Aung, H. L. | bioRxiv Science

bioRxiv2019

The evolution of nitroimidazole antibiotic resistance in Mycobacterium tuberculosis

Our inability to predict whether certain mutations will confer antibiotic resistance has made it difficult to rapidly detect the emergence of resistance, identify pre-existing resistant populations and manage our use of antibiotics to effective treat patients and prevent or slow the spread of resistance. Here we investigated the potential for resistance against the new antitubercular nitroimidazole prodrugs pretomanid and delamanid to emerge in Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Deazaflavin-dependent nitroreductase (Ddn) is the only identified enzyme within M. tuberculosis that activates these prodrugs, via an F420H2-dependent reaction. We show that the native menaquinone-reductase activity of Ddn is important in aerobic respiration and essential for emergence from dormancy, which suggests that for resistance to spread and pose a threat to human health, the native activity of Ddn must be at least partially retained. We tested 75 unique mutations, including all known sequence polymorphisms identified among ~15,000 sequenced M. tuberculosis genomes. Several mutations abolished pretomanid activation in vitro, without causing complete loss of the native activity. We confirmed that a transmissible M. tuberculosis isolate from the hypervirulent Beijing family already possesses one such mutation and is resistant to pretomanid, even though it was never exposed to pretomanid. Notably, delamanid was still effective against this strain, which is consistent with structural analysis that indicates delamanid and pretomanid bind to Ddn differently. We suggest that the mutations identified in this work be monitored for informed use of delamanid and pretomanid treatment and to slow the emergence of resistance.

molecular biology↗

bioRxiv2019

Dispersal of Mycobacterium tuberculosis to indigenous populations driven by historical European trade in the South Pacific

The Mycobacterium tuberculosis complex lineage 4 (L4), also known as the \"Euro-American\" lineage, is the most widely dispersed of the seven human adapted lineages. L4 is comprised of ten sublineages including L4.4, which has a moderate global distribution and is the most common L4 sublineage in New Zealand. We have used a phylodynamics approach and a dataset of 236 global M. tuberculosis genomes to trace the origins and dispersal of L4.4 strains in New Zealand that are predominantly found in M[a]ori and Pacific people. We identify an L4.4.1.1 sublineage clade of European origin, likely French, that is prevalent in indigenous populations in both New Zealand and Canada. Molecular dating suggests that expansion of European trade networks in the early 19th century led to dispersal of this clade to the South Pacific. We also identify historical and social factors within the region that have contributed to the local spread and expansion of these strains, including recent Pacific migrations to New Zealand and the rapid urbanization of M[a]ori in the 20th century. Our results offer new insight into the dispersal of M. tuberculosis in the South Pacific region and provide a striking example of the role of historical European migrations in the dispersal of M. tuberculosis.\n\nAuthor SummaryTuberculosis kills more people worldwide than any other infectious disease and indigenous populations are disproportionately affected by the disease. Here, we have used a large global dataset of Mycobacterium tuberculosis bacterial genomes to trace the historical origins of tuberculosis strains in New Zealand that are most frequently found in M[a]ori and Pacific people. These strains are locally known as the Rangipo and Otara strains (both M[a]ori place names) and belong to the \"Euro-American\" lineage of M. tuberculosis. Via genome analysis, we find that these strains are closely related to M. tuberculosis strains found in indigenous populations in Canada that have a European origin. We used a molecular dating approach (a molecular clock) to infer the ages of these strains and date divergence events. The timing we infer corresponds to the introduction of these strains to Polynesia via expanding European trade networks in the South Pacific in the early 19th century and suggests that the Otara strain has migrated to New Zealand from the Pacific Islands multiple times. Our results provide insight into human social phenomena underlying the expansion and dispersal of M. tuberculosis and reassert the important role of European colonial migrations in the global dispersal of the M. tuberculosis Euro-American lineage. This work also highlights the pejorative and stigmatizing mislabelling of the New Zealand strains with indigenous M[a]ori place names, suggesting that these strains should be renamed.

evolutionary biology↗