Potential metabolic resistance mechanisms to ivermectin in Anopheles gambiae: a synergist bioassay study
<strong>Background</strong> Despite remarkable success obtained with current malaria vector control strategies in the last 15 years, additional innovative measures will be needed to achieve the ambitious goals for malaria control set for 2030 by the World Health Organization (WHO). New t...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
BioMed Central
2021
|
| _version_ | 1826286113763885056 |
|---|---|
| author | Nicolas, P Kiuru, C Wagah, MG Muturi, M Duthaler, U Hammann, F Maia, MF Chaccour, C |
| author_facet | Nicolas, P Kiuru, C Wagah, MG Muturi, M Duthaler, U Hammann, F Maia, MF Chaccour, C |
| author_sort | Nicolas, P |
| collection | OXFORD |
| description | <strong>Background</strong>
Despite remarkable success obtained with current malaria vector control strategies in the last 15 years, additional innovative measures will be needed to achieve the ambitious goals for malaria control set for 2030 by the World Health Organization (WHO). New tools will need to address insecticide resistance and residual transmission as key challenges. Endectocides such as ivermectin are drugs that kill mosquitoes which feed on treated subjects. Mass administration of ivermectin can effectively target outdoor and early biting vectors, complementing the still effective conventional tools. Although this approach has garnered attention, development of ivermectin resistance is a potential pitfall. Herein, we evaluate the potential role of xenobiotic pumps and cytochrome P450 enzymes in protecting mosquitoes against ivermectin by active efflux and metabolic detoxification, respectively.
<br>
<strong>Methods</strong>
We determined the lethal concentration 50 for ivermectin in colonized Anopheles gambiae; then we used chemical inhibitors and inducers of xenobiotic pumps and cytochrome P450 enzymes in combination with ivermectin to probe the mechanism of ivermectin detoxification.
<br>
<strong>Results</strong>
Dual inhibition of xenobiotic pumps and cytochromes was found to have a synergistic effect with ivermectin, greatly increasing mosquito mortality. Inhibition of xenobiotic pumps alone had no effect on ivermectin-induced mortality. Induction of xenobiotic pumps and cytochromes may confer partial protection from ivermectin.
<br>
<strong>Conclusion</strong>
There is a clear pathway for development of ivermectin resistance in malaria vectors. Detoxification mechanisms mediated by cytochrome P450 enzymes are more important than xenobiotic pumps in protecting mosquitoes against ivermectin. |
| first_indexed | 2024-03-07T01:38:57Z |
| format | Journal article |
| id | oxford-uuid:962beadb-a0da-409c-a9c1-8c9f22a9ff90 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:38:57Z |
| publishDate | 2021 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | oxford-uuid:962beadb-a0da-409c-a9c1-8c9f22a9ff902022-03-26T23:51:16ZPotential metabolic resistance mechanisms to ivermectin in Anopheles gambiae: a synergist bioassay studyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:962beadb-a0da-409c-a9c1-8c9f22a9ff90EnglishSymplectic ElementsBioMed Central2021Nicolas, PKiuru, CWagah, MGMuturi, MDuthaler, UHammann, FMaia, MFChaccour, C<strong>Background</strong> Despite remarkable success obtained with current malaria vector control strategies in the last 15 years, additional innovative measures will be needed to achieve the ambitious goals for malaria control set for 2030 by the World Health Organization (WHO). New tools will need to address insecticide resistance and residual transmission as key challenges. Endectocides such as ivermectin are drugs that kill mosquitoes which feed on treated subjects. Mass administration of ivermectin can effectively target outdoor and early biting vectors, complementing the still effective conventional tools. Although this approach has garnered attention, development of ivermectin resistance is a potential pitfall. Herein, we evaluate the potential role of xenobiotic pumps and cytochrome P450 enzymes in protecting mosquitoes against ivermectin by active efflux and metabolic detoxification, respectively. <br> <strong>Methods</strong> We determined the lethal concentration 50 for ivermectin in colonized Anopheles gambiae; then we used chemical inhibitors and inducers of xenobiotic pumps and cytochrome P450 enzymes in combination with ivermectin to probe the mechanism of ivermectin detoxification. <br> <strong>Results</strong> Dual inhibition of xenobiotic pumps and cytochromes was found to have a synergistic effect with ivermectin, greatly increasing mosquito mortality. Inhibition of xenobiotic pumps alone had no effect on ivermectin-induced mortality. Induction of xenobiotic pumps and cytochromes may confer partial protection from ivermectin. <br> <strong>Conclusion</strong> There is a clear pathway for development of ivermectin resistance in malaria vectors. Detoxification mechanisms mediated by cytochrome P450 enzymes are more important than xenobiotic pumps in protecting mosquitoes against ivermectin. |
| spellingShingle | Nicolas, P Kiuru, C Wagah, MG Muturi, M Duthaler, U Hammann, F Maia, MF Chaccour, C Potential metabolic resistance mechanisms to ivermectin in Anopheles gambiae: a synergist bioassay study |
| title | Potential metabolic resistance mechanisms to ivermectin in Anopheles gambiae: a synergist bioassay study |
| title_full | Potential metabolic resistance mechanisms to ivermectin in Anopheles gambiae: a synergist bioassay study |
| title_fullStr | Potential metabolic resistance mechanisms to ivermectin in Anopheles gambiae: a synergist bioassay study |
| title_full_unstemmed | Potential metabolic resistance mechanisms to ivermectin in Anopheles gambiae: a synergist bioassay study |
| title_short | Potential metabolic resistance mechanisms to ivermectin in Anopheles gambiae: a synergist bioassay study |
| title_sort | potential metabolic resistance mechanisms to ivermectin in anopheles gambiae a synergist bioassay study |
| work_keys_str_mv | AT nicolasp potentialmetabolicresistancemechanismstoivermectininanophelesgambiaeasynergistbioassaystudy AT kiuruc potentialmetabolicresistancemechanismstoivermectininanophelesgambiaeasynergistbioassaystudy AT wagahmg potentialmetabolicresistancemechanismstoivermectininanophelesgambiaeasynergistbioassaystudy AT muturim potentialmetabolicresistancemechanismstoivermectininanophelesgambiaeasynergistbioassaystudy AT duthaleru potentialmetabolicresistancemechanismstoivermectininanophelesgambiaeasynergistbioassaystudy AT hammannf potentialmetabolicresistancemechanismstoivermectininanophelesgambiaeasynergistbioassaystudy AT maiamf potentialmetabolicresistancemechanismstoivermectininanophelesgambiaeasynergistbioassaystudy AT chaccourc potentialmetabolicresistancemechanismstoivermectininanophelesgambiaeasynergistbioassaystudy |