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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.

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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.

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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.

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