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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Mitochondrial complex III Qi -site inhibitor resistance mutations found in laboratory selected mutants and field
Pierre Mounkoro1, Thomas Michel1, Rafik Benhachemi1
1Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.
Background:
Complex III inhibitors targeting the Qi -site have been known for decades; some are used or being developed as antimicrobial compounds. Target site resistance mutations have been reported in laboratory-selected mutants and in field isolates. Here, we present a brief overview of mutations found in laboratory-selected resistant mutants. We also provide a study of mutations observed in field isolates of Plasmopara viticola, in particular the ametoctradin resistance substitution, S34L that we analysed in the yeast model.
Results:
A survey of laboratory mutants showed that resistance could be caused by a large number of substitutions in the Qi -site. Four residues seemed key in term of resistance: N31, G37, L198 and K228. Using yeast, we analysed the effect of the ametoctradin resistance substitution S34L reported in field isolates of P. viticola. We showed that S34L caused a high level of resistance combined with a loss of complex III activity and growth competence.
Conclusion:
Use of single site Qi -site inhibitors is expected to result in the selection of resistant mutants. However, if the substitution is associated with a fitness penalty, as may be the case with S34L, resistance development might not be an insuperable obstacle, although careful monitoring is required. © 2018 Society of Chemical Industry.
Insights
Complex III Qi-site inhibitors can cause resistance mutations. A specific mutation (S34L) in Plasmopara viticola confers high resistance but may also reduce fitness, potentially limiting its spread.
Area of Science:
- Biochemistry
- Molecular Biology
- Agricultural Science
Background:
- Complex III Qi-site inhibitors are established antimicrobial agents, with some under development.
- Resistance mutations in target sites have been documented in laboratory and field isolates.
Purpose of the Study:
- To review mutations conferring resistance in laboratory-selected mutants.
- To investigate mutations in Plasmopara viticola field isolates, focusing on the ametoctradin resistance substitution S34L using a yeast model.
Main Methods:
- Survey of laboratory-selected mutants for Qi-site substitutions.
- Analysis of the ametoctradin resistance substitution S34L in a yeast model.
Main Results:
- Multiple Qi-site substitutions confer resistance; N31, G37, L198, and K228 are key residues.
- The S34L substitution in P. viticola causes high resistance, decreased Complex III activity, and reduced growth competence.
Conclusions:
- Single-site Qi-site inhibitors are likely to select for resistant mutants.
- The S34L substitution's associated fitness penalty may impede resistance development, though monitoring is crucial.
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