An international collaboration led by researchers in the US and South Africa have announced the first genome sequence of an extensively drug resistant (XDR) strain of the bacterium Mycobacterium tuberculosis, one linked to more than 50 deaths in a recent tuberculosis (TB) outbreak in KwaZulu-Natal, South Africa.
As part of this work, genomes of multi-drug resistant (MDR) and drug sensitive isolates were also decoded. Initial comparisons of the genome sequences reveal that the drug-resistant and drug-sensitive microbes differ at only a few dozen locations along the four-million-letter DNA code, revealing some known drug resistance genes as well as some additional genes that may also be important to the spread of TB. The researchers have taken an unusual step of immediately sharing both the genome sequence and their initial analysis far in advance of submitting a scientific paper, in order to accelerate work on drug-resistant TB by researchers around the world.
“Tuberculosis is a major threat to global public health that demands new approaches to disease diagnosis and treatment,” said Megan Murray, one of the project's principal investigators, an associate member of the Broad Institute of MIT and Harvard and an associate professor at the Harvard School of Public Health. “By looking at the genomes of different strains, we can learn how the tuberculosis microbe outwits current drugs and how new drugs might be designed.”
“Genome information is a powerful tool for understanding the biology of infectious disease, such as tuberculosis,” said Eric Lander, founding director of the Broad Institute of Harvard and MIT. “It is important that genomic data be made immediately available, particularly to researchers in areas most heavily burdened by disease.”
“The sequenced strain is responsible for the vast majority of the more than 300 XDR cases identified thus far in the KwaZulu-Natal province of South Africa,” said Willem Sturm, one of the project's principal investigators and a leading researcher of the XDR epidemic in KwaZulu-Natal, dean of the Nelson Mandela School of Medicine, and director of the MRC Genital Ulcer Disease Research Unit at the University of KwaZulu-Natal. “Genetic characterization of this strain is essential for developing tools to get this epidemic under control.”
Globally, tuberculosis (TB) is a major cause of infectious disease deaths. Nearly 2 billion people, comprising roughly one third of the world's population, are thought to carry M. tuberculosis, the culprit bacterium. Major obstacles to controlling the disease stem from the microbe's ability to evade current treatments, which typically require prolonged use by patients and are often not curative. MDR strains, for example, are resistant to two of the most effective first-line TB drugs, and XDR strains can circumvent first-line as well as some second-line drugs. Adding to the problem, inefficient diagnostic methods for TB make it difficult for doctors to determine whether an individual harbors a drug-resistant strain, often delaying proper therapy.
To shed light on the genetic changes that mediate drug resistance, an international team of scientists undertook a large-scale effort to sequence the genomes of drug sensitive, MDR, and XDR TB isolates of a strain responsible for the current XDR-TB epidemic in KwaZulu-Natal, South Africa. This strain corresponds to one found in patients in Tugela Ferry, a rural town in KwaZulu-Natal that has recently experienced a severe outbreak of XDR TB among patients infected with the human immunodeficiency virus (HIV). There, 52 of 53 people infected with this strain died. The research reflects a collaboration among researchers in the Microbial Sequencing Center at the Broad Institute of Harvard and MIT, Megan Murray of the Harvard School of Public Health, and Willem Sturm and his colleagues at the Nelson Mandela Medical School in South Africa.