Keystone Malaria Symposium 2022: a vibrant discussion of progress made and challenges ahead from drug discovery to treatment

Abstract

In recent years, the field of malaria research has made substantial progress in the areas of antimalarial drug resistance and discovery. These efforts are essential to combatting the devastating impact of malaria, which, in 2020, resulted in an estimated 241 million cases and 627 000 deaths. Recent advances in this area were presented at a Keystone Symposium entitled ‘Malaria: Confronting Challenges from Drug Discovery to Treatment’, held in person in Breckenridge, Colorado, in April 2022. Herein, we present a summary of the proceedings of this vibrant scientific exchange, which brought together a superb group of faculty, postdocs, and students from around the globe. Mariko Kanai Laura M. Hagenah Elizabeth A. Ashley Kelly Chibale David A. Fidock The Keystone Symposia conference on ‘Malaria: Confronting Challenges from Drug Discovery to Treatment’ (D2-2022) was held at Beaver Run Conference Center, in Breckenridge, Colorado, from April 10 to April 13, 2022. The conference was organized by Drs David Fidock (Columbia University Irving Medical Center), Kelly Chibale (University of Cape Town), and Elizabeth Ashley (Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit), and was sponsored by the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID), Bill & Melinda Gates Foundation, GlaxoSmithKline, and Novartis. The meeting proved to be a terrific scientific exchange, with outstanding talks and posters and engaged discussions during the scientific and poster sessions and workshops. This meeting was very well attended, with 207 participants in total. With over 100 abstracts already submitted three months prior, the meeting added two workshops to the six main scientific sessions, thus enabling more attendees to present their work. 20 speakers presented long talks, another 23 gave short talks, and 27 presented lightning talks, providing for a scientifically rich forum. The broad cross-section of community participation was reflected in the attendee affiliations, with 75% from academia and representation from industry and government (Figure 1A ). Students and postdocs were well represented, comprising over half of all academic attendees (Figure 1B). In total, 147 attendees were in person, with another 60 attending the meeting virtually (Figure 1C). The global nature of malaria research was also reflected in the broad geographic representation, with US and overseas attendees each comprising half the total, and excellent attendance from Africa, Asia, South America, Australia, the UK, and Europe (Figure 1D,E). As shown using a word cloud algorithm [1.Demsar J. et al.Orange: data mining toolbox in Python.J. Mach. Learn. Res. 2013; 14: 2349-2353Google Scholar], the meeting focused primarily on antimalarial drug resistance in Plasmodium falciparum, along with drug discovery efforts (Figure 2).Figure 2Word cloud of the 100 most frequently occurring words in the meeting abstracts.Show full captionThe size of the word denotes its frequency among the abstract titles. Words were preprocessed to filter words that were less than three characters in length, stopwords, numbers, symbols, common verbs, nouns, adverbs, and conjunctions.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The size of the word denotes its frequency among the abstract titles. Words were preprocessed to filter words that were less than three characters in length, stopwords, numbers, symbols, common verbs, nouns, adverbs, and conjunctions. This meeting set out to achieve the following aims. Aim 1. To provide a unique opportunity to learn about current research developments in antimalarial drug discovery and development, with the latest results presented by leaders in academia, industry, and global stakeholder organizations. Aim 2. To convene scientists who collectively span the spectrum from basic to translational to clinical research relevant to antimalarial therapeutics and drug resistance. Aim 3. To create a forum that provides an intellectually enriching environment conducive to exchanging data, thinking creatively about how to tackle the major problems we are facing with developing new and effective antimalarial drugs and combinations, leveraging knowledge about existing resistance to maximize their remaining efficacy in a region-specific way, exploring the myriad factors that dictate malaria epidemiology across regions, and advancing scientific debate and discussion. Aim 4. To encourage active participation of early-career and endemic-country researchers through an interactive forum and to provide valuable networking opportunities. The Keynote address entitled ‘Falciparum Malaria Drug Resistance, Treatment and Elimination in Southeast Asia’ was given by Dr Arjen Dondorp (Mahidol-Oxford Tropical Medicine Research Unit). Dr Dondorp set the stage for the meeting by first clarifying several key definitions: (i) artemisinin (ART) resistance manifests as a 10–100-fold reduced rate of ring-stage parasite killing in the host, which presents as a delayed parasite clearance clinical phenotype and can be detected in vitro as parasites with reduced early ring stage susceptibility; (ii) ART-based combination therapy (ACT) efficacy (and failure) depends on the combined efficacy of the ART derivative and the partner drug [e.g., ACT failure in the Greater Mekong Subregion (GMS) is due to both ART and partner drug resistance, whereas ACT failure documented in the Democratic Republic of Congo is due to sulfadoxine-pyrimethamine resistance and not ART resistance]. He also presented data suggesting that the ART-resistant phenotype may also be associated with reduced schizont susceptibility (possibly by increased rosetting) as well as increased transmissibility (through increased gametocytemia and reduced gametocyte susceptibility). In the eastern GMS, the k13 (Pfkelch13) genotypes responsible for partial ART resistance have changed after dihydroartemisinin-piperaquine (DHA-PPQ) was discontinued [e.g., the multidrug-resistant KEL1/PLA1 lineage selected in Cambodia during the period of DHA-PPQ treatment has been replaced with other strains following the switch to artesunate-mefloquine as first-line therapy in 2016–2017]. In the GMS, P. falciparum malaria elimination is generally making excellent progress. In Africa, K13-mediated ART resistance has emerged independently (including R561H in Rwanda and A675V and C469Y in Uganda). Dr Dondorp suggested several strategies to contain ART resistance, including a wider deployment of single-dose primaquine as a gametocidal agent and potential benefits of using triple ACTs [2.Peto T.J. et al.Triple therapy with artemether-lumefantrine plus amodiaquine versus artemether-lumefantrine alone for artemisinin-resistant, uncomplicated falciparum malaria: an open-label, randomised, multicentre trial.Lancet Infect. Dis. 2022; 22: 867-878Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar], antimalarial stewardship, effective surveillance, and prospects to introduce new drugs [e.g., cipargamin (KAE609) and ganaplacide (KAF156)]. The first session, ‘Innovations in Antimalarial Drug Discovery’, was chaired by Dr Dyann Wirth (Harvard T.H. Chan School of Public Health). Dr Elizabeth Winzeler (University of California, San Diego) presented the Malaria Drug Accelerator consortiumi, which aims to deliver early lead antimalarial compounds against high-value targets using a systematic pipeline for structure-guided drug discovery [3.Yang T. et al.MalDA, accelerating malaria drug discovery.Trends Parasitol. 2021; 37: 493-507Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar]. Recent work includes in vitro evolution against antimalarial compounds in Saccharomyces cerevisiae for faster target identification, which revealed some targets as well as a general trend of more transcription factor mutations in S. cerevisiae than in Plasmodium. Dr Jacquin Niles (Massachusetts Institute of Technology) described conditional gene expression platforms for target validation and antimalarial drug discovery [4.Nasamu A.S. et al.An integrated platform for genome engineering and gene expression perturbation in Plasmodium falciparum.Sci. Rep. 2021; 11: 342Crossref PubMed Scopus (10) Google Scholar], which has been applied in phenotypic screens against over 30 diverse targets. Future work includes multiplexing target conditional knockdown parasites and performing quantitative next-generation sequencing analysis of these pools. Dr Susan Wyllie (University of Dundee) discussed the multiple approaches that her laboratory is conducting for antimalarial target identification studies, with a specific focus on chemical proteomic approaches (including pulldowns and thermal proteome profiling) that can provide evidence of on-target engagement and elucidate compound promiscuity and that have been optimized for Plasmodium and kinetoplastid parasites [5.Corpas-Lopez V. Wyllie S. Utilizing thermal proteome profiling to identify the molecular targets of anti-leishmanial compounds.STAR Protoc. 2021; 2100704Crossref PubMed Scopus (1) Google Scholar]. Dr Wyllie also emphasized the need for orthogonal approaches for successful target identification studies. Dr Jerzy Dziekan (Nanyang Technological University) presented his work using lysate and intact-cell mass spectrometry-based cellular thermal shift assays [6.Dziekan J.M. et al.Cellular thermal shift assay for the identification of drug-target interactions in the Plasmodium falciparum proteome.Nat. Protoc. 2020; 15: 1881-1921Crossref PubMed Scopus (27) Google Scholar] to identify Medicines for Malaria Venture (MMVii) compound library–protein interactions, showing the identification of acyl-CoA synthetase 10 (ACS10) as a candidate target of MMV665915. Dr Alison Roth (Walter Reed Army Institute of Research) presented an in vitro robotics and high-throughput imaging analysis-assisted P. cynomolgi screening method [7.Vanachayangkul P. et al.Safety, pharmacokinetics, and activity of high-dose ivermectin and chloroquine against the liver stage of Plasmodium cynomolgi infection in rhesus macaques.Antimicrob. Agents Chemother. 2020; 64e00741-20Crossref PubMed Scopus (6) Google Scholar] and machine learning approaches to identify novel hypnozoite-acting compounds, of which the former has yielded seven compounds and one lead series that has progressed to the next stage. The second session, ‘Advancing Drug Discovery Efforts’, chaired by Dr Christian Doerig (RMIT University), focused on spotlighting research focusing on the development of antimalarials with novel modes of action and targets. Dr Jeremy Burrows (MMV) discussed the challenges and progress made in antimalarial drug discovery, including overcoming resistance to antimalarials in current ACTs [8.Duffey M. et al.Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials.Trends Parasitol. 2021; 37: 709-721Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar]. He emphasized MMV’s focus on phenotypic irresistible compounds and target-based screening to prioritize the development of compounds with novel modes of actionii. Additionally, he presented a new pharmacokinetic/pharmacodynamic modeling tool (MMVSolaiii) to predict human pharmacokinetics and dosing. Dr Laura Sanz (GlaxoSmithKline) proposed GSK701 (MMV1582367), an ACS10 inhibitor, as a fast-acting potential ART replacement in a combination therapy for uncomplicated malaria. This drug is now moving into first-in-human studies. Dr Kelly Chibale spoke about Plasmodium kinases as promising antimalarial drug targets. He presented his work on the anticancer mTOR inhibitor, Sapanisertib, for malaria treatment, as it has been shown to interact with multiple P. falciparum kinases. Overall, he highlighted the benefits of repurposing and repositioning human kinase inhibitors as potential antimalarials [9.Arendse L.B. et al.Plasmodium kinases as potential drug targets for malaria: challenges and opportunities.ACS Infect. Dis. 2021; 7: 518-534Crossref PubMed Scopus (9) Google Scholar]. Dr Andrew Tobin (University of Glasgow) discussed targeting P. falciparum kinases, focusing on the cyclin-dependent-like kinase PfCLK3 that does not have a clear ortholog in humans [10.Mahindra A. et al.Development of potent PfCLK3 inhibitors based on TCMDC-135051 as a new class of antimalarials.J. Med. Chem. 2020; 63: 9300-9315Crossref PubMed Scopus (8) Google Scholar]. Potent PfCLK3 inhibitors, based on the TCMDMC-135051 compound, have good activity against liver- and asexual blood-stage parasites, and prevent gametocyte development. Dr Didier Leroy (MMV) provided updates on the antimalarial candidate MMV688533 [11.Murithi J.M. et al.The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance.Sci. Transl. Med. 2021; 13: eabg6013Crossref PubMed Scopus (6) Google Scholar]. This promising new drug candidate is undergoing mechanism of action confirmation and is currently in Phase 1 clinical trials, with combination trials scheduled. On the second day, the first session was ‘Experimental Models and Other Human Plasmodia’ (Chair: Dr Beatriz Baragaña, University of Dundee). Dr John Adams (University of South Florida) described the use of piggyBac P. falciparum mutants in chemogenomic screens to elucidate genotype–phenotype relationships to heat shock [12.Zhang M. et al.The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite.Nat. Commun. 2021; 12: 4563Crossref PubMed Scopus (6) Google Scholar] and responses to drugs including ART derivatives and proteasome inhibitors. Dr Adams has also adapted piggyBac mutagenesis for P. knowlesi cultured in human red blood cells. Dr Flaminia Catteruccia (Harvard T.H. Chan School of Public Health) showed that her group’s strategy of using antimalarial compounds to kill P. falciparum parasites in the mosquito [13.Paton D.G. et al.Exposing Anopheles mosquitoes to antimalarials blocks Plasmodium parasite transmission.Nature. 2019; 567: 239-243Crossref PubMed Scopus (48) Google Scholar] can be applied to insecticide-resistant Anopheles mosquitoes and ART-resistant parasites (harboring the causal K13 C580Y mutation). Dr Catteruccia also presented antimalarial screening results that identified P. falciparum cytochrome B, PfATP4, dihydrofolate reductase, and elongation factor 2 as promising targets for killing P. falciparum parasites in the mosquito. Dr James McCarthy (Peter Doherty Institute for Infection and Immunity) highlighted promising clinical trial data for an ACT partner drug candidate ZY-19489 [14.Barber B.E. et al.Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection study.Lancet Infect. Dis. 2022; 22: 879-890Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar], as well as retrospective in silico pharmacokinetic/pharmacodynamic modeling on an earlier OZ439-PPQ study [15.Andrews K.A. et al.Retrospective analysis using pharmacokinetic/pharmacodynamic modeling and simulation offers improvements in efficiency of the design of volunteer infection studies for antimalarial drug development.Clin. Transl. Sci. 2021; 14: 712-719Crossref PubMed Scopus (2) Google Scholar]. Dr McCarthy also showed clinical data supporting 50 mg tafenoquine as the smallest dose that can kill gametocytes [16.Webster R. et al.Transmission blocking activity of low dose tafenoquine in healthy volunteers experimentally infected with Plasmodium falciparum.Clin. Infect. Dis. 2022; (ciac503. Published online June 22, 2022. https://dx.doi.org/10.1093/cid/ciac503)Crossref PubMed Google Scholar]. Christopher Bower-Lepts (University of Cambridge) described a P. berghei artificial chromosome chemogenomic screening system to identify targets of antimalarial drug candidates, and the validation of this method using antimalarial compounds with known targets. Dr Sachel Mok (Columbia University Irving Medical Center) presented work on mapping resistance determinants of ART derivatives, their partner drugs, and preclinical candidates using a novel P. falciparum genetic cross performed in a humanized mouse model. Dr Michael Ferdig (University of Notre Dame) provided an update on their P. falciparum genetic crosses [17.Button-Simons K.A. et al.The power and promise of genetic mapping from Plasmodium falciparum crosses utilizing human liver-chimeric mice.Commun. Biol. 2021; 4: 734Crossref PubMed Scopus (3) Google Scholar], with a specific focus on amino acid transporter PfAAT1 as a potential modulator of chloroquine resistance. Dr Donelly van Schalkwyk (London School of Hygiene & Tropical Medicine) presented evidence for Plasmodium species-specific differences in susceptibility to PfATP4 inhibitors revealed using an ATP4 orthologue replacement strategy in P. knowlesi. The final session of the day was ‘Antimalarial Use and Drug Resistance’, chaired by Dr Geoffrey McFadden (University of Melbourne). This session focused on the elucidation of resistance mechanisms and leveraging that knowledge to design the best treatment strategies. Dr Didier Ménard (Institut Pasteur Paris and University of Strasbourg) presented data on the emergence of mutant K13-mediated ART resistance in Africa, possibly due to local epidemiological changes [18.Uwimana A. et al.Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda.Nat. Med. 2020; 26: 1602-1608Crossref PubMed Scopus (187) Google Scholar]. Dr Ménard underscored the need for monitoring ART and partner drug resistance in the field, understanding the biology of resistant parasites, and deploying new drug combinations active on resistant parasites. Dr David Fidock highlighted the central role of hemoglobin endocytosis, degradation and detoxification in the mode of action of multiple first-line antimalarials. Dr Fidock presented genetic investigations into PPQ and ART resistance by introducing mutations in PfCRT and K13, respectively [19.Dhingra S.K. et al.Plasmodium falciparum resistance to piperaquine driven by PfCRT.Lancet Infect. Dis. 2019; 19: 1168-1169Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,20.Stokes B.H. et al.Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness.Elife. 2021; 10e66277Crossref Scopus (21) Google Scholar]. Dr Leann Tilley (University of Melbourne) presented work on a nucleoside sulfamate, ML901, that has a novel P. falciparum tyrosine tRNA synthetase target. These nucleoside sulfamates have a new inhibition mechanism, whereby a highly potent inhibitor is generated at the site of action [21.Xie S.C. et al.Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy.Science. 2022; 376: 1074-1079Crossref PubMed Scopus (3) Google Scholar]. Preparing for the possibility of ART resistance spreading through Africa, Dr Colin Sutherland (London School of Hygiene & Tropical Medicine) proposed active testing of alternative treatment strategies using current drugs, such as sequential ACT regimens. He also emphasized the importance of validation of genetic markers through routine in vivo molecular surveillance of ACT efficacy. Dr Pierre Buffet (University of Paris and Necker Hospital) described a spleen-mimetic screening approach to identify safe drugs to block P. falciparum transmission, including orally administered antimicrobial agents that show strong activity against gametocytes [22.Duez J. et al.High-throughput microsphiltration to assess red blood cell deformability and screen for malaria transmission-blocking drugs.Nat. Protoc. 2018; 13: 1362-1376Crossref PubMed Scopus (13) Google Scholar]. On the third day, the first session, ‘Reducing the Burden of Malaria Part I’, was chaired by Dr Caroline Ng (University of Nebraska Medical Center). Dr Thierry Diagana (Novartis Institute for Tropical Diseases) presented their portfolio and framework, including the discovery of imidazothiadiazoles (including INE963) as a second-generation fast-acting irresistible antimalarial [23.Taft B.R. et al.Discovery and preclinical pharmacology of INE963, a potent and fast-acting blood-stage antimalarial with a high barrier to resistance and potential for single-dose cures in uncomplicated malaria.J. Med. Chem. 2022; 65: 3798-3813Crossref PubMed Scopus (1) Google Scholar], KAF156 for chemoprophylaxis, and KAE609 for severe malaria. Current research priorities include machine learning-based quantitative structure–activity relationships to predict phenotypic assay activity, and the in vitro identification of hypnozoite-active compounds. Dr Abdoulaye Djimdé (University of Science, Techniques and Technologies) presented genomics work by the Plasmodium Diversity Network Africa (PDNA) that highlighted the need for district-level stratification for malaria interventions [24.Fofana B. et al.Differential incidence of malaria in neighboring villages in a high-transmission setting of southern Mali.Am. J. Trop. Med. Hyg. 2022; 106: 1209-1214Crossref Scopus (1) Google Scholar], and efforts to detect deletions in hrp2/3 genes that lead to rapid diagnostic test escape. Dr Djimdé also emphasized that genetics and genomics education, consideration of regulatory and ethical issues, hardware and capacity building, and engagement of non-governmental organizations are all key for translating genomics knowledge into policy decisions. Dr Janice Culpepper (Bill & Melinda Gates Foundation) proposed the need for transformational tools to eradicate malaria, including single-dose treatment drugs, long-acting endectocides used potentially in combination with mass drug administration, and new strategies for chemoprevention. Dr Culpepper also called for appropriate and timely policy recommendations to enable country uptake of these tools, and improved surveillance and health/delivery systems to implement these tools. Dr Beatriz Baragaña (University of Dundee) presented work supporting the use of acetyl-CoA synthetase PfAcAS as a novel multistage antimalarial target (the target of MMV019721, [25.Summers R.L. et al.Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention.Cell Chem. Biol. 2022; 29: 191-201Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]). Dr Baragaña’s group has solved a liganded full-length AcAS structure from a yeast orthologue and has also optimized MMV019721 to develop novel PfAcAS inhibitors. Dr Lauren Arendse (University of Cape Town) highlighted the potential benefits of polypharmacology [9.Arendse L.B. et al.Plasmodium kinases as potential drug targets for malaria: challenges and opportunities.ACS Infect. Dis. 2021; 7: 518-534Crossref PubMed Scopus (9) Google Scholar] by identifying VE-821 as a dual inhibitor of PfPI4K and PfPK6, and summarized efforts to develop targeted covalent inhibitors. Dr Christian Doerig discussed using host cell kinases as targets for host-directed malaria therapy, for which several were recently discovered using a Kinexus antibody microarray [26.Adderley J.D. et al.Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention.Nat. Commun. 2020; 11: 4015Crossref PubMed Scopus (15) Google Scholar]. Host-directed therapy presents the considerable advantage of depriving the parasite from a direct pathway to resistance (selection of mutations in the target that reduce its affinity for the drug), as the target is not under the parasite’s genetic control. Dr Doerig also presented network-based modeling and targeted screens against a kinase chemogenomic set. Dr Stuart Ralph (University of Melbourne) showed how the delayed death antibiotics doxycycline and clindamycin reduce hemoglobin uptake and digestion, and antagonize ART in P. falciparum, which may have implications for current prophylaxis and treatment strategies. The last session, ‘Reducing the Burden of Malaria Part II’, chaired by Dr Colin Sutherland (London School of Hygiene & Tropical Medicine), continued the conversation on reducing the mortality and morbidity of malaria. Dr Philip Rosenthal (University of California, San Francisco) showed that, while current ACTs remain efficacious in Africa, the recent emergence of novel K13 mutations in Uganda may cause concern for malaria treatment and control in this region. This emergence, coinciding with decreasing resistance to 4-aminoquinolines (due to changes in treatment strategy) and increasing resistance to sulfadoxine-pyrimethamine, warrants continued surveillance for changes in drug sensitivity [27.Asua V. et al.Changing prevalence of potential mediators of aminoquinoline, antifolate, and artemisinin resistance across Uganda.J. Infect. Dis. 2021; 223: 985-994Crossref PubMed Scopus (35) Google Scholar]. Dr Elizabeth Ashley summarized the recent clinical trials in Southeast Asia on triple ACTs that have shown evidence of efficacy and safety and have been predicted to delay and potentially prevent resistance [28.van der Pluijm R.W. et al.Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial.Lancet. 2020; 395: 1345-1360Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar]. Triple ACTs are currently under evaluation to integrate with other strategies, with the priority being to preserve the current antimalarial efficacy (e.g., lumefantrine) as long as possible or until new antimalarials are available. Dr Ric Price (Menzies School of Health Research) presented underdosing (e.g., with chloroquine or primaquine) and poor adherence as the most common cause of P. vivax treatment failure [29.Taylor W.R.J. et al.Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial.Lancet. 2019; 394: 929-938Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar]. He also underscored the need for a better G6PD test to ensure that the right doses of primaquine are given to prevent hemolytic events. Dr Price emphasized the importance of community engagement and education to ensure the appropriate treatment regimens are being used in areas with endemic P. vivax. Dr Marielle Bouyou-Akotet (Université des Sciences de la Santé, Gabon) detailed challenges faced by National Malaria Control Programs, which include heterogeneity of in-country intervention implementation and difficulty in sustaining genomic surveillance. She also highlighted the lessons learned such as the need for rapid response, real-time data, focus on community care, and investment in impact, not just for coverage. Dr Bouyou-Akotet emphasized the need to strengthen coordinated efforts across different sectors and country-level evidence needed to support decision making. Shifting the focus back towards drug resistance, the conference ended with Dr Lauriane Sollelis (University of Glasgow) presenting her data showing that different indels of ben and glen long noncoding RNA alleles correlate with variation in ap2 transcription factor expression and sexual stage conversion in P. falciparum. A career roundtable event, including the conference organizers as well as Drs Caroline Ng and Judith Straimer (Novartis Institute for Tropical Diseases), was held for trainees to discuss career trajectories in academia (clinical or nonclinical) or industry. Two workshops (chaired by Drs Kelly Chibale and Elizabeth Ashley) were also created to provide opportunities for more scientists to share their work through short or lightning talksiv. Workshop 1 began with a talk by Dr Steven Maher (University of Georgia) who described the use of an in vitro radical cure liver-stage assay to identify compounds active against P. vivax hypnozoites [30.Maher S.P. et al.A phenotypic screen for the liver stages of Plasmodium vivax.Bio. Protoc. 2021; 11e4253Crossref PubMed Scopus (3) Google Scholar]. Monica Bohmer (University of Central Florida) presented a novel type II kinase inhibitor, TL5-135, with antiplasmodial activity and a low risk of resistance generation. Dr Darren Creek (Monash University) identified targets of aminopeptidase inhibitors by thermal proteome profiling, limited proteolysis mass spectrometry, and metabolomics. Ioanna Deni (University of Paris) showed recent data on several classes of P. falciparum-specific proteasome inhibitors and highlighted the low resistance risk of vinyl sulfone inhibitors that synergize with ART derivatives, suggesting they could be good candidates for future use in ACTs. Dr Stanley Xie (University of Melbourne) pursued this theme by describing amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome β5 active site [31.Xie S.C. et al.Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome.Proc. Natl. Acad. Sci. U. S. A. 2021; 118e2107213118Crossref Scopus (5) Google Scholar]. Dr R. Kip Guy (University of Kentucky) summarized the progress of MMV609, an ATP4 inhibitor that has been shown to be effective against the asexual blood stages, liver stage, and sexual stages. Workshop 2 began with a mathematical modeling presentation from Dr Maciej Boni (Pennsylvania State University) with results suggesting that triple ACTs could be the most effective way to prevent treatment failure and the emergence of resistance. Dr Robert Summers (Harvard T.H. Chan School of Public Health) presented PfAcAS as a viable drug target in P. falciparum and showed that inhibition of this protein affects protein acetylation and chromatin remodeling [25.Summers R.L. et al.Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention.Cell Chem. Biol. 2022; 29: 191-201Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. The lighting talks from both sessions are listed onlineiv. These workshops provided a vibrant forum to learn about recent research from a large number of meeting attendees. At the meeting’s conclusion, Drs Fidock, Chibale, and Ashley agreed that it was a fruitful and engaging meeting filled with exciting science. Key outcomes and future directions included: a call for researchers to continue to organize these Keystone malaria meetings to bring the malaria community together; advocating to funders that malaria research is vital to combatting this major global infectious disease; that new scientific knowledge, methodology, and technical capabilities, improvements in clinical practice, and collaborations result from such a uniquely interdisciplinary meeting; and that providing presentation opportunities and career development events to trainees and new investigators are essential to ensuring sustained vigor and innovation in malaria research. We look forward to many more outstanding Keystone Symposia on malaria that bring together researchers committed to applying cutting-edge science to combat the vast burden of malaria across the intertropical regions of the world. The organizers express their deepest thanks to all the presenters and other attendees for making this a great meeting. We also thank the Keystone Symposia staff who provided terrific help with organizing this meeting, in particular Allison Ogdon, Debbie Ware, Nick Dua, Stephanie Miller, and Jeff Lehman. M.K. gratefully acknowledges funding support from the Japan Student Services Organization and a scholarship from the New York Hideyo Noguchi Memorial Society. L.M.H. received funding from the NIH [ F31 AI157410 , Principal Investigator (PI): L. Hagenah; and T32 AI106711 , PI: D. Fidock]. D.A.F. gratefully acknowledges funding from the NIH ( R01 AI109023 , AI050234 , AI124678 ), MMV ( RD08/0015 ), and the Bill & Melinda Gates Foundation ( INV-033538 ). K.C. gratefully acknowledges funding from Neville Isdell, the Bill & Melinda Gates Foundation (Global Health Grant Number OPP1066878 ), NIH ( R01 AI152092 ), MMV ( RD/09/0002 , RD 17-0004 and RD/18/0001 ), Merck KGaA , South African Medical Research Council (SAMRC) , Strategic Health Innovation Partnerships (SHIP) unit of the SAMRC, South African Technology Innovation Agency (TIA) , and South African Department of Science and Innovation/National Research Foundation . E.A.A. is funded by the Wellcome Trust ( 220211/Z/20/Z ). We are thankful to Dr Sachel Mok for performing the Word Cloud analysis and providing Figure 2. iwww.malariada.org iiwww.mmv.org iiiwww.mmv.org/mmv-open/mmvsola ivhttps://tks.keystonesymposia.org/index.cfm?e=Web.Meeting.Flyer&MeetingID=1898