Applying Structural Genomics and Drug Discovery to Understanding Drug Resistance
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Drug resistance is rapidly becoming the most significant health problem worldwide. This applies not only to drug resistantinfectious agents in developing countries. It is estimated that most cancer death are now caused by resistant cancer cells, anddrug resistant bacterial disease resulted in 23,000 deaths in the US in 2013 (CDC).The mortality from tuberculosis (TB) worldwide continues to increase. Even 50 years after discovering the drugs capable ofcuring TB, the global burden of this ancient disease is still substantial. In 2012, an estimated 8.6 million people became ill withTB and 1.3 million people died, according to the World Health Organization (WHO). Each year, roughly 500,000 childrendevelop TB and as many as 74,000 die from the disease. For HIV-infected individuals, co-infection with TB represents theleading cause of death. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB are recognized as a growing problem, threatening overall TBcare efforts. The past 20 years have seen the worldwide appearance of multidrug-resistant (MDR) tuberculosis, followed byextensively drug-resistant (XDR) tuberculosis, which was first described in 2006. About 3.6% of new tuberculosis (TB) patientsin the world have Multidrug-Resistant strains (MDR-TB). Levels are much higher about 20% in those previously treated for TB.The frequency of MDR-TB varies substantially between countries. About 10% of MDR-TB cases are also resistant to the twomost important second-line drug classes also known as Extensively Drug-Resistant TB (XDR-TB). By September 2013, 92countries had reported at least one XDR-TB case. The year 2007 saw the occurrence of strains that are resistant to allantituberculosis drugs, now known as Totally Drug-Resistant (TDR) TB. MDR tuberculosis is caused by Mycobacteriumtuberculosis that is resistant at least to isoniazid and rifampicin, and XDR tuberculosis by mycobacteria resistant to rifampicinand isoniazid, any fluoroquinolone, and one of the three injectable drugs, capreomycin, kanamycin, and amikacin. Drugresistance severely threatens tuberculosis control, since it raises the possibility of a return to an era in which drugs are no longereffective. To achieve global control of this epidemic, there is an urgent need for new TB drugs, which can:(1) shorten treatmentduration;(2) target MDR or XDR strains; (3) simplify treatment by reducing the daily pill burden; (4) lower dosing frequency (forexample, a once-weekly regimen); and (5) be co-administered with HIV medicationsPioneering studies have demonstrated that establishment of resistance requires a reversible phenotypic shift without which thebacilli rapidly lose viability. An essential component of this shift is the change from aerobic to anaerobic metabolism. We haveshown that a key player in this metabolic shift is the glyoxylate shunt, as mutants defective for isocitrate lyase are unable topersist in the murine infection model. While the major focus of the project will be on TB the lessons learned and the novel strategies will have broader implications.