Antibiotic resistance
Download documents
Related Items
Links
Antibiotics have revolutionised the treatment of infectious bacterial diseases. However with antibiotic use, antibiotic resistant bacteria will eventually evolve, as the few bacteria able to survive exposure to these compounds grow and spread. This means that, unlike other types of drugs, poor or excessive use of antibiotics can result in a total loss of their effectiveness. This problem has been addressed in two ways; firstly the continuous development of new antibiotics (an arms race with the bacteria), and secondly by using antibiotics more wisely to reduce the chance of resistance emerging.
The primary focus of antibiotic resistance research at KIT Biomedical Research is currently the treatment of tuberculosis, a disease caused by a slow growing bacterium (Mycobacterium tuberculosis). Mixtures of three or more antibiotics, if given for six months or longer, can result in effective cure with little or no chance of resistance developing. But these relatively complex and long treatment protocols have been poorly adhered to in certain parts of the world leading to the development of highly resistant bacterial strains. If they spread these resistant strains make the standard treatment ineffective, requiring the use of more expensive, more toxic, and less effective second line drugs.
We study the mechanisms that lead to resistance and develop methods for detecting resistant strains. This information can be used to identify specific strains or mixtures of antibiotics that are more likely to result in the development of resistance and may help to design more robust (and effective?) treatment protocols.
Approach
We use molecular methods, notably DNA amplification, M. tuberculosis specific MLPA, and DNA array-based assays to detect genetic changes associated with drug resistance in bacteria. We study bacteria that have become resistant in the wild (patient isolates) as well as bacteria that acquire resistance in the laboratory and compare the behaviour of these strains to help us model and understand how resistance develops in the environment.
Focal points
- Elucidation of mechanisms of drug resistance in Mycobacterium tuberculosis
- Development of methods to detect drug resistance in M. tuberculosis
- Study the effects of sequential acquisition of drug resistance
Example
The KIT is leading one of four the work packages that make up TBAdapt an EU funded (STREP) project with 11 partners. The project will study the hypothesis that the current TB epidemic is fuelled by the selection of more adapted variants of M. tuberculosis by the measures used to control the epidemic; anti-TB treatment and BCG vaccination. These selection mechanisms are investigated by studying the population structure of M. tuberculosis. Furthermore, the mechanisms of bacterial adaptability and the influence of genetic variability among M. tuberculosis strains on virulence, fitness, acquisition of drug resistance and protection against vaccination are investigated.
The role of the KIT is to investigate and co-ordinate studies of differences in the ability of the different genetic lineages to develop genetic diversity and thus become drug resistant. We will also in investigate and differences in the genetic cost of drug resistance as a results of different resistance mechanisms and similar resistance mechanism in different genetic clades.
Publications
- Anthony, R.M. - Effect of secondary structure on single nucleotide polymorphism detection with a porous microarray matrix; implications for probe selection.
- Anthony, R.M. - Direct detection of Staphylococcus aureus mRNA using a flow through microarray
- Anthony, R.M. - Acquisition of rifabutin resistance by a rifampicin resitant mutant of Mycobacterium tuberculosis involves an unusual spectrum of mutations and elevated frequency.
- Brown, T.J. - The use of macroarrays for the identification of MDR Mycobacterium tuberculosis
- Bergval, I.L. - Specific mutations in the Mycobacterium tuberculosis rpoB gene are associated with increased dnaE2-expression.