Characterizing pyrethroid resistance and mechanisms in Anopheles gambiae (s.s.) and Anopheles arabiensis from 11 districts in Uganda

Mawejje, Henry; Weetman, David; Epstein, Adrienne; Lynd, Amy; Opigo, Jimmy; Maiteki‐Sebuguzi, Catherine; Lines, Jo; Kamya, Moses R.; Rosenthal, Philip J.; Donnelly, Martin; Dorsey, Grant; Staedke, Sarah G.

doi:10.1016/j.crpvbd.2022.100106

Cited by 3 publications

(2 citation statements)

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“…There were an estimated 241 million cases and 627 000 deaths worldwide from malaria in 2020, an increase in morbidity and mortality compared to 2018. These data represent a slowdown in progress toward malaria control, which is attributed to the emergence of resistance in Plasmodium falciparum to artemisinin combination therapies − and in Anopheline mosquito vectors to insecticides. , These factors hamper current disease- and vector-control programs that constitute malaria elimination efforts. Renewed progress toward these goals requires a new generation of antimalarials with mechanisms of action that are different from currently used drugs, as well as drugs that act on multiple parasite stages.…”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials

Gilleran,

Ashraf,

Delvillar

et al. 2024

J. Med. Chem.

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Controlling malaria requires new drugs against Plasmodium falciparum. The P. falciparum cGMP-dependent protein kinase (PfPKG) is a validated target whose inhibitors could block multiple steps of the parasite's life cycle. We defined the structure− activity relationship (SAR) of a pyrrole series for PfPKG inhibition. Key pharmacophores were modified to enable full exploration of chemical diversity and to gain knowledge about an ideal core scaffold. In vitro potency against recombinant PfPKG and human PKG were used to determine compound selectivity for the parasite enzyme. P. berghei sporozoites and P. falciparum asexual blood stages were used to assay multistage antiparasitic activity. Cellular specificity of compounds was evaluated using transgenic parasites expressing PfPKG carrying a substituted "gatekeeper" residue. The structure of PfPKG bound to an inhibitor was solved, and modeling using this structure together with computational tools was utilized to understand SAR and establish a rational strategy for subsequent lead optimization.

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Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials

Gilleran,

Ashraf,

Delvillar

et al. 2024

J. Med. Chem.

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“…Resistance levels in An. arabiensis are typically lower than in indoor biting species, probably due to their reduced exposure to insecticides, but is nonetheless appreciable to some active ingredients (Pinda et al, 2020;Orondo et al, 2021;Matiya et al, 2022;Mawejje et al, 2023). This is a cause for concern since An.…”

Section: Introductionmentioning

confidence: 99%

Copy number variants underlie the major selective sweeps in insecticide resistance genes inAnopheles arabiensisfrom Tanzania

Lucas,

Nagi,

Kabula

et al. 2024

Preprint

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To keep ahead of the evolution of resistance to insecticides in mosquitoes, national malaria control programmes must make use of a range of insecticides, both old and new, while monitoring resistance mechanisms. Knowledge of the mechanisms of resistance remains limited inAnopheles arabiensis, which in many parts of Africa is of increasing importance because it is apparently less susceptible to many indoor control interventions. Furthermore, comparatively little is known in general about resistance to non-pyrethroid insecticides such as pirimiphos-methyl (PM), which are crucial for effective control in the context of resistance to pyrethroids. We performed a genome-wide association study to determine the molecular mechanisms of resistance to deltamethrin (commonly used in bednets) and PM, inAn. arabiensisfrom two regions in Tanzania. Genomic regions of positive selection in these populations were largely driven by copy number variants (CNVs) in gene families involved in resistance to these two insecticides. We found evidence of a new gene cluster involved in resistance to PM, identifying a strong selective sweep tied to a CNV in theCoeae2g-Coeae6gcluster of carboxylesterase genes. Using complementary data fromAn. coluzziiin Ghana, we show that copy number at this locus is significantly associated with PM resistance. Similarly, for deltamethrin, resistance was strongly associated with a novel CNV allele in theCyp6aa/Cyp6pcluster. Against this background of metabolic resistance, target site resistance was very rare or absent for both insecticides. Mutations in the pyrethroid target siteVgscwere at very low frequency in Tanzania, yet combining these samples with threeAn. arabiensisindividuals from West Africa revealed a startling diversity of evolutionary origins of target site resistance, with up to 5 independent origins ofVgsc-995 mutations found within just 8 haplotypes. Thus, despite having been first recorded over 10 years ago,Vgscresistance mutations in TanzanianAn. arabiensishave remained at stable low frequencies. Overall, our results provide a new copy number marker for monitoring resistance to PM in malaria mosquitoes, and reveal the complex picture of resistance patterns inAn. arabiensis.

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Longitudinal survey of insecticide resistance in a village of Central Region of Burkina Faso reveals co-occurrence of 1014F, 1014S and 402L mutations in Anopheles coluzzii and Anopheles arabiensis

Perugini,

Pichler,

Guelbeogo

et al. 2024

Preprint

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Introduction. Pyrethroid resistance is one of the major threats for effectiveness of insecticide-treated bed nets (ITNs) in malaria vector control. Genotyping of mutations in the voltage gated sodium channel (VGSC) gene is widely used to easily assess the evolution and spread of pyrethroid target-site resistance among malaria vectors. L1014F and L1014S substitutions are the most common and best characterized VGSC mutations in major African malaria vector species of the Anopheles gambiae complex. Recently, an additional substitution involved in pyrethroid resistance i.e. V402L, has been detected in Anopheles coluzzii from West Africa lacking any other resistance alleles at locus 1014. We here monitored the evolution of target-site resistance mutations L1014F/S and V402L in A. coluzzii and A. arabiensis specimens from a Burkina Faso village over a 10-year range after the massive ITN scale-up started in 2010. Methods. A. coluzzii (N = 300) and A. arabiensis (N = 362) specimens collected in 2011, 2015 and 2020 at Goden village were genotyped by TaqMan assays and sequencing for the three target site resistance mutations; allele frequencies were statistically investigated over the years. Results. A divergent trend in resistant allele frequencies was observed in the two species: 1014F decreased in A. coluzzii (from 0.76 to 0.52) but increased in A. arabiensis (from 0.18 to 0.70); 1014S occurred only in A. arabiensis and slightly decreased over time (from 0.33 to 0.23); 402L increased in A. coluzzii (from 0.15 to 0.48) and was found for the first time in one A. arabiensis specimen. In 2020 the co-occurrence of different resistance alleles reached 43% in A. coluzzii (alleles 410L and 1014F) and 32% in A. arabiensis (alleles 1014F and 1014S). Conclusions. Overall, an increasing level of target-site resistance was observed among the populations with only 1% of the two malaria vector species being wild type at both loci, 1014 and 402, in 2020. This, together with the co-occurrence of different mutations in the same specimens, calls for future investigations on the possible synergism between resistance alleles and their phenotype to implement local tailored intervention strategies.

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Characterizing pyrethroid resistance and mechanisms in Anopheles gambiae (s.s.) and Anopheles arabiensis from 11 districts in Uganda

Cited by 3 publications

References 72 publications

Structure–Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials

Structure–Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials

Copy number variants underlie the major selective sweeps in insecticide resistance genes inAnopheles arabiensisfrom Tanzania

Longitudinal survey of insecticide resistance in a village of Central Region of Burkina Faso reveals co-occurrence of 1014F, 1014S and 402L mutations in Anopheles coluzzii and Anopheles arabiensis

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