| 1. |
- Maisnier-Patin, Sophie, et al.
(author)
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Adaptation to the deleterious effects of antimicrobial drug resistance mutations by compensatory evolution
- 2004
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In: Research in Microbiology. - : Elsevier BV. - 0923-2508 .- 1769-7123. ; 155:5, s. 360-369
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Journal article (peer-reviewed)abstract
- Compensatory mutations, due to their ability to mask the deleterious effects of another mutation, are important for the adaptation and evolution of most organisms. Resistance to antibiotics, antivirals, antifungals, herbicides and insecticides is usually associated with a fitness cost. As a result of compensatory evolution, the initial fitness costs conferred by resistance mutations (or other deleterious mutations) can often be rapidly and efficiently reduced. Such compensatory evolution is potentially of importance for (i) the long-term persistence of drug resistance, (ii) reducing the rate of fitness loss associated with the accumulation of deleterious mutations in small asexual populations, and (iii) the evolution of complexity of cellular processes.
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| 2. |
- Maisnier-Patin, Sophie, et al.
(author)
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Genomic buffering mitigates the effects of deleterious mutations in bacteria
- 2005
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 37:12, s. 1376-1379
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Journal article (peer-reviewed)abstract
- The relationship between the number of randomly accumulated mutations in a genome and fitness is a key parameter in evolutionary biology1, 2, 3, 4, 5. Mutations may interact such that their combined effect on fitness is additive (no epistasis), reinforced (synergistic epistasis) or mitigated (antagonistic epistasis). We measured the decrease in fitness caused by increasing mutation number in the bacterium Salmonella typhimurium using a regulated, error-prone DNA polymerase (polymerase IV, DinB). As mutations accumulated, fitness costs increased at a diminishing rate. This suggests that random mutations interact such that their combined effect on fitness is mitigated and that the genome is buffered against the fitness reduction caused by accumulated mutations. Levels of the heat shock chaperones DnaK and GroEL increased in lineages that had accumulated many mutations, and experimental overproduction of GroEL further increased the fitness of lineages containing deleterious mutations. These findings suggest that overexpression of chaperones contributes to antagonistic epistasis
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| 3. |
- Paulander, Wilhelm, et al.
(author)
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Amplification of the Gene for Isoleucyl-tRNA Synthetase Facilitates Adaptation to the Fitness Cost of Mupirocin Resistance in Salmonella enterica
- 2010
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In: Genetics. - : Oxford University Press (OUP). - 0016-6731 .- 1943-2631. ; 185:1, s. 305-312
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Journal article (peer-reviewed)abstract
- Mutations that cause resistance to antibiotics in bacteria often reduce growth rate by impairing some essential cellular function. This growth impairment is expected to counterselect resistant organisms from natural populations following discontinuation of antibiotic therapy. Unfortunately (for disease control) bacteria adapt and improve their growth rate, often without losing antibiotic resistance. This adaptation process was studied in mupirocin-resistant (Mup(R)) strains of Salmonella enterica. Mupirocin (Mup) is an isoleucyl-adenylate analog that inhibits the essential enzyme, isoleucyl- tRNA synthetase (IleRS). Mutations causing Mup(R) alter IleRS and reduce growth rate. Fitness is restored by any of 23 secondary IleRS amino acid substitutions, 60% of which leave resistance unaffected. Evidence that increased expression of the original mutant ileS gene (Mup(R)) also improves fitness while maintaining resistance is presented. Expression can be increased by amplification of the ileS gene (more copies) or mutations that improve the ileS promoter (more transcription). Some adapted strains show both ileS amplification and an improved promoter. This suggests a process of adaptation initiated by common amplifications and followed by later acquisition of rare point mutations. Finally, a point mutation in one copy relaxes selection and allows loss of defective ileS copies. This sequence of events is demonstrated experimentally. A better understanding of adaptation can explain why antibiotic resistance persists in bacterial populations and may help identify drugs that are least subject to this problem.
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| 4. |
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| 5. |
- Paulander, Wilhelm, et al.
(author)
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Multiple mechanisms to ameliorate the fitness burden of mupirocin resistance in Salmonella typhimurium
- 2007
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In: Molecular Microbiology. - : Wiley. - 0950-382X .- 1365-2958. ; 64:4, s. 1038-1048
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Journal article (peer-reviewed)abstract
- We examined how the fitness costs of mupirocin resistance caused by mutations in the chromosomal isoleucyl–tRNA synthetase gene (ileS) can be ameliorated. Mupirocin-resistant mutants were isolated and four different, resistance-conferring point mutations in the chromosomal ileS gene were identified. Fifty independent lineages of the low-fitness, resistant mutants were serially passaged to evolve compensated mutants with increased fitness. In 34/50 of the evolved lineages, the increase in fitness resulted from additional point mutations in isoleucine tRNA synthetase (IleRS). Measurements in vitro of the kinetics of aminoacylation of wild-type and mutant enzymes showed that resistant IleRS had a reduced rate of aminoacylation due to altered interactions with both tRNAIle and ATP. The intragenic compensatory mutations improved IleRS kinetics towards the wild-type enzyme, thereby restoring bacterial fitness. Seven of the 16 lineages that lacked second-site compensatory mutations in ileS, showed an increase in ileS gene dosage, suggesting that an increased level of defective IleRS compensate for the decrease in aminoacylation activity. Our findings show that the fitness costs of ileS mutations conferring mupirocin resistance can be reduced by several types of mechanisms that may contribute to the stability of mupirocin resistance in clinical settings.
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| 6. |
- Paulander, Wilhelm, et al.
(author)
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The fitness cost of streptomycin resistance depends on rpsL mutation, carbon source and RpoS (sigmaS)
- 2009
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In: Genetics. - : Oxford University Press (OUP). - 0016-6731 .- 1943-2631. ; 183:2, s. 539-546
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Journal article (peer-reviewed)abstract
- Mutations that cause antibiotic resistance often produce associated fitness costs. These costs have a detrimental effect on the fate of resistant organisms in natural populations and could be exploited in designing drugs, therapeutic regimes, and intervention strategies. The streptomycin resistance (StrR) mutations K42N and P90S in ribosomal protein S12 impair growth on rich medium. Surprisingly, in media with poorer carbon sources, the same StrR mutants grow faster than wild type. This improvement reflects a failure of these StrR mutants to induce the stress-inducible sigma factor RpoS (sigmaS), a key regulator of many stationary-phase and stress-inducible genes. On poorer carbon sources, wild-type cells induce sigmaS, which retards growth. By not inducing sigmaS, StrR mutants escape this self-imposed inhibition. Consistent with this interpretation, the StrR mutant loses its advantage over wild type when both strains lack an RpoS (sigmaS) gene. Failure to induce sigmaS produced the following side effects: (1) impaired induction of several stress-inducible genes, (2) reduced tolerance to thermal stress, and (3) reduced translational fidelity. These results suggest that RpoS may contribute to long-term cell survival, while actually limiting short-term growth rate under restrictive growth conditions. Accordingly, the StrR mutant avoids short-term growth limitation but is sensitized to other stresses. These results highlight the importance of measuring fitness costs under multiple experimental conditions not only to acquire a more relevant estimate of fitness, but also to reveal novel physiological weaknesses exploitable for drug development.
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