Potentiation of Available Antibiotics by Targeting Resistance – An Emerging Trend in Tuberculosis Drug Development

Abstract

Mycobacterial infections are one of the leading causes of death through disease world-wide (World Health Organization, 2010), encompassing infections such as tuberculosis (TB), leprosy, Buruli ulcers, and opportunistic non-tuberculosis mycobacterial (NTM) infections in immune-compromised individuals, especially patients with acquired immune deficiency syndrome (AIDS). The World Health Organization has estimated that one third of the world’s population is currently infected with Mycobacterium tuberculosis, the causative agent of TB, although only ten percent of those infected will develop active disease (World Health Organization, 2010). Highest TB incidences are located in sub-Saharan Africa and Southeast Asia, coinciding with human immunodeficiency virus (HIV) hot spots (World Health Organization, 2010). The extremely high level of intrinsic resistance to most antimicrobial drug classes exhibited by M. tuberculosis has left us with a very limited arsenal of useful anti-TB drugs (Nguyen & Thompson, 2006). The five available first-line drugs, isoniazid (INH), rifampicin (RIF), ethambutol (EMB), pyrazinamide, and streptomycin, are all more than sixty years old (Nguyen & Pieters, 2009, Nguyen & Thompson, 2006). Furthermore, the current standard regimen (DOTS) for TB is comprised of six to nine months of daily antibiotic treatment with a combination of four out of these five drugs, often leading to poor patient adherence and incomplete courses of treatment. The rapid rate of mutations occurring in bacteria in general, together with the frequent exposure of M. tuberculosis to sub-optimal doses of drugs, have granted ample opportunity for this pathogen to acquire additional resistance by amassing sequential mutations in drug-target encoding genes (Nguyen & Pieters, 2009, Nguyen & Thompson, 2006). Accordingly, we now face the problem of multiple drug resistant (MDR) and extensively drug resistant (XDR) M. tuberculosis strains. MDR strains exhibit resistance to at least the two most potent first-line drugs (RIF and INH). Besides RIF and INH, XDR strains are resistant to any fluoroquinolones and to at least one of the three injectable second-line drugs (capreomycin, kanamycin, and amikacin) (World Health Organization, 2006). Infections with such strains require further prolonged and aggressive treatment courses employing