Tailor-made therapy of multidrug-resistant TB
The successful treatment of multidrug-resistant tuberculosis requires clarification in advance as to which antibiotics the pathogens are resistant to. Classic testing in the laboratory is very time-consuming and delays the start of therapy. Researchers from the Research Center Borstel, the Leibniz Lung Center, and the German Center for Infection Research (DZIF) have now prepared a catalogue of all mutations in the genome of tuberculosis bacteria and on the basis of a genome sequencing can quickly and cheaply predict which medicines are most effective for tuberculosis treatment. The results of this work were published in the professional journal Clinical Infectious Diseases.
Globally, tuberculosis is the most common bacterial infectious
disease leading to death. The pathogen causing tuberculosis,
Mycobacterium tuberculosis, has a number of peculiarities. One
is that it is growing very slowly. While other typical
pathogens, such as pneumococcal and pseudomonads, can already be
identified by their growth in the microbiological laboratory in
the first 72 hours, several weeks usually pass before
tuberculosis bacteria grow in the lab. Thus it often takes
one to two months before the efficacy of individual medicines
can be tested.
However, these efficacy tests are
essential for the effective treatment of multidrug-resistant
tuberculosis (MDR-TB), which is becoming increasingly common. In
these cases, the pathogen has become resistant, i.e.
insensitive, to the best tuberculosis drugs, rifampicin and
isoniazid. This is due to changes in the genome, so-called
mutations, which almost always occur at the same points in the
genome. Treatment of MDR-TB is protracted, costly and frequently
associated with side effects.
For the selection of
antibiotics in a combination therapy, doctors have so far
depended on the results of the drug test after cultivation.
“Currently, 15 drugs are available for second-line
therapy, of which at least four are used in combination,”
explains Prof. Christoph Lange, coordinator of the clinical
study at the Research Center Borstel.
In order to
accelerate the choice of the most effective antibiotics, DZIF
scientists at the Research Center Borstel, led by Prof. Stefan
Niemann, have created a catalogue of mutations in the genetic
material of tuberculosis bacteria that permits prediction of
antibiotic resistances of the bacteria against all drugs. Unlike
many other bacteria, the genetic material of the tuberculosis
bacteria hardly changes over time. The genome of tuberculosis
bacteria carries roughly 4.4 millions of building blocks (base
pairs) that store the information for about 4,000 genes.
Hans-Peter
Grobbel, medical student and predoctoral DZIF fellow in
Christoph Lange's team, supported by his fellow student Niklas
Köhler, Professor Matthias Merker, Dr Sönke Andres and
Dr Harald Hoffmans, has examined the results of antibiotic
resistance predictions through overall genome analyses. Using
tuberculosis bacteria from70 patients with MDR-TB treated at the
Borstel Department of Medicine, researchers compared the
molecular prediction of antibiotic resistance with actual
cultural test results. They were contributed by
Prof. Florian Maurer, Head of the National Reference Laboratory
for Tuberculosis Bacteria in Borstel. The scientists also
examined whether reliable combinations of drugs for the
treatment of MDR-TB could be compiled based on the prediction of
the bacteria’s genetic material.
“Ninety-nine
per cent of all drugs in combination therapies that we have
assembled based on the results of molecular predictions from the
genetic material of tuberculosis bacteria are also effective
according to traditional microbiological antibiotic resistance
testing,” Grobbel explains. By now, the molecular methods
are both cheap and fast. Ideally, patients can already receive
tailored MDR-TB treatment in the first week of their
tuberculosis diagnosis.
