Essay On Mycobacterium Tuberculosis

Introduction

Drug resistance in mycobacterium tuberculosis (TB) has become a severe global health threat. The fight against TB is now facing major challenges due to the appearance of Multi-Drug Resistant Tuberculosis (MDR-TB) and more recently, the virtually untreatable Extensively Drug Resistant Tuberculosis (XDR-TB). MDR-TB are strains that are resistant to both top first-line drugs, Isoniazid and Rifampin, while XDR-TB are MDR-TB strains that are also resistant to any fluoroquinolone and one or more of 3 injectable drugs. With this new resistance, there emerges a great need to find new drugs that are as effective, yet bypass the problem of resistance. One method of research is to find new vulnerabilities of tuberculosis to use as new target sites of drugs. This method is highly expensive (Scheffler, Colmer, Tynan, Demain, & Gullo, 2013), and requires intense and lengthy research just to implicate the new target site. An alternative is to develop new drugs that work on the same already known target as the first-line drugs, but by a different mechanism, thereby bypassing the resistance of the TB to the drug.

Isoniazid (also referred to as isonicotinic acid hydrazide or INH), one of the top two first-line drugs, is a powerful anti-TB drug that works by inhibiting the action of InhA, a crucial enzyme in the process of manufacturing the cell wall. In recent years however, there have emerged strains of TB that are increasingly resistant to Isoniazid. Instead of searching for new targets, there is a goal to expand on this already terrific target, and by doing so, find drugs that inhibit InhA, but do it by a different mechanism, thereby, showing efficacy against MDR-TB strains.

Epidemiology

The World Health Organization estimates th...

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...315T mutation (Zhang & Yew, 2009). This is due to a single point mutation in the heme binding catalytic domain of KatG, causing a change at position 315 from a serine to an asparagine. The S315T mutant is observed to have a narrower heme access channel on KatG (4.7 Å compared to the wild type of 6 Å), suggesting that the loss of access of INH to the oxidizing site of KatG might be the key to INH-resistance (Timmins & Deretic, 2006). While isolates with this mutation completely lose the ability to form the isonicotinoyl-NAD/NADP adducts, most retain good catalase activity, and are able to survive despite the mutation (Gumbo, 2011). Less commonly, resistance is also seen in the promoter region of the InhA gene, causing the overexpression of InhA, and in mutations at the active site of InhA, causing InhA to have less affinity for the INH-NAD adduct (Zhang & Yew, 2009).