According to conventional wisdom, when a disease-causing microbe mutates and develops resistance to a drug, it tends to lose some of its ability to spread. Does the bacterium that causes tuberculosis (TB) become less transmissible when it becomes drug-resistant? If so, can scientists detect this change? Such questions are driving research by NIAID grantee Megan Murray, M.D., a physician and epidemiologist at the Harvard School of Public Health in Boston. She and her colleagues are answering them through approaches that extend from the microscopic -- sequencing TB's genes -- to whole communities -- an ambitious field study that will involve tens of thousands of Peruvian people.
Up to one-third of the world's population is infected with TB bacteria, but most of those infected will never develop an active case of tuberculosis. Those who do get sick can usually be cured because most strains of TB bacteria are drug-susceptible. Some strains, however, are multidrug-resistant (MDR TB); they are impervious to at least two of the first-line antibiotics. Extensively drug-resistant (XDR TB) strains resist not only first-line drugs, but also at least one second-line drug. MDR TB is bad, but XDR TB is worse. During a 2006 outbreak in KwaZulu-Natal, South Africa, 52 of the 53 people suffering from XDR TB died.
TB control depends in part on distinguishing cases of drug-susceptible TB from drug-resistant ones so that appropriate therapy can begin. Currently, there are no widely available rapid, accurate diagnostic tests for TB drug susceptibility. In a step towards developing such tests, Dr. Murray and her colleagues from South Africa and the United States collected clinical samples of XDR TB strains from the 2006 KwaZulu-Natal outbreak. Using new technology that allows rapid genetic sequencing, the researchers determined the order of 95 percent of the XDR strain's four million DNA subunits.
Next, they compared that genome sequence to sequences of MDR and drug-susceptible TB strains. Surprisingly, says Dr. Murray, drug-resistant strains appear to differ from drug-susceptible ones at only a few dozen genetic sites. The knowledge of which genes give TB the ability to resist drugs helps lay the groundwork for better diagnostic tests to distinguish drug-resistant from drug-susceptible strains, she adds.
Dr. Murray is now building on the genome findings with a new grant from NIAID. The five-year grant supports three projects aimed at better understanding how MDR and XDR TB strains retain their transmissibility, even after acquiring drug resistance mutations.
The first project will follow up to 30,000 men and women in Peru who have been infected with TB bacteria and are thus at risk of developing active TB disease. American researchers, working in collaboration with healthcare experts from Peru's Socios en Salud, will collect data on human and bacterial factors that influence whether a particular individual becomes ill after exposure to TB bacteria. The investigators also will collect TB samples and create an archive of MDR and XDR TB strains.
The second project will use the TB archive to uncover differences in genetic sequences or metabolic properties between drug-susceptible and drug-resistant strains, while a third effort will combine field and lab data to develop mathematical models of tuberculosis transmission. Because the models will be built using information from real people with TB, says Dr. Murray, they could be useful in predicting when and how drug-resistant TB strains may emerge and cause disease outbreaks. Such knowledge could help physicians stay one step ahead of TB.