Mitochondrial complex III Q_i -site inhibitor resistance mutations found in laboratory selected mutants and field isolates

Background: Complex III inhibitors targeting the Q_i -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 Q_i -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 Q_i -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.