Drying during spread helps TB bacteria drive drug resistance

Tuberculosis remains a major global health threat because the bacterium that causes it, Mycobacterium tuberculosis (Mtb), can evolve resistance to the drugs used to treat it. A key phase in the life of Mtb is transmission between people, which often occurs via tiny droplets and aerosols expelled when an infected person breathes, coughs, or talks. These airborne particles are exposed to drying, or desiccation, which is a stressful condition for microbes. In new work led by corresponding author Ka Young Rhee, researchers asked how the physical stresses of aerosolization and desiccation affect Mtb and whether those stresses could influence the emergence of drug resistance. They found that the drying and DNA damage associated with aerosolization are not merely harmful events; instead, they can create opportunities for genetic change. The study links a transmission-specific stress — desiccation-induced DNA damage — to the potential for Mtb populations to diversify genetically, with clear consequences for strains that carry known resistance alleles.

The team observed that the process of aerosolization impairs survival of strains harboring the rifampin resistance allele S450L. In other words, strains with this particular rifampin resistance mutation are less likely to survive the physical stresses experienced during airborne spread. To support this observation, the researchers turned to large-scale genetic data: whole genome sequence data from over 50,000 clinically circulating strains of Mtb were analyzed and found to be consistent with the experimental findings. Together, the experimental observation that aerosolization and desiccation cause DNA damage and reduce survival of certain resistant strains, plus the population-level signature in whole genome sequence data, underpin the conclusion. These lines of evidence point to an evolved relationship between transmission stress and genetic change in Mtb, showing that desiccation-induced DNA damage can act as a source of genetic diversification and influence drug resistance patterns.

If Mtb uses transmission-related stresses to generate genetic diversity, that changes how we think about the origins of drug resistance. Rather than resistance arising only through steady accumulation of mutations during long infections or treatment, some variation could be created or selected during the act of transmission itself. The finding that strains with the rifampin resistance allele S450L fare worse during aerosolization suggests that the physical bottlenecks of spread shape which resistant variants persist and spread in the population. The work led by Ka Young Rhee raises new questions about how environmental conditions and human behaviors that affect aerosol formation and drying might influence the evolution of Mtb. It also highlights the value of combining laboratory observations with large-scale genomic surveillance to understand where and how drug resistance emerges and which resistant strains are most likely to transmit.