Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis.
OBJECTIVE
Multidrug resistant (MDR) bacteria are a growing threat to global health. Studies focusing on single antibiotics have shown that drug resistance is often associated with a fitness cost in the absence of drug. However, little is known about the fitness cost associated with resistance to multiple antibiotics.


METHODS
We used Mycobacterium smegmatis as a model for human tuberculosis (TB) and an in vitro competitive fitness assay to explore the combined fitness effects and interaction between mutations conferring resistance to rifampicin (RIF) and ofloxacin (OFX); two of the most important first- and second-line anti-TB drugs, respectively.


RESULTS
We found that 4 out of 17 M. smegmatis mutants (24%) resistant to RIF and OFX showed a statistically significantly higher or lower competitive fitness than expected when assuming a multiplicative model of fitness effects of each individual mutation. Moreover, 6 out of the 17 double drug-resistant mutants (35%) had a significantly higher fitness than at least one of the corresponding single drug-resistant mutants. The particular combinations of resistance mutations associated with no fitness deficit in M. smegmatis were the most frequent among 151 clinical isolates of MDR and extensively drug-resistant (XDR) Mycobacterium tuberculosis from South Africa.


CONCLUSIONS
Our results suggest that epistasis between drug resistance mutations in mycobacteria can lead to MDR strains with no fitness deficit, and that these strains are positively selected in settings with a high burden of drug-resistant TB. Taken together, our findings support a role for epistasis in the evolution and epidemiology of MDR- and XDR-TB.
Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4002 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland and DST/NRF Centre of Excellence for Biomedical Tuberculosis Research/MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Health Sciences, Stellenbosch University, 7505 Cape Town, South Africa.
Sònia
S
Borrell
Youjin
Y
Teo
Federica
F
Giardina
Elizabeth M
EM
Streicher
Marisa
M
Klopper
Julia
J
Feldmann
Borna
B
Müller
Tommie C
TC
Victor
Sebastien
S
Gagneux
antimicrobial; epidemiology; infection; microbiology