Metabolomic Changes Underpinning Permethrin Resistance in the Anopheles gambiae Vector from Cameroon

Abstract Insecticide resistance reduces the effectiveness of current malaria-vector-control interventions. To understand the mechanisms underlying permethrin resistance in field-derived Anopheles gambiae 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 insights into mechanisms driving permethrin resistance. Resistant mosquitoes exhibited upregulated levels of inosine, nicotinic acid, dipeptides, amino acids, fumarate, uracil, and aldopentoses. 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, leading to susceptible phenotypes. These findings provide deeper metabolic insight into An. gambiae permethrin resistance and compel further investigations into how these metabolic pathways contribute to the emergence of pyrethroid cross-resistance.