Toward Overcoming Pyrethroid Resistance in Mosquito Control: The Role of Sodium Channel Blocker Insecticides

Area of Science:

• Molecular biology
• Entomology
• Biochemistry

Background:

• Mosquito-borne diseases cause significant mortality, with vector control via insecticides being crucial.
• Insecticide resistance, particularly in voltage-gated sodium channels (VGSCs), threatens public health.
• Sodium channel blocker insecticides (SCBIs) show promise for mosquito control, but their resistance mechanisms require elucidation.

Purpose of the Study:

• To investigate the molecular mechanisms underlying SCBI action and resistance in mosquito VGSCs.
• To identify the entry pathway and binding site interactions of SCBIs within mosquito VGSCs.
• To explain the impact of specific mutations on SCBI efficacy and explore potential cross-resistance.

Main Methods:

• Extensive molecular dynamics simulations (equilibrium and enhanced sampling, 3.2 μs total).
• Analysis of ligand-protein interactions within the mosquito VGSC central cavity.
• Identification of key residues involved in SCBI and pyrethroid binding.

Main Results:

• The DIII-DIV fenestration was identified as the primary entry route for the active SCBI metabolite DCJW into the mosquito VGSC.
• The F1852 residue is critical in regulating SCBI access to the binding site, explaining the F1852T resistance mutation.
• DCJW exhibits higher toxicity than its parent compound, indoxacarb, due to its smaller size.
• Several residues were identified as common binding sites for SCBIs and non-ester pyrethroids, suggesting potential cross-resistance.

Conclusions:

• Understanding SCBI binding and entry mechanisms is vital for developing effective mosquito control strategies.
• The F1852T mutation confers resistance by hindering SCBI access to the VGSC binding site.
• Potential cross-resistance between SCBIs and pyrethroids highlights the need for integrated pest management approaches.