Research Articles (UP Centre for Sustainable Malaria Control (UP CSMC))

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Targeted protein degradation as a novel therapeutic strategy against infectious diseases
Birkholtz, Lyn-Marie; Olivier, Tiaan; Welcome, Tyrick; Strauss, Erick (Elsevier, 2026-04)
Targeted protein degradation (TPD) represents an emerging antimicrobial strategy that is predominantly still in preclinical development stages. Chimeric molecules (i.e., PROteolysis-TArgeting Chimera [PROTACs]) that can direct molecular targets for degradation by hijacking a cell's proteolytic machinery offer significant advantages over traditional small-molecule therapeutics. These include diversifying the druggable proteome by targeting previously 'undruggable' non-enzymatic and structural proteins, lowering the effective therapeutic concentration, enabling lower drug concentrations, and delaying resistance development. Recent reports of BacPROTACs that are active against Mycobacterium tuberculosis have set the stage to exploit TPD for antimicrobial drug development, yet despite its clear relevance to African-endemic diseases challenged by multidrug resistance-notably HIV, tuberculosis, and malaria-TPD-based infectious disease therapeutic development remains in its early stages. This review highlights the recent advances in the development and application of PROTACs as antimicrobials and provides an outlook for TPD's strategic value in addressing the growing threat posed by drug-resistant pathogens.
From pan-active to parasite-selective antiparasitic agents : a scaffold hopping approach
Borsari, Chiara; Santarem, Nuno; Coertzen, Dina; Mazzolari , Asia; Corfu, Alexandra Ioana; Coelho, Catarina; Barbosa, Francisca; Tamborini, Lucia; Birkholtz, Lyn-Marie; Raffellini , Lorenzo; Keminer, Oliver; Basilico, Nicoletta; Parapini, Silvia; Gul, Sheraz; Cordeiro-da-Silva, Anabela; Conti, Paola (Elsevier, 2025-12)
Vector-borne parasitic diseases (VBPDs) represent a major global public health concern, with human African trypanosomiasis (HAT), Chagas disease, leishmaniasis, and malaria collectively threatening millions of people, particularly in developing regions. Climate change may further influence their transmission and geographic spread, increasing the global burden. As drug resistance continues to rise, there is an urgent need for novel therapeutic agents to expand treatment options and limit disease progression. Exploiting a cell-based phenotypic approach, we had previously developed 1,3,4-oxadiazole derivatives, as broad-spectrum low-toxicity agents active against protozoan parasites including Plasmodium falciparum, Leishmania spp. and Trypanosoma brucei. Herein, we applied a scaffold-hopping approach to develop novel chemotypes by replacing the central 1,3,4-oxadiazole core with 1,2,4-oxadiazole and oxazole rings. A systematic investigation allowed us to generate two novel libraries of compounds and carry out extensive Structure-Activity-Relationship studies and early drug discovery pharmacological liability characterization. Starting from pan-active 1,3,4-oxadiazole-based antiparasitic agents, we identified two anti-kinetoplastid molecules bearing the 1,2,4-oxadiazole core and one promising anti-T. brucei agent featuring an oxazole core. Our work paves the way for the development of novel chemotypes to successfully fight parasitic infections.
A new assay for molecular identification of Anopheles squamosus (Diptera: Culicidae) using internal transcribed spacer 2
Nguyen, Valerie T.; Ali, Renee L.M.N.; Burini, Bianca C.; Dryden, Dalia S.; Riddin, Megan A.; Saili, Kochelani; Simulundu, Edgar; Reeves, Lawrence E.; Norris, Douglas E.; Lee, Yoosook (BioMed Central, 2025-10-16)
BACKGROUND : Anopheles squamosus is a widespread mosquito species in sub-Saharan Africa. It is a potential vector for human malaria parasites and has been found naturally infected with Plasmodium falciparum and Plasmodium vivax. Morphological identification is challenging even with pristine specimens and current molecular methods such as the use of the internal transcribed spacer 2 (ITS2) polymerase chain reaction (PCR) cannot distinguish An. squamosus from morphologically similar Anopheles species. Described in the following methods is the development and validation of a new PCR assay that will reliably identify An. squamosus. METHODS : Multiple alignments of previously published ITS2 contig sequences in NCBI from An. squamosus and An. species 11 and 15, were used to identify candidate ITS2 regions for primer design. Six sets of primers were evaluated overall for specificity of species identification. The one set with An. squamosus species-specific amplification was tested using 78 specimens morphologically identified from Zambia and South Africa. RESULTS : A new assay consisting of a forward (ITS2-ASQ-R10, 5'-CCC TCG AAG GGT GCT GTG-3') and reverse (ITS2-ASQ-R10 5'-AAT CCA CGG TGT GAT GGC-3') primer reliably (> 94.9%) amplified an ITS2 fragment of 301 bp length for An. squamosus. The An. squamosus-specific primer set can be multiplexed with existing ITS2 assays frequently used for anopheline species identification. CONCLUSIONS : The development of this robust PCR assay for An. squamosus is vital to accurate identification of this species in malaria vector surveillance efforts. Improved understanding of the anopheline community composition will lead to better targeted methods of vector eradication and malaria prevention. To further the validation of this ITS2 PCR assay, more species of Anopheles should be compared in addition to An. squamosus collected in different regions. To refine and optimize the PCR process with these primers, touchdown PCR can be used to increase specificity. Applying genomic tools to correctly identify An. squamosus will allow for a better understanding of their role in malaria transmission and may lead to genomic insights into what influences their behaviour, thus leading to new innovations in malaria elimination.
Breast milk bisphenol concentrations in Canada and South Africa and associations with body size among South African infants
Elsiwi, Basant; Bayen, Stephane; Chi, Zhi Hao; Goodyer, Cynthia G.; Hales, Barbara F.; Robaire, Bernard; Bornman, Maria S. (Riana); Obida, Muvhulawa; Moodie, Erica E.M.; Chevrier, Jonathan (Elsevier, 2025-11)
OBJECTIVE : Infants may be exposed to bisphenols (BP) via breastfeeding. These chemicals are known endocrine disruptors and may interfere with infant growth. However, their presence in breast milk and their associations with infant size remain unexplored in South Africa, where infants may be especially vulnerable to toxic effects. METHODS : We measured BPA, BPS, and BPAF in breast milk samples obtained 4–8 weeks postpartum from mothers residing in rural (Vhembe district; n = 193) and urban (Pretoria; n = 189) areas of South Africa and compared them to samples from Montreal, Canada (n = 206). Infant length and head circumference were measured in South Africa, with z-scores computed based on World Health Organization (WHO) growth charts. Random forest plots were used to identify top-ranked BP predictors, and linear marginal structural models were used to estimate associations between BP concentrations and infant size. RESULTS : BP concentrations were highest in Vhembe relative to Pretoria; in Montreal, only BPS was detected. Microwaving food in plastic containers and maternal diet were important determinants of exposure. In the combined South African sites, total BPAF detection was associated with greater infant length (β = 0.38 SD, 95 % CI: 0.09, 0.68) and head circumference (β = 0.52 SD, 95 % CI: 0.23, 0.81). Associations were strongest in Pretoria. In contrast, a tenfold increase in total BPA concentration was associated with a 0.20 SD decrease in head circumference (95 % CI: −0.39, −0.01) in Vhembe. CONCLUSION : Findings point to high BP exposure in rural Africa and suggest that exposure to BPA and BPAF may be related to altered growth among South African infants. HIGHLIGHTS • BPA, BPS and BPAF breastmilk levels were higher in Vhembe vs Pretoria and Montreal • Microwaving plastics and diet were associated with higher concentrations • Free and total BPAF were associated with greater length and head circumference • Total BPA was associated with smaller head circumference
A novel class of orally bioavailable phenylglycine–benzoxaborole conjugates with antimalarial activity and potentially novel mechanism of action
Morake, Mokhitli; Taylor, Dale; Coertzen, Dina; Njoroge, Mathew; Krugmann, Liezl; Leshabane, Meta Kgaogelo; Da Rocha, Shante; Qahash, Tarrick; Girling, Gareth; Coyle, Rachael; Lee, Marcus C.S.; Wittlin, Sergio; Llinas, Manuel; Birkholtz, Lyn-Marie; Basarab, Gregory S.; Chibale, Kelly (American Chemical Society, 2026-01-08)
A new class of benzoxaboroles with a phenylglycine appendage was found to display in vitro blood stage activity against the human malaria parasite Plasmodium falciparum (Pf). Structure–activity relationship studies of the starting hit compound 3 resulted in compounds active against PfNF54 drug-sensitive and PfK1 drug-resistant strains with an in vitro antiplasmodium IC50 < 0.4 μM, selectivity over mammalian cell-lines (selectivity index > 47) and high aqueous solubility (160 to >200 μM). Selected compounds showed good in vitro metabolic stability when incubated with human, rat, and mouse liver microsomes and showed no cross-resistance against barcoded mutant lines. Two frontrunner compounds, 6 and 7, were dosed orally at 50 mg·kg–1 using a standard quadrupole dosing regimen in a P. berghei mouse infection model and showed encouraging in vivo efficacy. This work identifies a promising new class of phenylglycine-based benzoxaboroles, which warrants further medicinal chemistry optimization.
Targeting Aurora kinases as essential cell-cycle regulators to deliver multi-stage antimalarials against Plasmodium falciparum
Langeveld, Henrico; Maree, Marche; Thibaud, Jessica L.; Salomane, Nicolaas; Bridgwater, Rosie; Famodimu, Mufuliat T.; Godoy, Luiz C.; Pasaje, Charisse Flerida A.; Boonyalai, Nonlawat; Laureano de Souza, Mariana; Fong, Justin; Rabie, Tayla Anne; Van der Watt, Mariette Elizabeth; Birkholtz, Lyn-Marie (Wiley, 2025-12)
Kinases play critical roles in the development and adaptation of Plasmodium falciparum and present novel opportunities for chemotherapeutic intervention. Mitotic kinases that regulate the proliferation of the parasites by controlling nuclear division, segregation, and cytokinesis. We evaluated the potential of human Aurora kinase (Aur) inhibitors to prevent P. falciparum development by targeting members of the Aurora-related kinase (Ark) family in this parasite. Several human AurB inhibitors exhibited multistage potency (< 250 nM) against all proliferative stages of parasite development, including asexual blood stages, liver schizonts, and male gametes. The most potent compounds, hesperadin, TAE684, and AT83, exhibited > 1000x selectivity towards the parasite. Importantly, we identified PfArk1 as the principal vulnerable Ark family member, with specific inhibition of PfArk1 as the primary target for hesperadin. Hesperadin’s wholecell and protein activity validates it as a unique PfArk1 tool compound. Inhibition of PfArk1 results in the parasite’s inability to complete mitotic processes, presenting with unsegregated, multi-lobed nuclei caused by aberrant microtubule organization. This suggests PfArk1 is the main Aur mitotic kinase in proliferative stages of Plasmodium, characterized by bifunctional AurA and B activity. This paves the way for drug-discovery campaigns based on hesperadin targeting PfArk1.
Optimization and characterization of the antimalarial activity of N-aryl acetamides that are susceptible to mutations in ROM8 and CSC1
Nguyen, William; Boulet, Coralie; Dans, Madeline G.; Loi, Katie; Jarman, Kate E.; Barnes, Claudia B.G.; Yeo, Tomas; Sheth, Tanaya; Mukherjee, Partha; Chakraborty, Arnish; Famodimu, Mufuliat T.; Delves, Michael J.; Pollard, Harry; Sutherland, Colin J.; Coyle, Rachael; Sevilleno, Nicole; Boonyalai, Nonlawat; Lee, Marcus C.S.; Rabie, Tayla Anne; Birkholtz, Lyn-Marie; Baud, Delphine; Brand, Stephen; Chowdury, Mrittika; De Koning-Ward, Tania F.; Fidock, David A.; Gilson, Paul R.; Sleebs, Brad E. (American Chemical Society, 2025-07)
New antimalarials are needed due to the threat of emerging resistance against existing antimalarial therapies. A phenotypic screen uncovered the N-aryl acetamide class that inhibits the development of P. falciparum asexual ring-stage parasites. The structure–activity relationship of this class was investigated, and key modifications were introduced that produced WEHI-326 with potent antimalarial activity. Enhancing the metabolic stability of this class will be a future challenge to achieve efficacy in a malaria mouse model. WEHI-326 was found to have a moderate barrier to resistance and a moderate rate of asexual kill, potently inhibited gametocyte and gamete development, and in turn, blocked the transmission of parasites to the mosquito. Forward genetics and cross-resistance profiling determined that parasites resistant to N-aryl acetamides had mutations in rhomboid protease 8 (ROM8) and the putative cation channel, CSC1. WEHI-326 will be an important tool in unraveling the role of ROM8 and CSC1 in P. falciparum development.
Novel inhibitors of Plasmodium Phosphatidylinositol 4-kinase IIIβ with low propensity for resistance : life cycle stage activity and in vivo efficacy in a humanized mouse malaria infection model
Dziwornu, Godwin A.; Mmonwa, Mmakwena M.; Coertzen, Dina; Krugmann, Liezl; Salomane, Nicolaas; Leshabane, Meta Kgaogelo; Thomas, Jean Argyle; Da Rocha, Shanté; Reader, Janette; Masike, Keabetswe; Njoroge, Mathew; Sevilleno, Nicole; Coyle, Rachael; Boonyalai, Nonlawat; Mayville, Emily; Lee, Marcus C.S.; Fidock, David A.; Coulson, Lauren B.; Woodland, John G.; Wicht, Kathryn J.; Ghorpade, Sandeep R.; Birkholtz, Lyn-Marie; Chibale, Kelly (American Chemical Society, 2025-08)
Please read abstract in the article.
Factors affecting integration of an early warning system for antimalarial drug resistance within a routine surveillance system in a pre-elimination setting in Sub-Saharan Africa
Kagoro, Frank M.; Allen, Elizabeth; Raman, Jaishree; Mabuza, Aaron; Magagula, Ray; Kok, Gerdalize; Malatje, Gillian; Guerin, Philippe J.; Dhorda, Mehul; Maude, Richard J.; Barnes, Karen I. (Public Library of Science, 2025-06)
To address the current threat of antimalarial resistance, countries need innovative solutions for timely and informed decision-making. Integrating molecular surveillance for drug-resistant malaria into routine malaria surveillance in pre-elimination contexts offers a potential early warning mechanism for further investigation and response. However, there is limited evidence on what influences the performance of such a system in resource-limited settings. From March 2018 to February 2020, a sequential mixed-methods study was conducted in primary healthcare facilities in a South African pre-elimination setting to explore factors influencing the flow, quality and linkage of malaria case notification and molecular resistance marker data. Using a process-oriented framework, we undertook monthly and quarterly data linkage and consistency analyses at different levels of the health system, as well as a survey, focus group discussions and interviews to identify potential barriers to, and enhancers of, the roll-out and uptake of this integrated information system. Over two years, 4,787 confirmed malaria cases were notified from 42 primary healthcare facilities in the Nkomazi sub-district, Mpumalanga, South Africa. Of the notified cases, 78.5% (n = 3,758) were investigated, and 55.1% (n = 2,636) were successfully linked to their Plasmodium falciparum molecular resistance marker profiles. Five tangible processes—malaria case detection and notification, sample collection, case investigation, analysis and reporting—were identified within the process-oriented logic model. Workload, training, ease of use, supervision, leadership, and resources were recognized as cross-cutting influencers affecting the program’s performance. Approaching malaria elimination, linking molecular markers of antimalarial resistance to routine malaria surveillance is feasible. However, cross-cutting barriers inherent in the healthcare system can influence its success in a resource-limited setting.
Ferrocenyl quinoline-benzimidazole hybrids : a multistage strategy to combat drug-resistant malaria
Golding, Taryn M.; Garnie, Larnelle F.; Rabie, Tayla Anne; Reader, Janette; Birkholtz, Lyn-Marie; Wicht, Kathryn J.; Smith, Gregory S. (American Chemical Society, 2025-07)
Molecular hybridization and metal incorporation are widely employed strategies for drug development aimed at enhancing pharmacological efficacy while mitigating the emergence of drug resistance. The effectiveness of these approaches is supported by numerous studies demonstrating their success against a range of diseases. Despite the deployment of malaria vaccines, effective treatment remains hindered by the persistent emergence of drug-resistant Plasmodium falciparum strains, contributing to an alarming global disease burden. Inspired by the antimalarial candidate ferroquine, this study focused on the design and synthesis of ferrocenyl-based quinoline-benzimidazole molecular hybrids. The hybrids were evaluated for their in vitro blood-stage antiplasmodial activity against drug-sensitive NF54 and multidrug-resistant K1 P. falciparum strains, exhibiting potent submicromolar activity. Notably, incorporating an N,N-dimethylaminomethyl side chain significantly enhanced activity against both strains. Further assays revealed a compound with multistage antiplasmodial activity, targeting both immature and mature gametocytes. Mechanistic studies implicated the inhibition of hemozoin formation as a key mode of action, supported by in vitro cellular heme fractionation analysis. Additionally, fluorescence assays indicated the generation of reactive oxygen species under oxidative conditions, suggesting a complementary pathway contributing to the compounds’ antiplasmodial activity. These findings highlight the potential of ferrocenyl-based molecular hybrids as promising candidates in antiplasmodial drug development.
Patterns of patent and sub-patent Plasmodium falciparum infections in household members of children under seasonal malaria chemoprevention coverage in the health district of Nanoro, Burkina Faso
Kambou, Sié A. Elisee; Sondo, Paul; Kabore, Bérenger; Bayala, Ipéné Mylène Carenne; Kouevi, Amélé Fifi Chantal; Compaore, Eulalie W.; Millogo, Kié Solange; Ismaïla, Bouda; Rouamba, Toussaint; Kazienga, Adama; Karim, Derra; Rouamba, Eli; Dahal, Prabin; Otienoburu, Sabina D.; Raman, Jaishree; Dhorda, Mehul; Bamba, Sanata; Guerin, Philippe J.; Tinto, Halidou (BioMed Central, 2025-09)
BACKGROUND : Seasonal Malaria Chemoprevention (SMC) has been adopted since 2014 in Burkina Faso to reduce malaria burden in children under 5 years. However, the intervention’s expected potential has not yet been achieved in real-life conditions, suggesting other factors may influence its effectiveness. Asymptomatic carriers, including patent and sub-patent Plasmodium falciparum infections in household members seems to be a potential factor maintaining the high malaria burden in children under SMC coverage. This study assessed the patterns of these infections in household members living around children under SMC coverage in Nanoro, Burkina Faso. METHODS : A cross-sectional survey nested to a large SMC study named “SMC_RST” was conducted during the 2022 SMC campaign in Nanoro, including 745 participants. Sub-patent infections were defined as varATS qPCR-positive/RDT-negative, and patent infections as positive by both methods. Prevalence of patent and sub-patent malaria infections were presented with 95% confidence intervals (CI), accounting for clustering of individuals within households. Multinomial regression with robust standard errors assessed the effect of age, sex, and locations on risk of malaria infection. RESULTS : Out of 745 participants, diagnostic results regarding malaria status were available for 650 (87.2%). Plasmodium falciparum infections in household members were detected in 68.6% (446/650, 95% CI: 64.7–72.5), including 27.4% (178/650, 95% CI: 23.9–30.8) patent and 41.2% (268/650, 95% CI: 37.3–45.2) sub-patent infections. Patent infections declined with age: 37.7%, (95% CI: 31.9–43.5) among 5–14 years, 25% (95% CI: 17.0–33.0) among 15–24 years, and 17.1% (95% CI: 12.6–21.5) among ≥ 25 years. Prevalence of sub-patent infection was 38.0% (95% CI: 32.4–43.7) among 5–14 years, 49.2% (95% CI:40.3–58.1) among 15–24 years and 40.7% (95% CI: 34.5–46.8) among ≥ 25 years. No significant difference across villages was observed in terms of prevalence of household members with patent (χ2 = 4.16, P-value = 0.38) or sub-patent infections (χ2 = 3.92, P-value = 0.41). CONCLUSION : Over two-thirds of the household members living with children under SMC coverage area in Nanoro, Burkina Faso, harboured patent and sub-patent P. falciparum infection. Among those aged 15 years and older, asymptomatic carriage was largely sub-patent. This study supports the extension of the SMC intervention to school-aged children and the implementation of interventions such as testing and treatment of household members of children under SMC coverage.
Cutaneous volatile and semi-volatile organic compounds as markers of malaria-infection by wearable samplers and two-dimensional gas chromatography—time-of-flight-mass spectrometry
Pretorius, Daniel Thomas; Rohwer, Egmont Richard; Naude, Yvette (Elsevier, 2025-11)
Malaria has been found to alter normal cutaneous volatile organic compound (VOC) profiles, suggesting their potential application as markers of Plasmodium infection. The cutaneous VOCs and semi-VOCs (SVOCs) of malaria-negative and -positive individuals, who visited two local clinics in the Vhembe district of Limpopo Province, South Africa, were extracted into wearable silicone rubber (polydimethyl siloxane [PDMS]) sampling bands adhered to the surface of the epidermis. After sampling of epidermal VOCs from participants the samplers were analysed by thermal desorption-comprehensive two-dimensional gas chromatography-time-of-flight-mass spectrometry (TD-GC × GC-TOFMS). Individual cutaneous VOCs and SVOCs profiles were constructed from these complex chromatographic profiles in order to identify potential signatures of Plasmodium infection. Fatty acid compounds associated with rancid malodour, and previously reported as mosquito attractants, were found at an overall greater abundance in chemical profiles of malaria-positive cases. A targeted analysis was performed for compounds previously reported to be associated with Plasmodium infection, viz., heptanal, (E)-2-octenal, 2-octanone, octanal, nonanal and (E)-2-decenal. The linearity (R2) range was 0.93–0.99 for a matrix matched (simulated cutaneous sampling) calibration range of 2.5–60 ng. Limits of detection (LOD) ranged from 0.4 pg (2-octanone) to 6.3 pg ((E)-2-octenal), whilst limits of quantification (LOQ) ranged from 1.4 pg to 21.1 pg. The mean percentage recoveries (n = 2) ranged from 77.8 % ((E)-2-decenal) to 118.9 % (2-octanone). The percentage relative standard deviations ( %RSDs; n = 2) ranged from < 1 % for 2-octanone, octanal and nonanal to 27.1 % for (E)-2-octenal. We found that this particular suite of compounds, previously reported as indicators of malaria, was in fact non-specific for Plasmodium infection when compared to control subjects with comorbidities. A previously unreported (in a malaria-infection context) compound, (E)-2-octen-1-ol, correlated with malaria-positive participants, but was also observed for two malaria-negative participants, which could indicate latent malaria. In chronic cases, Plasmodium vivax can occur in reservoirs outside of the bloodstream, and thus blood-based diagnostic tests can miss latent infection. A key advantage of the epidermal sampler over blood tests is that the former collects whole-body organic compounds, and is therefore not limited to blood-borne markers of infection. As such it appears to be feasible for future investigations.
Sensitive and modular amplicon sequencing of Plasmodium falciparum diversity and resistance for research and public health
Aranda-Diaz, Andres; Vickers, Eric Neubauer; Murie, Kathryn; Palmer, Brian; Hathaway, Nicholas; Gerlovina, Inna; Boene, Simone; Garcia-Ulloa, Manuel; Cistero, Pau; Katairo, Thomas; Semakuba, Francis Ddumba; Nsengimaana, Bienvenu; Gwarinda, Hazel; Garcia-Fernandez, Carla; Louie, William; Esayas, Endashaw; Da Silva, Clemente; Datta, Debayan; Kiyaga, Shahiid; Wiringilimaana, Innocent; Feleke, Sindew Mekasha; Bennett, Adam; Smith, Jennifer L.; Gadisa, Endalamaw; Parr, Jonathan B.; Conrad, Melissa D.; Raman, Jaishree; Tukwasibwe, Stephen; Ssewanyana, Isaac; Rovira-Vallbona, Eduard; Tato, Cristina M.; Briggs, Jessica; Mayor, Alfredo; Greenhouse, Bryan (Nature Portfolio, 2025-03)
Please read abstract in the article.
The epidemiology of malaria in four districts in southern Mozambique receiving indoor residual spray as part of a cross-border initiative
Maharaj, Rajendra; Abdelatif, Nada; Maquina, Mara; Seocharan, Ishen; Lakan, Vishan; Paaijmans, Krijn; Maartens, Francois; Aide, Pedro; Saute, Francisco (BioMed Central, 2025-01)
BACKGROUND : Imported malaria from southern Mozambique drives low levels of disease transmission in KwaZulu-Natal, South Africa. Therefore, the South African Department of Health funded implementation of indoor residual spraying (IRS) in Mozambiquan districts identified as sources of malaria infection for border communities in KwaZulu-Natal. IRS was initiated in districts of Guija, Inharrime, Panda and Zavala. To determine impact of spraying on malaria transmission in these districts, data relating to incidence and prevalence was collected before spraying (2018) and before the second round of spraying was completed (2023). Implementation of IRS was also monitored to ensure optimal spray coverage was achieved. METHODS : The study was a cross-sectional survey conducted in 6 sentinel sites in each of the four afore-mentioned districts, focusing on children 6 months to < 15 years from selected households. There was a baseline and an endline cross-sectional survey. Baseline prevalence took place during March–April 2022 whereas the endline surveys occurred during February–March 2023. One hundred and twenty children from each sentinel site were tested for malaria using rapid diagnostic tests. Monthly malaria cases were obtained from health facilities in each study district. Spray data was obtained from LSDI2 initiative who implemented IRS in the targeted districts. RESULTS : The study showed a definite impact of IRS on malaria prevalence in the targeted districts. Prevalence for sentinel sites in Guija district indicated that the prevalence of malaria increased slightly from baseline to endline in all sentinel sites in Guija. Overall, there was no significant change in prevalence in Zavala, from baseline to endline (p-value = 0.611). Panda’s overall malaria prevalence decreased from 19.20% to 10.82% (p-value < 0.001) whereas overall prevalence in Inharrime, decreased from 27.68% to 19.50% (p-value < 0.001). Malaria prevalence in children younger than 5 years decreased significantly in all four districts. In Panda there was a decrease in numbers of males and females being infected between surveys (p < 0.001), whereas for Inharrime the decrease was significant in females (p < 0.001). High coverage with IRS (> 95%) resulted in greater population protection. CONCLUSION : The study revealed that IRS implementation decreased malaria prevalence in Inharrime and Panda but not in Guija and Zavala. To ensure that cross-border movement of people does not result in increased malaria transmission, targeting areas identified as source of infection in travelers is paramount to reaching elimination.
Assessing Anopheles species collection techniques in a low malaria transmission area: implications for vector surveillance and control
Mashatola, Thabo; Tshikae, Power; Govere, John; Mazarire, Theresa T.; Brooke, Basil; Munhenga, Givemore (BioMed Central, 2025-07)
BACKGROUND : Effective entomological surveillance is crucial for malaria control, especially in low transmission settings. This study aimed to compare the performance of three mosquito collection methods (clay pots, carbon dioxide (CO2)-baited tents, and human landing catches (HLC)) for malaria vector surveillance in the low transmission area of Nkomazi, South Africa. METHODS : From March 2019 to March 2020, adult mosquitoes were collected monthly from three different sites over five consecutive nights and mornings. Each collection method was used at each site to capture both outdoor resting and host-seeking mosquitoes. The collected mosquitoes were morphologically identified to the Anopheles genus and species, followed by confirmation using molecular PCR assays. The species composition, relative abundance, and diversity were evaluated, and statistical tests, including Kruskal–Wallis and ANOVA, were used to assess differences in abundance and diversity across collection sites and methods. A Generalized Linear Mixed Model was applied to assess the impact of various factors on species abundance. RESULTS : A total of 1337 Anopheles mosquitoes were collected, with 98.5% being females. CO2-baited tents yielded the highest number of mosquitoes (57.6%), followed by HLC (39.1%) and clay pots (3.3%). Species composition included 52.4% of the Anopheles gambiae complex and 13.6% of the Anopheles funestus group. While species richness varied significantly between collection methods, with CO2-baited tents showing the highest richness, no significant differences were observed in abundance across sites or methods. The clay pot method was associated with significantly lower species abundance compared to HLC and CO2-baited tents. Species abundance fluctuated across months, with February and November showing a higher record. Males were less prevalent than females. Additionally, species abundance was lower in Block C and Vlakbult compared to Block A. CONCLUSIONS : This study highlights the importance of choosing appropriate mosquito collection methods based on specific entomological indicators and transmission dynamics. While CO2-baited tents provided the highest species richness, clay pots, despite yielding fewer mosquitoes, are effective for capturing outdoor resting malaria vectors. These findings suggest that a combination of collection methods is essential for inclusive malaria vector surveillance, facilitating tailored strategies for effective malaria control and resource optimization.
Cape Verde is the third African country to eliminate malaria : here’s how
De Jager, Tiaan; Kruger, Taneshka (Medpharm Publications, 2024-03)
Cape Verde has been certified malaria-free by the World Health Organization (WHO). The archipelago to the west of Senegal consists of 10 islands, and has a population of over 500 000 people. It is the third country in Africa to be declared malaria-free, after Mauritius (in 1973) and Algeria (in 2019). This brings the total of malaria-free countries to 43 worldwide. Achieving malaria-free certification is no simple feat. As specialists in malaria prevention and control, we explain Cape Verde’s long journey to eliminating the disease that killed over 600 000 people worldwide in 2022.
The ATM kinase inhibitor AZD0156 is a potent inhibitor of Plasmodium falciparum phosphatidylinositol 4-kinase (PI4Kβ) and is an attractive candidate for medicinal chemistry optimization against malaria
Woodland, John G.; Coertzen, Dina; Wicht, Kathryn J.; Hidalgo, Virginia Franco; Pasaje, Charisse Flerida A.; Godoy, Luiz C.; Qahash, Tarrick; Mmonwa, Mmakwena M.; Dziwornu, Godwin A.; Wambua, Lynn; Harries, Sarah; Korkor, Constance M.; Njoroge, Mathew; Krugmann, Liezl; Taylor, Dale; Leshabane, Meta Kgaogelo; Langeveld, Henrico; Rabie, Tayla Anne; Reader, Janette; Van der Watt, Mariette Elizabeth; Venter, Nelius; Erlank, Erica; Aswat, Ayesha S.; Koekemoer, Lizette L.; Yeo, Tomas; Jeon, Jin H.; Fidock, David A.; Gamo, Francisco Javier; Wittlin, Sergio; Niles, Jacquin C.; Llinas, Manuel; Coulson, Lauren B.; Birkholtz, Lyn-Marie; Chibale, Kelly (Wiley, 2025-07)
New compounds targeting human malaria parasites are critical for effective malaria control and elimination. Here, we pursued the imidazoquinolinone AZD0156 (MMV1580483), a human ataxia-telangiectasia mutated (ATM) kinase inhibitor that completed Phase I clinical trials as an anticancer agent. We validated its in vitro activity against the two main forms of the Plasmodium falciparum parasite in the human host, viz. the asexual blood (symptomatic) stage and sexual gametocyte (transmission) stage. Resistance selection, cross-resistance, biochemical, and conditional knockdown studies revealed that AZD0156 inhibits P. falciparum phosphatidylinositol 4-kinase type III beta (PfPI4Kβ), a clinically-validated target for the treatment of malaria. Metabolic perturbations, fixed-ratio isobolograms, killing kinetics and morphological evaluation correlated AZD0156 inhibition with other known PI4Kβ inhibitors. The compound showed favorable in vivo pharmacokinetic properties and 81% antimalarial efficacy (4 × 50 mg kg−1) in a P. berghei mouse malaria infection model. Importantly, a cleaner biochemical profile was measured against human kinases (MAP4K4, MINK1) implicated in embryofoetal developmental toxicity associated with the PfPI4Kβ inhibitor MMV390048. This improved kinase selectivity profile and structural differentiation from other PI4Kβ inhibitors, together with its multistage antiplasmodial activity and favorable pharmacokinetic properties, makes AZD0156 an attractive candidate for target-based drug repositioning against malaria via a medicinal chemistry optimization approach.
Investigation of the mechanisms affecting corrosion susceptibility of wrought aeronautical aluminium alloys Al-Cu-Li (AA2198) and Al-Cu-Mg (AA2024) for different pre-stretching levels
Charalampidou, Christina Margarita; Pretorius, Christiaan C.E.; Salojee, Muhammed Yusuf; Karousos, Dionysios; Khodja, Malika; Mostert, Roelf Johannes; Alexopoulos, Nikolaos D. (Elsevier, 2025-03)
Aluminium (Al) alloy sheets are usually stretched to manufacture aircraft structures with complex geometries. The corrosion susceptibility of AA2198 Al alloy is examined as a function of the extent of pre-stretching, using a wide range of advanced microscopy, electrochemical techniques, and tensile mechanical testing. Intergranular corrosion attack manifested in sub-surface secondary cracking for the 1.5 % pre-stretching level. A mechanism of deformation-induced chemical heterogeneity is believed to be responsible for the resulting intergranular corrosion, in which δ′-phase nucleation following pre-stretching allows for the removal of matrix Li within highly deformed grains, creating a micro-galvanic coupling between neighbouring grains. At pre-stretching levels of 4.0 % and higher, a transition to transgranular corrosion was observed, whilst the electron backscattered diffraction results indicated that recovery occurs at these pre-stretching levels. At 7.5. % pre-stretching level, the charge transfer resistance values were essentially increased due to the segregation of Li to sub-grain boundaries, allowing for more matrix Li removal and, hence, to the more rapid transgranular attack. On the contrary, the level of corrosion degradation of the tensile properties of AA2024-T3, although being more severe than that of the AA2198 alloy, is not essentially influenced by varying the extent of pre-stretching.
Medicinal chemistry progression of sapanisertib, the anticancer and dual Plasmodium phosphatidylinositol 4-kinase beta and cGMP-dependent protein kinase inhibitor, for malaria
Gachuhi, Samuel; Kamunya, Stephanie; Fienberg, Stephen; Wambua, Lynn; Salomane, Nicolaas; Mayoka, Godfrey; Taylor, Dale; Coertzen, Dina; Van der Watt, Mariette Elizabeth; Reader, Janette; Birkholtz, Lyn-Marie; Wittlin, Sergio; Krugmann, Liezl; Coulson, Lauren B.; Chibale, Kelly (American Chemical Society, 2025-06)
We recently demonstrated that the anticancer human mTOR inhibitor sapanisertib displays antimalarial activity in a malaria mouse model of infection and inhibits multiple Plasmodium kinases, including the high-value targets phosphatidylinositol 4-kinase type III beta (PI4Kβ) and cGMP-dependent protein kinase (PKG). Herein, we explore structure-activity relationships for sapanisertib analogues with benzyl and pyridyl substituents at the 7-position of the pyrazolopyrimidine core. New analogues with improved safety profiles were identified, including analogues with dual Plasmodium PI4Kβ and PKG inhibitory activity (exemplified by 19), as well as potent Plasmodium PI4Kβ inhibitors with minimal inhibitory activity against PKG (exemplified by 20). Compound 19 displayed potent antiplasmodium activity, high microsomal metabolic stability, and a good safety profile (hERG IC50 > 30; cytotoxicity selectivity index = 99). In vivo proof-of-concept, where a 4 × 50 mg kg-1 oral dose of 19 resulted in an 80% reduction in parasitemia in P. berghei-infected mice, further demonstrated the lead potential of this series. against respiratory-related infections with economic potential.
In vitro antiplasmodial activity and cytotoxicity of three Ziziphus (Rhamnaceae) species from South Africa
Mabuza, Mcebisi Junior; Kaiser, M.; Tshikalange, T.E.; Yusuf, Abdullahi Ahmed; Bapela, Mahwahwatse Johanna (Elsevier, 2025-06)
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