Killing Mosquitoes Is Not the Only Way To Tackle Malaria
A new approach to antimalarial development, aided by high-throughput screening, could help to overcome resistance.
Malaria is a life-threatening disease caused by Plasmodium parasite species and is largely spread between people through the bites of infected female Anopheles mosquitoes.
Of the five Plasmodium species that infect humans, Plasmodium falciparum is the deadliest and is most prevalent in Africa, which carries a disproportionately high malaria burden. The World Health Organisation reported that, in 2024, 95% of malaria cases and 95% malaria deaths occurred in Africa.
Current approaches to tackling malaria
Currently, approaches to tackling malaria include preventative chemotherapies, chemoprophylaxis for travellers, treating confirmed cases with antimalarials, and controlling the mosquito vector.
Insecticide-treated bed nets (ITNs) and indoor residual spraying are the two major methods of controlling the mosquito vector to prevent malaria spread. ITNs protect against malaria spread through shielding against mosquito bites, interfering with host-seeking mosquito behavior and either killing or reducing fertility in mosquitoes that land on the net.
The mass use of ITNs is estimated to have averted 1.5 billion malaria cases globally between 2000 and 2022.
However, malaria still infects over 250 million people per year and claims more than half a million lives, mostly among children under the age of 5.
Part of the burden of tackling malaria lies in political and economic challenges, Dr. Federico Appetecchia, a postdoctoral researcher at the Harvard T.H. Chan School of Public Health, told Technology Networks.
“More sustained funding and more vertical malaria programmes could homogenize and increase the surveillance systems, supply chain, and general health services,” he said. “However, it’s widely acknowledged that the main portion of the burden is carried by technical challenges—with the rapid growing resistance of both Plasmodium parasites and Anopheles mosquitoes having drastically weakened the efficacy of traditional malaria control tools.”
Emerging drug and insecticide resistance in malaria
Resistance to antimalarial drugs is on the rise. P. falciparum has evolved resistance to nearly all of the currently available drugs, with several genes having been identified as playing key roles in malaria resistance against the current gold-standard treatment, artemisinin-based combination therapy. Resistance to antimalarial drugs has also been observed in P. vivax.
Anopheles mosquitoes are also becoming resistant to the insecticides used in ITNs. ITNs initially contained insecticides from the pyrethroid class, but as malaria vector mosquitoes became increasingly resistant, nets with additional active agents have been recommended to increase their efficacy.
“Today, several endemic regions observe that over 90% of the mosquito population is resistant to traditional insecticides (pyrethroids) used in ITNs,” said Appetecchia. “While showing improved effectiveness, mechanisms driving resistance to new insecticides have already been observed, indicating that insecticide resistance is constantly evolving and constitutes a persistent threat to public health.”
“We must employ not only solutions that control malaria by ‘running faster’ than evolution of resistance, but also others that allow us to take another track toward eradication.”
A new approach to preventing malaria transmission
The stages of the malaria parasite life cycle that occur while it resides in mosquitoes are some of the most vulnerable to therapeutic intervention, yet historically, antimalarial drugs have been developed to target the in-human lifecycle stages.
“By killing parasites in mosquitoes, we have an enormous opportunity to block transmission with minimal to no risk of parasite resistance development,” explained Appetecchia. “A few years ago, the Catteruccia lab came up with a new elegant concept: deliver potent antimalarial drugs to mosquitoes as we do with insecticides—using treated bed nets.”
“Instead of choosing between killing mosquitoes or treating humans, we can combine insecticides and antimalarials on the same nets,” he continued. “Where insecticides fail because of mosquito resistance, the antimalarials can still kill the parasite within those resistant mosquitoes and prevent transmission.”
To use an antimalarial targeting the mosquito-based life stages of P.falciparum on bed nets, Appetecchia and his colleagues needed to identify a novel antimalarial chemotype that differs from those used to treat people.
However, current drugs that target these stages of mosquito development are limited and are already known to have antiparasitic activity in humans.
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Finding novel compounds active against mosquito stages of P.falciparum is key, Appectecchia emphasized. To identify drugs targeting these stages, research was limited to using in vivo screening approaches in mosquitoes. “Since working with mosquitoes is very challenging, these methods are very low-throughput,” said Appetecchia. “In previous work... it took us more than 2 years to screen just 100 compounds.”
An in vitro platform to screen for new antimalarials
A robust, scalable in vitro culture system for the mosquito stages of P.falciparum could overcome the obstacles of working with mosquitoes, allowing high-throughput screening (HTS) of thousands of potential compounds.
“We generated the first in vitro platform optimized for HTS of inhibitors of mosquito stages of P. falciparum development,” explained Appetecchia. “We used this semi-automated system to perform a HTS of small molecules, which identified hundreds of compounds that kill parasites in the mosquito, accelerating the identification of next-generation transmission-blocking drugs.”
In his talk at the Society for Laboratory Automation and Screening (SLAS) conference 2026, Appetecchia will introduce this novel approach and discuss the development of the new screening platform.
Appetecchia and his team are currently triaging the hits from the HTS, validating the compounds in counter-screening assays and performing target deconvolution studies to identify the mechanisms of action.
“An ideal candidate will have a novel mechanism of action and distinct physicochemical properties suitable for incorporation into ITNs,” he said. “We have already identified some promising potent candidates.”
The next steps in his research will involve entering a hit-to-lead campaign to transform the hits from the screen into optimized compounds with greater efficacy and reduced toxicities. They will also assess the compounds’ in vivo activity using Anopheles gambiae mosquitoes and perform structure–activity relationship analyses to synthesize compounds that are effectively taken up through a mosquito's legs when it lands on a bed net.
At SLAS 2026, Appetecchia will also “try to convince you that not killing mosquitoes is not as bad as it sounds.”
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