How Bioinformatics will make that Persistent Hacking Cough Shush up

How Bioinformatics will make that Persistent Hacking Cough Shush up

Tuberculosis. You have probably heard about Victorian beauties. Of frail little things with lily-white faces and flights of fantasies that became immortalized in verse. Of Snow white with hacking cough, hollow cheeks, thick yellow sputum, night sweats, weakness, and paper weight. Poetic, they called it. They also called it Pthisis and consumption and romanticized these noble suffering souls.

Now, right now, it is no longer romantic to have TB. This global public health emergency is a significant cause of morbidity and mortality, accounting for nearly 1.5 million deaths every year. Statistics show that 12 million (yes, 178 out of every 100,000) odd souls have consumption. Regimens composed of SPIRE (streptomycin, pyrazinamide, isonaizid, rifampicin, ethambutol) have had cure rates of over 90% but it’s getting uglier since there are now deadlier multidrug resistant TB (MDR-TB) strains that are not sensitive to isoniazid and rifampicin. Heck, there is even extremely drug-resistant TB (XDR-TB).

Tuberculosis is caused by M. tuberculosis, a mycobacterium related to 5 other siblings all of which share significant homology and make up the mycobacterium tuberculosis complex (MTBC). M. tuberculosis is like the mythological Achiles. It is a bacterium that became invulnerable by being bathed in River Styx. But its heel was not washed. Now we are shooting poisonous arrows at that heel. We are Paris, aiming poisoned arrows at the heel. The paradox now is that the mycobacterium’s strongest link-its complex cell wall that consists of a lipid bi-layer membrane, mycolic acids esterified to a matrix of arabinogalactan and peptidoglycan residues, and a rich array of lipids - is its weakest link. The mycobacterial cell wall is the bacteria’s heel.

Thanks to bioinformatics, our arsenal is getting deadlier and deadlier. We are looking at designer molecules targeted against LprA lipoproteins, LPprG lipoproteins, lipomannan (LM), 19kDa and 27kDa lipoproteins, and surface-exposed mammalian cell entry (Mce) proteins. All these are cell wall ligands that mediate the mycobacterium’s entry into the host cell. Our arsenal includes rationally designed ligands that block human host receptors through which the mycobacterium gets into the host cell; ligands that block cholesterol receptors, toll-like receptors (TLRs), Dectin-1, CD 207, surfactant protein A receptors, DC-SIGN, scavenger receptors, and complement receptors. We also can retool molecules that will prevent host immune responses from being induced post ligand-receptor attachment. Our arsenal includes molecules that are designed to inhibit the synthesis of free lipids such as sulpholipids, glycopeptidolipids, glycosylated phenolpthiocerols, menaquinones, and pthiocerol dimycocerosates which intercalate with mycolic acids. Our arsenal includes molecules that prevent the production of trehalose dimycolate (TDM), pthiocerol dimycocerosate (DIM), phosphatidyl-myo-inositol mannosides (PIMs), lipomannan (LM), and lipoarabinomannan (LAM).

Looking at the metabolic pathways and networks involved in the biosynthesis of TDM, Phosphatidyl-myo-inositol Mannosides (PIMs), LAMS and LM, the linker unit, mycolic acids, and the plasma membrane, putative targets can be picked out and assessed for validity as a starting point. It is also possible to come up with anti-sense oligonucleotides that would stymie the expression of genes such as MptA that code enzymes such as ?(1 —6)-Mannopyranosyltransferase that take part in the biosynthesis of LAM and LM. In silico drug design is how bioinformatics will make that persistent hacking cough shush up. In silico drug design involving target identification and validation, lead identification and lead optimization will churn out newer and newer molecules that will cripple the pathways and bring the romanticism that comes with getting healed. This is how bioinformatics will make that persistent hacking cough shush up. Already, a couple of new therapies are under development.

Putative lead candidates include summit PLC compounds while those under optimization are riminophenazines, nitroimidazoles, GyrB inhibitor, mycobacterial gyrase inhibitors, MGyrX1 inhibitor, pyrazinamide analogues, LeuRS inhibitor, diarylquinoline, translocase-1 inhibitor, and InhA inhibitor. Several drugs are now at the preclinical stage and these include linezolid for XDR-TB, MOXIFLOXACIN, SQ-109 which is a derivative of ethambutol, pgatifloxacin and rifepentine. The in silico drug design approach will particularly be of greatest benefit to Asia and Africa which account for 59% and 26% respectively and together account for 85% of all the new TB infections globally.

It's now time to bring the open source initiative for TB drug development in Africa. Haven't we felt the sharpness of that hacking cough? And now ladies and gentlemen, the Africa Open Source Drugs Initiative

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