Positive Epistasis Drives the Acquisition of Multidrug Resistance

The evolution of multiple antibiotic resistance is an increasing global problem. Resistance mutations are known to impair fitness, and the evolution of resistance to multiple drugs depends both on their costs individually and on how they interact—epistasis. Information on the level of epistasis between antibiotic resistance mutations is of key importance to understanding epistasis amongst deleterious alleles, a key theoretical question, and to improving public health measures. Here we show that in an antibiotic-free environment the cost of multiple resistance is smaller than expected, a signature of pervasive positive epistasis among alleles that confer resistance to antibiotics. Competition assays reveal that the cost of resistance to a given antibiotic is dependent on the presence of resistance alleles for other antibiotics. Surprisingly we find that a significant fraction of resistant mutations can be beneficial in certain resistant genetic backgrounds, that some double resistances entail no measurable cost, and that some allelic combinations are hotspots for rapid compensation. These results provide additional insight as to why multi-resistant bacteria are so prevalent and reveal an extra layer of complexity on epistatic patterns previously unrecognized, since it is hidden in genome-wide studies of genetic interactions using gene knockouts.

[1]  R. MacLean,et al.  The cost of multiple drug resistance in Pseudomonas aeruginosa , 2009, Journal of evolutionary biology.

[2]  A. Buckling,et al.  The Distribution of Fitness Effects of Beneficial Mutations in Pseudomonas aeruginosa , 2009, PLoS genetics.

[3]  P. Phillips.  Epistasis — the essential role of gene interactions in the structure and evolution of genetic systems , 2008, Nature Reviews Genetics.

[4]  Remy Chait,et al.  Drug interactions modulate the potential for evolution of resistance , 2008, Proceedings of the National Academy of Sciences.

[5]  D. Hartl,et al.  Accelerated evolution of resistance in multidrug environments , 2008, Proceedings of the National Academy of Sciences.

[6]  Isabel Gordo,et al.  Adaptive Mutations in Bacteria: High Rate and Small Effects , 2007, Science.

[7]  P. Keightley,et al.  A Comparison of Models to Infer the Distribution of Fitness Effects of New Mutations , 2013, Genetics.

[8]  Sebastian Bonhoeffer,et al.  Epistasis between deleterious mutations and the evolution of recombination. , 2007, Trends in ecology & evolution.

[9]  R. Kishony,et al.  Antibiotic interactions that select against resistance , 2007, Nature.

[10]  C. Zeyl.  How missing genes interact , 2007, Nature Genetics.

[11]  R. Korona,et al.  Epistatic buffering of fitness loss in yeast double deletion strains , 2007, Nature Genetics.

[12]  Ronald W. Davis,et al.  Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions , 2007, Nature Genetics.

[13]  K. Hopkins,et al.  Rapid detection of gyrA and parC mutations in quinolone-resistant Salmonella enterica using Pyrosequencing technology. , 2007, Journal of microbiological methods.

[14]  B. Levin,et al.  Fitness Costs of Fluoroquinolone Resistance in Streptococcus pneumoniae , 2006, Antimicrobial Agents and Chemotherapy.

[15]  Toru Mori,et al.  Detection of Multidrug Resistance in Mycobacterium tuberculosis , 2006, Journal of Clinical Microbiology.

[16]  C. D. Long,et al.  The Competitive Cost of Antibiotic Resistance in Mycobacterium tuberculosis , 2006, Science.

[17]  Nigel F. Delaney,et al.  Darwinian Evolution Can Follow Only Very Few Mutational Paths to Fitter Proteins , 2006, Science.

[18]  R. Kishony,et al.  Functional classification of drugs by properties of their pairwise interactions , 2006, Nature Genetics.

[19]  Richard A. Watson,et al.  PERSPECTIVE:SIGN EPISTASIS AND GENETIC CONSTRAINT ON EVOLUTIONARY TRAJECTORIES , 2005 .

[20]  G. Church,et al.  Modular epistasis in yeast metabolism , 2005, Nature Genetics.

[21]  C. Petropoulos,et al.  Evidence for Positive Epistasis in HIV-1 , 2004, Science.

[22]  Lars Liljas,et al.  Compensatory adaptation to the deleterious effect of antibiotic resistance in Salmonella typhimurium , 2002, Molecular microbiology.

[23]  N. Ahmed,et al.  Molecular Characterization of Multidrug-Resistant Isolates of Mycobacterium tuberculosis from Patients in North India , 2002, Antimicrobial Agents and Chemotherapy.

[24]  C. Torres,et al.  Mechanisms of antibiotic resistance in Escherichia coli isolates obtained from healthy children in Spain. , 2002, Microbial drug resistance.

[25]  C. Wilke,et al.  Interaction between directional epistasis and average mutational effects , 2000, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[26]  M G Reynolds,et al.  Compensatory evolution in rifampin-resistant Escherichia coli. , 2000, Genetics.

[27]  B. Levin,et al.  Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria. , 2000, Genetics.

[28]  O. Berg,et al.  Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance. , 2000, Science.

[29]  B. Levin,et al.  The biological cost of antibiotic resistance. , 1999, Current opinion in microbiology.

[30]  D. Heymann,et al.  Containment of Antibiotic Resistance , 1998, Science.

[31]  R. Lenski,et al.  Test of synergistic interactions among deleterious mutations in bacteria , 1997, Nature.

[32]  S Bonhoeffer,et al.  Evaluating treatment protocols to prevent antibiotic resistance. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[33]  B. Levin,et al.  Adaptation to the fitness costs of antibiotic resistance in Escherichia coli , 1997, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[34]  S. Schrag,et al.  Reducing antibiotic resistance , 1996, Nature.

[35]  B. Stillman,et al.  Cold Spring Harbor Laboratory , 1995, Molecular medicine.

[36]  Måns Ehrenberg,et al.  Limitations of translational accuracy , 1996 .

[37]  R. Lenski,et al.  Long-Term Experimental Evolution in Escherichia coli. I. Adaptation and Divergence During 2,000 Generations , 1991, The American Naturalist.

[38]  A. Kondrashov.  Deleterious mutations and the evolution of sexual reproduction , 1988, Nature.

[39]  R. Jayaraman,et al.  SOS independent survival against mitomycin C induced lethality in a rifampicin-nalidixic acid-resistant mutant of Escherichia coli. , 1988, Mutation research.

[40]  L. Enquist,et al.  Experiments With Gene Fusions , 1984 .

[41]  L. Gorini,et al.  Interaction between mutations of ribosomes and RNA polymerase: a pair of strA and rif mutants individually temperature-insensitive but temperature-sensitive in combination. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[42]  M. Kimura,et al.  An introduction to population genetics theory , 1971 .