Scientists identify new drug target to combat airborne tuberculosis

Tuberculosis bacteria released into the air from infected individuals dry out to form infectious particles that are second only to measles in contagiousness. Weill Cornell Medicine investigators have discovered specific mechanisms that enable the bacteria not only to survive drying but also to generate mutations linked to antibiotic resistance. This suggests that transmission involves more than the passive movement of bacteria between people and may be a period during which the pathogen evolves.

Tuberculosis, a lung infection caused by Mycobacterium tuberculosis (MTb), affects nearly 11 million people and causes roughly 1.2 million deaths globally each year.

The study, published Aug. 26 in Nature Microbiology, demonstrated that desiccation specifically elicited a DNA repair response that both promoted Mtb's survival and increased the appearance of mutations that made the bacteria resistant to the antibiotic rifampin. The researchers also identified a promising new drug target-by reducing the activity of a DNA repair gene called Mfd, they could impair the survival of drug-resistant tuberculosis bacteria.

Tuberculosis has evolved the ability to spread efficiently from person to person. Our findings shed light on this understudied stage of the tuberculosis life cycle and lay the groundwork for new strategies to interrupt transmission and combat drug resistance."

Dr. Kyu Rhee, senior author, professor of medicine, Division of Infectious Diseases and professor of microbiology and immunology, Weill Cornell Medicine

Tackling transmission

Tuberculosis spreads when an infected individual coughs, speaks, or breathes, sending microscopic droplets containing bacteria into the air. As these droplets evaporate, they shrink into tiny particles known as droplet nuclei that can remain suspended in the air long enough to be inhaled by someone else.

By mimicking the conditions that lead to the drying and rehydration of MTb in the laboratory, the team showed that desiccation causes oxidative stress in the bacteria, leading to DNA damage. The bacteria responded by activating a DNA repair program that helped them survive and recover once moisture became available again. The results suggest that tuberculosis has evolved specific mechanisms to withstand the stresses of airborne transmission. 

"Mutations are a critical component of bacterial evolution," said study lead author Dr. Christopher Brown, the William Randolph Hearst Foundation Clinical Scholar in Microbiology and Infectious Diseases at Weill Cornell and a physician at NewYork-Presbyterian/Weill Cornell Medical Center. "DNA damage incurred during transmission could contribute to the genetic diversity that allows tuberculosis to adapt and, in some cases, acquire drug resistance."

Blocking rifampin resistance

Rifampin is a cornerstone of tuberculosis treatment and helps shorten therapy to about four to six months. However, rifampin resistance is a growing problem worldwide, primarily driven by genetic mutations in bacteria that render the drug ineffective. Drug-resistant forms of the disease often require much longer treatment regimens.

"In the absence of rifampin, patients will need to take costly and toxic drugs longer," said Dr. Rhee, who is also an attending physician at NewYork-Presbyterian/Weill Cornell Medical Center.

The team identified a potential approach to prevent the emergence of rifampin resistance. Silencing the Mfd gene during aerosolization experiments in the laboratory reduced the survival of rifampin-resistant tuberculosis bacteria. Dr. Rhee noted that other investigators have also identified Mfd as a potential contributor to antibiotic resistance and are exploring ways to target it therapeutically.

The researchers also analyzed more than 50,000 tuberculosis genomes isolated from patients worldwide. They found that strains carrying mutations in Mfd were significantly less likely to harbor the most common rifampin-resistance mutation, supporting laboratory evidence that Mfd helps certain drug-resistant TB strains survive transmission.

"The more we learn about tuberculosis' ability to spread, the more opportunities we will have to design effective strategies that will make an impact at a global scale," Dr. Brown said. "In the future, therapies that target the transmission stage of the tuberculosis life cycle could complement existing treatments and help slow the emergence and spread of drug-resistant disease."

The project was funded by a $16.3 million grant from the National Institutes of Allergy and Infectious Disease.