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In vitro efficacy of next-generation dihydrotriazines and biguanides against babesiosis and malaria parasites.

ABSTRACT: Babesia and Plasmodium pathogens, the causative agents of babesiosis and malaria, are vector-borne intraerythrocytic protozoan parasites, posing significant threats to both human and animal health. The widespread resistance exhibited by these pathogens to various classes of antiparasitic drugs underscores the need for the development of novel and more effective therapeutic strategies. Antifolates have long been recognized as attractive antiparasitic drugs as they target the folate pathway, which is essential for the biosynthesis of purines and pyrimidines, and thus is vital for the survival and proliferation of protozoan parasites. More efficacious and safer analogs within this class are needed to overcome challenges due to resistance to commonly used antifolates, such as pyrimethamine, and to address liabilities associated with the dihydrotriazines, WR99210 and JPC-2067. Here, we utilized an in vitro culture condition suitable for the continuous propagation of Babesia duncani, Babesia divergens, Babesia MO1, and Plasmodium falciparum in human erythrocytes to screen a library of 50 dihydrotriazines and 29 biguanides for their efficacy in vitro and compared their potency and therapeutic indices across different species and isolates. We identified nine analogs that inhibit the growth of all species, including the P. falciparum pyrimethamine-resistant strain HB3, with IC₅₀ values below 10 nM, and display excellent in vitro therapeutic indices. These compounds hold substantial promise as lead antifolates for further development as broad-spectrum antiparasitic drugs.

SUBMITTER: Vydyam P

PROVIDER: S-EPMC11373198 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature

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In vitro efficacy of next-generation dihydrotriazines and biguanides against babesiosis and malaria parasites.

Vydyam Pratap P Chand Meenal M Gihaz Shalev S Renard Isaline I Heffernan Gavin D GD Jacobus Laura R LR Jacobus David P DP Saionz Kurt W KW Shah Raju R Shieh Hong-Ming H-M Terpinski Jacek J Zhao Wenyi W Cornillot Emmanuel E Ben Mamoun Choukri C

Antimicrobial agents and chemotherapy 20240813 9

Babesia and Plasmodium pathogens, the causative agents of babesiosis and malaria, are vector-borne intraerythrocytic protozoan parasites, posing significant threats to both human and animal health. The widespread resistance exhibited by these pathogens to various classes of antiparasitic drugs underscores the need for the development of novel and more effective therapeutic strategies. Antifolates have long been recognized as attractive antiparasitic drugs as they target the folate ...[more]

PMID: 39136469

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Project description:BackgroundCluster-randomized controlled trials (cluster-RCTs) have demonstrated variation in the epidemiological efficacy of different next-generation insecticide-treated net (ITN) types, with some providing shorter-lived impact than others. Further studies are needed to assess changes in the insecticidal durability of these ITNs over time to complement cluster-RCT results.MethodsA series of experimental hut trials were performed to evaluate the bioefficacy of new and field-aged next-generation ITNs (PermaNet® 3.0, Royal Guard®, Interceptor® G2) compared to a pyrethroid-only net (Interceptor®) against pyrethroid-resistant malaria vectors in Covè, southern Benin. Field-aged nets were withdrawn from households at 12, 24 and 36 months. Net pieces cut from whole ITNs were analysed for chemical content, and susceptibility bioassays were performed during each trial to assess changes in insecticide resistance in the Covè vector population.ResultsInterceptor® G2 induced superior mosquito mortality than the other ITNs across all time points. The improved mortality with Interceptor® G2 compared to Interceptor® was evident across all time points but was greater with new nets (odds ratio (OR) = 8.6, 95% CI [7.4, 10.1]) than field-aged nets (OR = 2.5, 95% CI [1.8, 3.5] at 12 months, OR = 2.4, 95% CI [1.6, 3.7] at 24 months and OR = 2.9, 95% CI [1.6, 5.1] at 36 months). New Royal Guard® reduced mosquito fertility compared to the other ITNs, but this improvement fell after field-ageing, particularly at 24 months when it was similar to Interceptor® (11% vs 3%, p = 0.08). When new, mortality was significantly higher with PermaNet® 3.0 compared to Interceptor® (OR = 3.6, 95% CI [3.0, 4.2]); however, this benefit was lost with field-aged nets at 12 months (OR = 1.1, 95% CI [0.8, 1.5]) and 24 months (OR = 0.6, 95% CI [0.4, 0.9]). Retention of the non-pyrethroid compound in next-generation nets was low after 36 months (27% for PermaNet® 3.0, 26% for Royal Guard® and 15% for Interceptor® G2).ConclusionsInterceptor® G2 outperformed the other ITNs, confirming the superiority of pyrethroid-chlorfenapyr nets over other net types. When new, all next-generation ITNs showed superior bioefficacy compared to Interceptor®; however, the size of this improvement fell after field-ageing due to poor durability of the non-pyrethroid compound. These findings emphasize the need to enhance the insecticidal durability of next-generation ITNs.

Dataset Information

In vitro efficacy of next-generation dihydrotriazines and biguanides against babesiosis and malaria parasites.

Publications

<i>In vitro</i> efficacy of next-generation dihydrotriazines and biguanides against babesiosis and malaria parasites.

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