TB significance and the impact of drug-resistant strains
Tuberculosis, caused by infection with the bacterium Mycobacterium tuberculosis (MTB), is a major global disease burden killing 1.5 million people a year, largely in the third world. Despite the goal to eradicate TB in the US, it also remains a serious concern in this country and other developed nations.
Over 9 million new tuberculosis infections occur every year, making it the fastest growing infectious disease comprising a significant unmet medical need worldwide. Typical antibiotic treatment regimens last 6 months, at a cost (in the US) of ~$17,000. Because this rigorous regimen is a burden to impoverished populations, partial treatment is creating organisms resistant to the standard of care and estimated to be around 20% of cases worldwide.
Such multi-drug resistant (MDR) organisms require even more aggressive treatment, this time with second-line drugs (including 6 months injected antibiotics) with significant side effects and lasting two years or more ($150,000). This creates an obvious problem for third world patients who may not be able to travel or otherwise participate in such programs. Resistant organisms spread among this population have become a major contributing factor to the inability to eradicate endemic MTB.
About 10% of drug resistant cases are extensively drug resistant (XDR) with treatment cost for individual cases estimated at approximately $430,000. Approximately ~70% of these patients die within months of diagnosis. Given that MDR and XDR treatment regimens are beyond the resources of most third-world individuals, there is an overwhelming unmet medical need for better, faster treatment to stop the disease before resistant strains can develop.
Biophagy is exploring the stimulation of autophagy (see What is Autophagy) as way to exacerbate the ability of first line antibiotics to stop TB within a shorter time-frame. Although this utility has been speculated, no practical treatment regimen has been designed for effective pharmacological modulation and use in a general population. New autophagy stimulants are being designed to find more efficacious drugs to enhance the activity of MTB antibiotics and avoid patient progression to MDR/XDR strains.
Biophagy is using clinically approved drugs, natural products, and nutraceuticals as templates to create superior derivatives with reduced initial risk. The creation of chemical libraries based on the best examples will help us develop lead identification for future advanced development.
Since these drugs target host function for control of MTB, they are less likely to induce the generation of drug-resistant MTB compared to anti-bacterial drugs. Furthermore, this approach enhances the probability of finding potentiating drugs for multi-drug resistant strains without the use of more expensive and intensive second-line regimens.
As an intracellular bacterium, MTB has a variety of escape mechanisms to avoid destruction by the immune system. Infected individuals typically wall off affected pulmonary cells by formation of granulomas that ultimately protect the host; however, although the infection is contained, it does not provide sterile immunity. Impairment of the immune system by HIV/AIDS, diabetes, poor health, or age can result in the dissolution of granulomas and subsequent MTB release. This leads to a dangerous lung pathogenesis (with possible extrapulmonary complications) that can result in lethality and spread of the disease by aerosolized droplet formation during coughing.
The standard of care in primary infections, rifampin and isoniazid, requires vigilance on the part of both health care providers and patients to eradicate the infection as completely as possible or MDR/XDR strains can gain the upper hand. Recent studies have revealed that autophagy can engulf and target intracellular pathogens, including MTB, in infected macrophages. This activity is eliminated when autophagy is inhibited, demonstrating the potential for autophagy stimulators to increase the containment of MTB infection and thus exacerbate the action of antibiotics. In a mouse study, elimination of autophagy in macrophages resulted in more severe MTB infection, higher bacterial loads, and faster lethality compared to wild-type mice. Indeed, two first-line MTB antibiotics, isoniazid and pyrazinamide, induce autophagy formation in treated infected macrophages—which may explain part of their activity.
Biophagy is pursuing this approach to shorten the time necessary for first line antibiotics to act, thus reducing the emergence of MDR/XDR strains in populations where rapid treatment is necessary and expedient.