Metabolomic changes underpinning permethrin resistance in the <i>Anopheles gambiae</i> malaria vector from Cameroon

Insecticide resistance reduces the effectiveness of current malaria vector control interventions. To understand the mechanisms underlying permethrin resistance in field-derived <i>Anopheles gambiae</i> vectors collected from Cameroon, we used Ultra-High Performance Liquid Chromatography coupled with High-Resolution Tandem Mass Spectrometry (UHPLC-HRMS/MS) to comprehensively analyze metabolic changes in resistant and susceptible samples to gain insight into mechanisms driven permethrin resistance. Resistant mosquitoes exhibited upregulated levels of inosine, nicotinic acid, dipeptides, amino acids, fumarate, uracil, and aldopentose. These data suggest that altered metabolic-based detoxification, as well as target site and metabolic shifts, and enhanced energy production contribute to permethrin resistance. Conversely, susceptible mosquitoes showed increased levels of N-acetyl-aspartic acid, xanthurenic acid, 2-hydroxyglutarate, 3-hydroxykynurenine, propanoylcarnitine, and L-pipecolic acid. These metabolites are associated with neurotoxicity, energy disruption, as well as tryptophan and lysine catabolism. These findings elucidate the metabolic pathways of permethrin-resistance and underscore the mechanisms that could lead to the emergence of pyrethroid cross-resistance.