types of glycolipid inhibitors in mycobacterial research can be accessed in the recent publication ChemBioChem. 2017, 18, 1959-1970.

This study, Synthetic Arabinomannan Heptasaccharide Glycolipids Inhibit Biofilm Growth and Augment Isoniazid Effects in Mycobacterium smegmatis, by Maiti, K.; Syal, K.; Chatteri, D.; Jayaraman, N., was recently published in the journal ChemBioChem.

Comments

READ THIS NEXT

What Elements Are In Lipids?

Lipids are macromolecules, large organic molecules, that carry out many different functions needed for life. Lipids function to store energy, […]

The Surface Roughness Of 433 Eros From The NEAR Laser Rangefinder

The Near-Earth (not hazardous to Earth) asteroid 433 Eros was explored by the NEAR-Shoemaker spacecraft in 2000-2001. This mission, built […]

Taming Elusive Molecules For Energy Conversion, Pollutant Removal, And Generation Of Valuable Resources

Every day we are surrounded by chemical processes that improve our quality of life, while most of us are not […]

7 Continents Map

The map of the seven continents encompasses North America, South America, Europe, Asia, Africa, Australia, and Antarctica. Each continent on […]

A Synthetic Metabolism Approach For Boosting Plant Yields

In ‚ÄúAn Essay on the Principle of Population‚ÄĚ, published in 1798, Thomas Malthus put forward his famous population trap concept, […]

Is NH3 Polar Or Nonpolar?

Ammonia, chemical formula NH3, is a colorless gas frequently used in the production of fertilizer, as a cleaning chemical, and […]

Fixing Science Using A New Science Of Science

How do we understand and learn about the world? By gathering information. If we perform enough experiments and write down […]

Science Trends is a popular source of science news and education around the world. We cover everything from solar power cell technology to climate change to cancer research. We help hundreds of thousands of people every month learn about the world we live in and the latest scientific breakthroughs. Want to know more?