Tuberculosis – is the white plague winning?
Tuberculosis has had many names, including consumption, scrofula and the great white plague, but whatever you call it, this disease still claims one life every 10 seconds and global mortality rates are increasing despite the use of chemotherapy (Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis. 2008 Nature Reviews Microbiology 6: 41-52). Why have we not progressed further towards the eradication of this disease? There are many answers, including politics and poverty, and some less shameful excuses such as HIV and drug resistance. Whatever the reason, without new weapons in the armory against TB, the disease will continue to make ground.
Two factors, persistence and resistance, make the treatment of Mycobacterium tuberculosis infections particularly difficult. The term persistence describes the survival of the causative organism despite the use of antibiotics. The local concentration of antibiotics in lesions such as granulomas might not be adequate to kill the cells, or some bacteria might adopt a physiological state that renders them less susceptible to antibiotics. For these reasons, drug treatments must be extended. Currently, even the most effective regimes require a combination of at least 3 drugs and last for six months. Because patients feel better within 1 2 weeks, they have little motivation to continue with therapy, so the current World Health Organization guidelines call for treatment to be directly observed (DOTS). This can be difficult to provide in much of the world, including the areas where tuberculosis rates are highest.
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There is an excellent chance that patients who have tuberculosis can be cured using currently available drugs if they complete the required course of therapy. But what characteristics should new drugs have to improve on current treatments?
- Oral bioavailability: to avoid the need for injections.
- Good tolerance: to avoid unwanted side-effects might cause treatment to be abandoned.
- Widespread usability: including AIDS patients, young children and pregnant women.
- Compatibility with anti-retroviral drugs: because co-infection with HIV and TB is common.
- Infrequent dosing: once a day drugs improve treatment compliance.
- Activity against drug-resistant TB strains: possibly the most important factor with the rise of MDR and XDR-TB.
- Rapid clearance of chronic infection: so that treatment times can be shortened.
- Affordability: so they can be used in the areas of the world where TB is most prevalent.
Mycobacterium tuberculosis has no significant animal or environmental reservoirs and shows limited genetic diversity. In spite of this, TB continues to be a widespread and devastating disease. The need for new faster-acting drugs is clear. Recent work by my colleague Dr Mark Carr from the School of Biological Sciences at the University of Leicester might help in future drug development. The M. tuberculosis ESAT-6/CFP-10 complex consists of two proteins which, together, allow the bacteria to survive inside white blood cells. Removal of the genes for these proteins from the TB genome renders the bacteria unable to cause disease. Similarly, studies of the structure of the protein complex have shown that removal of a “long arm” from the molecule prevents the complex s ability to bind to the outer surface of human white blood cells. In the structure of the ESAT-6/CFP-10 complex above, the “long arm” is in red on the right side of CFP-10. When this is intact, it allows the complex to attach to the outside of host white blood cells. When the long arm is cleaved off, the complex shows greatly reduced attachment. This data provides an insight into the important components of this complex. Mark Carr says: “Current work is attempting to identify the exact components of the human white blood cells that this complex is targeting. Once found, this should give us a greater knowledge of the action of these molecular weapons of TB and give us the edge in the war against an ancient, reawakened foe.”
Related:
- Resuscitating Mycobacterium tuberculosis
- Gamma interferon – key, but not sufficient for protection against TB?
- Tuberculosis virulence gene inhibits apoptosis of infected host cells
- Extreme drug resistant tuberculosis (XDR-TB) update
Tags: Antibiotics, Bacteria, Biology, Health, Medicine, Microbiology, Podcast, Science, Tuberculosis, University of Leicester
