The P450 CYP6Z1 confers carbamate/pyrethroid cross-resistance in a major African malaria vector beside a novel carbamate-insensitive N485I acetylcholinesterase-1 mutation

Ibrahim, SulaimanSadi, Ndula, Miranda, Riveron, Jacob ORCID: https://orcid.org/0000-0002-5395-767X, Irving, Helen and Wondji, Charles ORCID: https://orcid.org/0000-0003-0791-3673 (2016) 'The P450 CYP6Z1 confers carbamate/pyrethroid cross-resistance in a major African malaria vector beside a novel carbamate-insensitive N485I acetylcholinesterase-1 mutation'. Molecular Ecology, Vol 25, Issue 14, pp. 3436-3452.

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Abstract

Carbamates are increasingly used for vector control notably in areas with pyrethroid resistance. However, a cross-resistance between these insecticides in major malaria vectors such as Anopheles funestus could severely limit available resistance management options. Unfortunately, the molecular basis of such cross-resistance remains uncharacterized in An. funestus, preventing effective resistance management.

Here, using a genome-wide transcription profiling, we revealed that metabolic resistance through up-regulation of cytochrome P450 genes is driving carbamate resistance. The P450s CYP6P9a, CYP6P9b and CYP6Z1 were the most up-regulated detoxification genes in the multiple resistant mosquitoes. However, in silico docking simulations predicted CYP6Z1 to metabolise both pyrethroids and carbamates, whereas CYP6P9a and CYP6P9b were predicted to metabolise only the pyrethroids. Using recombinant enzyme metabolism and inhibition assays we demonstrated that CYP6Z1 metabolizes bendiocarb and pyrethroids, whereas CYP6P9a and CYP6P9b metabolise only the pyrethroids. Other up-regulated gene families in resistant mosquitoes included several cuticular protein genes suggesting a possible reduced penetration resistance mechanism. Investigation of the target-site resistance in acetylcholinesterase 1 (ace-1) gene detected and established the association between the new N485I mutation and bendiocarb resistance (Odds ratio 7.3; P<0.0001). The detection of multiple haplotypes in single mosquitoes after cloning suggested the duplication of ace-1. A TaqMan genotyping of the N485I in nine countries revealed that the mutation is located only in Southern Africa with frequency of 10-15% suggesting its recent occurrence.

These findings will help in monitoring the spread and evolution of carbamate resistance and improve the design of effective resistance management strategies to control this malaria vector.

Item Type:	Article
Subjects:	QU Biochemistry > Enzymes > QU 136 Hydrolases QW Microbiology and Immunology > Immune Responses > QW 700 Infection. Mechanisms of infection and resistance. QX Parasitology > Insects. Other Parasites > QX 515 Anopheles WC Communicable Diseases > Tropical and Parasitic Diseases > WC 765 Prevention and control WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 190 Hemoglobin and other hemeproteins. Porphyrins (Associated with hemoglobin)
Faculty: Department:	Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI):	https://doi.org/10.1111/mec.13673
Depositing User:	Jessica Jones
Date Deposited:	03 May 2016 13:45
Last Modified:	28 Jul 2022 15:52
URI:	https://archive.lstmed.ac.uk/id/eprint/5870

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