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Genome Biology

, 15:490

Genomics of infectious diseases special issue

Abstract

BackgroundMycobacterium tuberculosis is characterized by a low mutation rate and a lack of genetic recombination. Yet, the rise of extensively resistant strains paints a picture of a microbe with an impressive adaptive potential. Here we describe the first documented case of extensively drug-resistant tuberculosis evolved from a susceptible ancestor within a single patient.

ResultsGenome sequences of nine serial M. tuberculosis isolates from the same patient uncovered a dramatic turnover of competing lineages driven by the emergence, and subsequent fixation or loss of single nucleotide polymorphisms. For most drugs, resistance arose through independent emergence of mutations in more than one clone, of which only one ultimately prevailed as the clone carrying it expanded, displacing the other clones in the process. The vast majority of mutations identified over 3.5 years were either involved in drug resistance or hitchhiking in the genetic background of these. Additionally, RNA-sequencing of isolates grown in the absence of drug challenge revealed that the efflux-associated iniBAC operon was up-regulated over time, whereas down-regulated genes include those involved in mycolic acid synthesis.

ConclusionsWe observed both rapid acquisitions of resistance to antimicrobial compounds mediated by individual mutations as well as a gradual increase in fitness in the presence of antibiotics, likely driven by stable gene expression reprogramming. The rapid turnover of resistance mutations and hitchhiking neutral mutations has major implications for inferring tuberculosis transmission events in situations where drug resistance evolves within transmission chains.

AbbreviationsAMKamikacin

bpbase pair

CFZclofazimine

CIconfidence interval

COGclusters of orthologous groups

CPRcapreomycin

DOTdirectly observed treatment

DSTdrug susceptibility testing

EMBethambutol

ETHethionamide

FLQfluoroquinolone

GUgrowth unit

INHisoniazid

KANkanamycin

LJLöwenstein-Jensen

MDR-TBmultidrug-resistant tuberculosis

OFXofloxacin

PASpara-aminosalicylic acid

PCRpolymerase chain reaction

PZApyrazinamide

RIFrifampicin

SNPsingle-nucleotide polymorphism

STRstreptomycin

TBtuberculosis

XDR-TBdrug-resistant tuberculosis

Electronic supplementary materialThe online version of this article doi:10.1186-s13059-014-0490-3 contains supplementary material, which is available to authorized users.

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Autor: Vegard Eldholm - Gunnstein Norheim - Bent von der Lippe - Wibeke Kinander - Ulf R Dahle - Dominique A Caugant - Turid Man

Fuente: https://link.springer.com/



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