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Mutation rates in strains of different Mycobacterium tuberculosis lineages associated with emergence of multi-drug resistant tuberculosis

E Rousseau(1) T Wirth(2,3) M Merker(4) S Niemann(1,5)

1:Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, 23845, Germany; 2:EPHE, PSL University, Paris, 75014, France; 3:Institut de Systématique, Evolution, Biodiversité, ISYEB, Muséum national d’Histoire naturelle, CNRS, Sorbonne Université, EPHE, Université des Antilles, Paris, 75005, France; 4:Evolution of the Resistome, Research Center Borstel, Borstel, 23845, Germany; 5:German Center for Infection Research, Partner site Hamburg-Lübeck-Borstel-Riems, Borstel, 23845, Germany

Antibiotic resistances are unequally distributed among strains of different Mycobacterium tuberculosis complex (MTBC) lineages. Strains belonging to the two most worldwide prevalent generalist lineages 4 (L4) and 2 (L2) have caused large outbreaks of multidrug resistant tuberculosis (MDR-TB) and in certain cases, those MDR-TB clades evolved toward the acquisition of resistances against additional MDR-TB drug. However, certain mechanisms and the resistance acquisition pace contributing to the success of those strains remains unclear.

Here, we experimentally determined resistance acquisition rates for rifampicin and bedaquiline in a collection of clinical L2 and L4 strains MTBC strains using fluctuation assays and whole-genome sequencing.

Modern L2 strains acquire spontaneous rifampicin resistance mutations twice faster than L4 strains in vitro. Most frequently acquired rifampicin resistance mutations were C1333T (His445Tyr), A1334G (His445Arg) and C1322T (Ser441Leu). All strains investigated acquired known resistance conferring mutations; no particular lineage specific mutation hotspot was identified. Preliminary results indicate that L2 strains also acquire bedaquiline resistances faster than L4 strains.

Our results indicate that the genetic background of modern L2 strains potentially allows for an accelerated spontaneous mutation rate leading to a faster resistance acquisition of modern L2 strains. The genetic make-up may also reduce fitness costs of drug resistance and/or favors the acquisition of compensatory mutations.

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