Mutations in extensively drug-resistant Mycobacterium tuberculosis that do not code for known drug-resistance mechanisms.
BACKGROUND
Highly lethal outbreaks of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are increasing. Whole-genome sequencing of KwaZulu-Natal MDR and XDR outbreak strains prevalent in human immunodeficiency virus (HIV)-infected patients by the Broad Institute identified 22 novel mutations which were unique to the XDR genome or shared only by the MDR and XDR genomes and not already known to be associated with drug resistance.


METHODS
We studied the 12 novel mutations which were not located in highly-repetitive genes to identify mutations that were truly associated with drug resistance or were likely to confer a specific fitness advantage.


RESULTS
None of these mutations could be found in a phylogenetically and geographically diverse set of drug-resistant and drug-susceptible Mycobacterium tuberculosis isolates, suggesting that these mutations are unique to the KZN clone. Examination of the 600-basepair region flanking each mutation revealed 26 new mutations. We searched for a convergent evolutionary signal in the new mutations for evidence that they emerged under selective pressure, consistent with increased fitness. However, all but 1 rare mutation were monophyletic, indicating that the mutations were markers of strain phylogeny rather than fitness or drug resistance.


CONCLUSIONS
Our results suggest that virulent XDR tuberculosis in immunocompromised HIV-infected patients can evolve without generalizable fitness changes or other XDR-specific mutations.
Division of Infectious Disease, Department of Medicine, and the Ruy V. Lourenço Center for the Study of Emerging and Reemerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
Alifiya S
AS
Motiwala
Yang
Y
Dai
Edward C
EC
Jones-López
Soo-Hee
SH
Hwang
Jong Seok
JS
Lee
Sang Nae
SN
Cho
Laura E
LE
Via
Clifton E
CE
Barry
David
D
Alland
D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D030561:Databases, Nucleic Acid; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D054908:Extensively Drug-Resistant Tuberculosis / Q000150:complications / Q000382:microbiology*; D019450:Genes, MDR; D015658:HIV Infections / Q000150:complications; D006801:Humans; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000187:drug effects / Q000235:genetics*; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
D000995:Antitubercular Agents