Causative agents of tuberculosis are aerobic, non-motile, slow growing, rod-shaped bacteria of the family mycobacteriaceae. The most common pathogen of tuberculosis infections in humans is M. tuberculosis, whose pathogenicity is primarily based on the induction of a strong cell-mediated immune response. In addition to Mycobacterium tuberculosis complex, the species M. bovis (ssp. bovis and caprae), M. africanum, M. microti, M. canetti and M. pinnipedii and the vaccine strain M. bovis BCG can be counted as potential causes.
Always combined treatment
The treatment of tuberculosis is carried out exclusively using a combination of drugs which differ in their mechanisms and sites of action (cytosol, lysosome etc.). Only this way can it be ensured that the tuberculosis bacteria biologically occurring in very different populations are killed at different stages or are stopped in their growth. A combination treatment also acts against the selection or development of resistant bacteria. Such disease initiators which are naturally resistant to a particular drug are always present in a case of tuberculosis and would be selected for when applying an inadequate therapy.
Five standard drugs + second-line drugs
In the treatment of tuberculosis, the following five standard drugs are available: isoniazid (INH), rifampicin (RMP), ethambutol (EMB), pyrazinamide (PZA) and streptomycin (SM). Beyond this, there are so-called second-line or reserve medications that come into use in instances of resistance or intolerance. However these are often less effective than the standard medication, or possess higher toxicity. As a standard short-term therapy for pulmonary tuberculosis in adults, 6-month chemotherapy is used in which during the first two months (initial phase) INH, RMP, PZA and EMB are given and in the next four months (stabilisation or continuity phase) treatment proceeds with INH and RMP. The WHO has recently ranked streptomycin as a second-line drug, as among other things it cannot be administered orally and is no longer used in many countries for the treatment of uncomplicated tuberculosis.
Multi-drug resistant TB
The WHO also assumes that 3.7% of all new cases worldwide and 20% of previously treated TB cases are multi-drug resistant. Multi-drug resistant tuberculosis (MDR-TB) is said to occur when a simultaneous resistance against at least the two main first-line drugs INH and RMP exists. Especially affected are patients in India, China, Russia, South Africa, Eastern Europe and Central Asia. In these regions, about one of 10 MDR cases is an extensively drug-resistant tuberculosis (XDR-TB). Such extremely resistant and therefore difficult to treat tuberculosis cases have been found in about 70 countries around the world – including in Germany. Annually worldwide approximately 25,000 new cases of XDR occur.
As defined by the WHO, an XDR-TB is a MDR-TB in which additional resistance to a fluoroquinolones exists and to at least one of the injectable anti-TB drugs (amikacin, capreomycin, kanamycin) and is therefore only able to be treated with great difficulty. New antimicrobial agents are therefore urgently needed in order to treat the growing number of XDR-TB patients effectively. A team of scientists from the UK and South Africa is now – on the basis of knowledge from traditional African medicine – setting aim on a novel biological point of attack so as to, especially with the multiple and extensively drug-resistant strains, get the bacteria under control.
South African tree with antibiotic activity
Most antibiotics are derived from fungi or bacteria. Antimicrobial agents from plants are far less common, “but they’re probably a valuable source of new agents”, write the study authors in the Journal of Biological Chemistry. In South Africa there is a tree named Euclea natalensis whose apparent antibiotic effect is used by the locals, who use its branches to brush their teeth. In traditional African medicine root extracts of this tree manage to also offer relief from bronchitis, pleurisy, chronic asthma and venous disorders. Already in 1999 a group of researchers were also able to prove that unprocessed extracts of the tree worked actively in vitro against both drug-sensitive and drug-resistant strains of M. tuberculosis: a discovery that fuels hope of possibly developing antibiotics that could be used especially against MDR-TB and XDR-TB strains.
Gyrase blocker – but not like all the others
British and South African scientists discovered the active substance in the tree extract to be diospyrin, a gyrase blocker belonging to the naphthoquinone group. This at first was not particularly exciting because gyrase blockers have already long been in use as antibiotics. However researchers led by Professor Tony Maxwell from the John Innes Centre in Norwich, United Kingdom, were able to reveal why diospyrin works differently, even against multi-drug resistant bacterial strains.
Gyrase is found in bacteria and plants, but not in animals and humans, and plays an important role in vital DNA replication. Therefore it is particularly suitable as a target for antimicrobial therapy. The enzyme is a DNA Type II topoisomerase, which changes the spatial orientation of closed DNA molecules by creating an ATP-dependent double-strand break in the DNA. Gyrase consists of two sub-units, GyrA and GyrB, which together make up the A2B2 complex. Chemically speaking, a distinction can already be made into four groups of gyrase inhibitors:
- Quinolones (with the subgroup fluoroquinolones)
Most of them inhibit gyrase activity by stabilising the DNA cutting complex. This process involves binding to a package which is comprised of the residues of GyrA, GyrB and DNA. Or they block the ATPase docking point of the enzyme. Diospyrin however apparently binds at a previously unknown point, namely the N-terminal domain of GyrB near the ATP-binding site and acts there as an allosteric inhibitor of the ATP-binding site. Thus diospyrin creates a bypass of the existing mechanisms of resistance in the tuberculosis pathogen. “The manner in which such diospyrin works helps us to explain why it works against both drug-sensitive and resistant strains of the tuberculosis pathogen”, says the lead author of the study, Professor Tony Maxwell. “Our discovery also illustrates the importance of ethnobotany and the importance of preserving biodiversity on the earth in order to find solutions to global health problems”, Maxwell continues. The highly promising approach must now be tested for its efficacy in vivo.
Tuberculosis – a global problem
Tuberculosis is a common bacterial infection and occupies among deadly infectious diseases second place worldwide after HIV/AIDS. In 2011 the World Health Organisation (WHO) counted nine million new cases and 1.4 million deaths from tuberculosis worldwide. Leading in producing these sad statistics are Asia and Africa. About a third of the world population are said to be infected with tuberculosis bacteria, but only about 5 to 10% of immunocompetent infected adults ever develop tuberculosis requiring treatment during their lifetime. During the first two years after the infection the disease risk is highest. In most cases the body manages to fight the TB bacteria successfully or to encapsulate them and hence permanently limit the infection. One is in such instances dealing with a latent tuberculous infection. This runs its course without any symptoms. The illness of tuberculosis manifests itself in approximately 80% of the patients as pulmonary tuberculosis, but in principle it can infect any organ. Accordingly this disease can present itself in multiform manner.
Particularly problematic is the situation in sub-Saharan Africa, as the tuberculosis epidemic is facilitated by the high HIV infection rates. About 85% of all newly occurring cases of tuberculosis are patients living in Africa, South-east Asia and the western Pacific region. In Germany during 2011 4,344 new tuberculosis infections were recorded. Among the jeopardising factors represented here are drug addiction, homelessness and poverty. Tuberculosis rates in Germany are also particularly high among immigrants from countries where tuberculosis is still found very often.