Identifying and combating new antibiotic resistance in tuberculosis early on
The antibiotic Bedaquiline (BDQ) was approved in 2014 specifically for the treatment of multidrug-resistant (MDR) tuberculosis (TB) and has since been an important component of successful MDR TB therapy. However, some TB strains have already developed resistance to it. The mutations in the genome of the bacteria that mediate BDQ resistance have not yet been sufficiently understood. This is the focus of a study recently published in the journal Lancet Microbe: Using evolutionary biology methods, researchers from Europe, the USA and India have succeeded in classifying new and previously unknown resistance mutations in an international collaborative project led by scientists from the Research Center Borstel, Leibniz Lung Center and the German Center for Infection Research (DZIF). In the future, this knowledge can be used in molecular diagnostics to ensure patients receive tailored antibiotic therapy.
Tuberculosis (TB) is one of the most dangerous bacterial infectious diseases, affecting more than 10 million people worldwide and causing about 1.6 million deaths. According to WHO estimates, about half a million patients become infected with a multidrug-resistant (MDR) strains of Mycobacterium tuberculosis complex (Mtbc) bacteria each year. At least four antibiotics are used for therapy over a period of several months, sometimes with considerable side effects. The newly developed antibiotic bedaquiline (BDQ) has been used very successfully to treat MDR-TB; however, BDQ-resistant strains emerged in TB patients shortly after its launch.
In a multicenter study involving the DZIF, the Leibniz Science Campus EvoLUNG and the Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI), experimental work in combination with computer models was used to define resistance mechanisms to BDQ, allowing rapid diagnosis of resistance in clinical Mtbc strains e.g. by sequencing of the bacterial genome. The aim was to establish a database that can be used to interpret mutations in the genome of this pathogen and predict resistance.
In the current study, in vitro laboratory procedures and in silico computer methods were used to better understand the impact of single mutations on the development of BDQ resistance. This newly reported data was combined with an extensive literature search to create a comprehensive mutation catalogue for BDQ resistance associated mutations.
"The novel evolutionary biology approach of this work, in which M. tuberculosis strains are exposed to antibiotics over a long period of time, has proven to be an excellent method to select resistant mutants with a large phenotypic and genetic diversity," says Prof. Stefan Niemann, last author of the study, Principal Investigator in the DZIF and the Cluster of Excellence PMI and spokesperson of the Leibniz Science Campus EvoLUNG.
"A surprising finding of this study was a novel resistance mechanism in which the M. tuberculosis strains showed a major rearrangement in the genome," adds Dr Lindsay Sonnenkalb from the Borstel Research Center, Leibniz Lung Center, one of the study's first authors. "This resistance mechanism has not been described before and could also occur in clinical M. tuberculosis strains."
The methods presented are currently being used in various international collaborative projects to determine resistance mechanisms to new antibiotic agents before they enter use. These data should enable the establishment of diagnostic procedures prior to first widespread use of the new drug.
The work of Dr Sonnenkalb and colleagues were supported by the Bill & Melinda Gates Foundation, the Wellcome Trust, the Leibniz Science Campus - Evolutionary Medicine of the Lung (EvoLUNG), the DFG Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI), the DFG Graduate School "Translational Evolutionary Research”, and the German Center for Infection Research (DZIF).
