Philip Rosenthal

• University of California, San Francisco

Background: The multiple emergences and continuing spread of partially artemisinin-resistant Plasmodium falciparum in Africa, where about 95% of malaria occurs, is a health challenge that requires urgent attention. The World Health Organization has developed a resistance response strategy that centers on enhancing surveillance, reducing drug pressu...

Background We conducted a double-blinded, randomized, controlled trial of 2757 pregnant women in Uganda, where resistance of malaria parasites to sulfadoxine-pyrimethamine is widespread. Women were randomly assigned (1:1:1) to monthly IPTp with sulfadoxine-pyrimethamine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus sulfado...

Introduction. The use of next-generation sequencing technologies (NGS) to study parasite populations and their response and evolution to interventions is important to support malaria control and elimination efforts. While whole genome sequencing (WGS) is optimal in terms of assessing the entire genome, it is costly for numerous samples. Targeted ap...

In 2021-23, a resurgence of malaria occurred in the Tororo District of Uganda following a change in formulations used for indoor residual spraying of insecticide (IRS). Prior analyses showed that this increase was temporally associated with the replacement of Anopheles gambiae sensu lato by An. funestus as the dominant local vector. To investigate...

Fetal growth restriction (FGR) is associated with perinatal death and adverse birth outcomes, as well as long-term complications, including increased childhood morbidity, abnormal neurodevelopment, and cardio-metabolic diseases in adulthood. Placental epigenetic reprogramming associated with FGR may mediate these long-term outcomes. Placental malar...

Background The gold standard measure of malaria exposure is the entomological inoculation rate (EIR), or the number of infectious bites an individual receives over a given period. Nevertheless, it is unclear whether household EIR reflects heterogeneity in individual infection risk. Methods To investigate this relationship, we used data collected fr...

For over two decades, artemisinin-based combination therapy (ACT) has been the standard of care for the treatment of uncomplicated falciparum malaria. However, artemisinin partial resistance (ART-R) is now prevalent in Southeast Asia and has emerged in eastern Africa, threatening ACT efficacy. Mechanistically, ART-R results from an endocytosis defe...

Background. The treatment and control of malaria in Africa is challenged by drug resistance, including Plasmodium falciparum transporter, folate pathway, and PfK13 mutations that mediate resistance to aminoquinolines, antifolates, and artemisinins, respectively. Characterization of drug susceptibility informs optimal control strategies. Methods. We...

Background: Molecular surveillance of drug-resistant Plasmodium falciparum is crucial for malaria control in endemic regions. Two targeted-resequencing tools, the Molecular Inversion Probe (MIP) drug resistance panel DR23K and the Multiplexed Amplicons for Drugs, Diagnostics, Diversity, and Differentiation using High-Throughput Targeted Resequencin...

Cyclic nucleotide–dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent Plasmodium falciparum P...

Surveillance of drug resistance and the discovery of novel targets—key objectives in the fight against malaria—rely on identifying resistance-conferring mutations in Plasmodium parasites. Current approaches, while successful, require laborious experimentation or large sample sizes. To elucidate shared determinants of antimalarial resistance that ca...

Artemisinin partial resistance (ART-R) has emerged in eastern Africa, necessitating regular surveillance of susceptibility of Plasmodium falciparum to artemisinins. The microscopy-based ring-stage survival assay (RSA) provides a laboratory correlate of ART-R but is limited by low throughput and subjectivity of microscopic counts of viable parasites...

Malaria diagnostic testing in high transmission settings remains a burden on healthcare systems. Here we present Remoscope, a portable automated imaging cytometer that scans fresh, unstained whole blood using a custom neural network on low-cost hardware. By screening up to two million red blood cells, Remoscope performs label-free quantitative stag...

Objectives Natural killer (NK) cells make important contributions to anti‐malarial immunity through antibody‐dependent cellular cytotoxicity (ADCC), but the role of different components of this pathway in promoting NK cell activation remains unclear. Methods We compared the functions and phenotypes of NK cells from malaria‐exposed and malaria‐naiv...

On August 14, 2024, following a regional declaration by the Africa Centres for Disease Control and Prevention, the World Health Organization declared mpox a Public Health Emergency of International Concern, marking the second such declaration in two years. A series of outbreaks involving the more virulent clade I virus (compared to clade II, which...

Co‐administration of dihydroartemisinin–piperaquine (DP) and sulfadoxine‐pyrimethamine (SP) for intermittent preventive treatment of malaria in pregnancy (IPTp) may be superior in preventing adverse birth outcomes compared with either therapy alone, but potential drug–drug interactions require investigation. We conducted intensive and sparse pharma...

Many questions remain about the prevalence and effects of SARS-CoV-2 infection in malaria-endemic African countries like Uganda, particularly in vulnerable groups such as pregnant women. We describe SARS-CoV-2 immunoglobulin (Ig)G and IgM antibody responses and clinical outcomes in mother-infant dyads enrolled in malaria chemoprevention trials in U...

The recent withdrawal of artefenomel from clinical development leaves no endoperoxide-class agents in the antimalarial pipeline. Synthetic endoperoxides with a desymmetrized structure have demonstrated promising physiochemical and in vivo properties. Here we expand on our initial investigation of trans-3″ carbamate substitution with a diverse array...

Tororo District, Uganda experienced a dramatic decrease in malaria burden from 2015–19 during 5 years of indoor residual spraying (IRS) with carbamate (Bendiocarb) and then organophosphate (Actellic) insecticides. However, a marked resurgence occurred in 2020, which coincided with a change to a clothianidin-based IRS formulations (Fludora Fusion/Su...

Novel antimalarials are urgently needed to combat rising resistance to available drugs. The imidazolopiperazine ganaplacide is a promising drug candidate, but decreased susceptibility of laboratory strains has been linked to polymorphisms in the Plasmodium falciparum cyclic amine resistance locus (PfCARL), acetyl-CoA transporter (PfACT), and UDP-ga...

Investment in community health workers is essential

Introduction Maternal intervillous monocytes (MIMs) and fetal Hofbauer cells (HBCs) are myeloid-derived immune cells at the maternal-fetal interface. Maternal reproductive history is associated with differential risk of pregnancy complications. The molecular phenotypes and roles of these distinct monocyte/macrophage populations and the influence of...

Newly arrived refugees offer insights into malaria epidemiology in their countries of origin. We evaluated asymptomatic refugee children within 7 days of arrival in Uganda from South Sudan and the Democratic Republic of Congo (DRC) in 2022 for parasitemia, parasite species, and Plasmodium falciparum drug resistance markers. Asymptomatic P. falcipar...

Background Fetal growth restriction (FGR) is associated with perinatal death and other adverse birth outcomes, as well as long term complications including increased childhood morbidity, abnormal neurodevelopment, and cardio-metabolic diseases in adulthood. FGR has been associated with placental epigenetic reprogramming, which may mediate these lon...

Recently, we identified KIR+CD8+ T cells as a previously underappreciated regulatory subset important in humans and mice to suppress self-reactivity, especially in the context of infections. To better understand what other roles these cells might play, we asked whether they are active during pregnancy. We first observed an increased frequency of KI...

In recent decades, neglected tropical diseases and poverty-related diseases have become a serious health problem worldwide. Among these pathologies, human African trypanosomiasis, and malaria present therapeutic problems due to the onset of resistance, toxicity problems and the limited spectrum of action. In this drug discovery process, rhodesain a...

Background: Tororo District, Uganda experienced a dramatic decrease in malaria burden from 2015-19 following 5 years of indoor residual spraying (IRS) with carbamate (Bendiocarb) and then organophosphate (Actellic) insecticides. However, a marked resurgence occurred in 2020, which coincided with a change to a clothianidin-based IRS formulations (Fl...

Malaria remains a leading cause of morbidity and mortality in Burkina Faso, which utilizes artemether–lumefantrine as the principal therapy to treat uncomplicated malaria and seasonal malaria chemoprevention with monthly sulfadoxine–pyrimethamine plus amodiaquine in children during the transmission season. Monitoring the activities of available ant...

Malaria, mostly due to Plasmodium falciparum infection in Africa, remains one of the most important infectious diseases in the world. Standard treatment for uncomplicated P. falciparum malaria is artemisinin-based combination therapy (ACT), which includes a rapid-acting artemisinin derivative plus a longer-acting partner drug, and standard therapy...

Background Artemisinin partial resistance, mediated by mutations in the Plasmodium falciparum Kelch13 protein (K13), rapidly spread in South-East Asia (SEA), undermining antimalarial efficacies of artemisinin-based combination therapies (ACT). Validated K13 mutations have recently arisen in Africa, but rates of increase are not well characterized....

Naphthyl bearing 1,3,4-thiadiazoleacetamides targeting the parasitic folate pathway as antimalarials and antileishmanial agents.

Maternal intervillous monocytes (MIMs) and fetal Hofbauer cells (HBCs) are myeloid-derived immune cells at the maternal-fetal interface. Little is known regarding the molecular phenotypes and roles of these distinct monocyte/macrophage populations. Here, we used RNA sequencing to investigate the transcriptional profiles of MIMs and HBCs in six norm...

Background: Partial resistance of Plasmodium falciparum to the artemisinin component of artemisinin-based combination therapies, the most important malaria drugs, emerged in Southeast Asia and now threatens East Africa. Partial resistance, which manifests as delayed clearance after therapy, is mediated principally by mutations in the kelch protein...

Background: Malaria in pregnancy (MIP) causes higher morbidity in primigravid compared to multigravid women; however, the correlates and mechanisms underlying this gravidity-dependent protection remain incompletely understood. We aimed to compare the cellular immune response between primigravid and multigravid women living in a malaria-endemic reg...

The 2022 global outbreak of human Mpox (formerly monkeypox) virus (MPXV) infection outside of the usual endemic zones in Africa challenged our understanding of the virus’s natural history, transmission dynamics, and risk factors. This outbreak has highlighted the need for diagnostics, vaccines, therapeutics, and implementation research, all of whic...

Background: SARS-CoV-2 has been well studied in resource-rich areas but many questions remain about effects of infection in African populations, particularly in vulnerable groups such as pregnant women. Methods: We describe SARS-CoV-2 immunoglobulin (Ig) G and IgM antibody responses and clinical outcomes in mother-infant dyads enrolled in malaria c...

Background Despite scale-up of seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine (SP-AQ) in children <5 years old in Burkina Faso, malaria incidence remains high, raising concerns regarding SMC effectiveness and selection of drug resistance. Using a case-control design, we determined associations between SMC drug...

ABSTRACT Malaria, especially Plasmodium falciparum infection, remains an enormous problem, and its treatment and control are seriously challenged by drug resistance. New antimalarial drugs are needed. To characterize the Medicines for Malaria Venture pipeline of antimalarials under development, we assessed the ex vivo drug susceptibilities to 19 co...

In recent decades, several structure-activity relationship (SAR) studies provided potent inhibitors of the cysteine proteases falcipain-2 (FP-2) and rhodesain (RD) from Plasmodium falciparum and Trypanosoma brucei rhodesiense, respectively. Whilst the roles of the warhead and residues targeting the P1 and P2 pockets of the proteases were extensivel...

Clinical development of the antimalarial artefenomel was recently halted due to formulation challenges stemming from the drug's lipophilicity and low aqueous solubility. The symmetry of organic molecules is known to influence crystal packing energies and by extension solubility and dissolution rates. Here we evaluate RLA-3107, a desymmetrized, regi...

Dihydroartemisinin-piperaquine (DP) is highly effective for malaria chemoprevention during pregnancy, but the standard dosing of DP that is used for nonpregnant adults may not be optimal for pregnant women. We previously reported that the pharmacokinetic exposure of total piperaquine (PQ; both bound and unbound to plasma proteins) is reduced signif...

Importance: Estimating the true burden of SARS-CoV-2 infection has been difficult in sub-Saharan Africa owing to asymptomatic infections and inadequate testing capacity. Antibody responses from serologic surveys can provide an estimate of SARS-CoV-2 exposure at the population level. Objective: To estimate SARS-CoV-2 seroprevalence, attack rates,...

With increasing reports of resistance to artemisinins and artemisinin-combination therapies, targeting the Plasmodium proteasome is a promising strategy for antimalarial development. We recently reported a highly selective Plasmodium falciparum proteasome inhibitor with anti-malarial activity in the humanized mouse model. To balance the permeabilit...

Tororo District, in Eastern Uganda, experienced a dramatic decline in malaria burden starting in 2014 following the implementation of indoor residual spraying of insecticide (IRS) in the setting of repeated long-lasting insecticide treated nets (LLINs) distribution campaigns. However, in 2020 malaria began to resurge in Tororo following a change in...

Abstract Background Methods used to sample mosquitoes are important to consider when estimating entomologic metrics. Human landing catches (HLCs) are considered the gold standard for collecting malaria vectors. However, HLCs are labour intensive, can expose collectors to transmission risk, and are difficult to implement at scale. This study compare...

Background Plasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia. Methods Individual patient data from eligible antimala...

Insecticide resistance threatens recent progress on malaria control in Africa. To characterize pyrethroid resistance in Uganda, Anopheles gambiae (s.s.) and Anopheles arabiensis were analyzed from 11 sites with varied vector control strategies. Mosquito larvae were collected between May 2018 and December 2020. Sites were categorized as receiving no...

Recurrent disease outbreaks caused by a range of emerging and resurging pathogens over the past decade reveal major gaps in public health preparedness, detection, and response systems in Africa. Underlying causes of recurrent disease outbreaks include inadequacies in the detection of new infectious disease outbreaks in the community, in rapid patho...

Malaria is the most lethal parasitic infections in the world. To address the emergence of drug resistance to current antimalarials, here we report the design and synthesis of new series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide hybrids by using multicomponent Petasis reaction as the key step and evaluated in vitro for their antimalarial e...

A library of quinoline‐based hydrazones bearing 1H‐1,2,3‐triazole core was designed, synthesized, and evaluated for their antiplasmodial activity against the drug‐resistant Plasmodium falciparum W2 strain. The inclusion of pyrazine‐2‐carboxylic acid with a flexible propyl spacer afforded the most active scaffold with an IC50 value of 0.26 μM. Mecha...

Artemisinin partial resistance may facilitate selection of Plasmodium falciparum resistant to combination therapy partner drugs. We evaluated 99 P. falciparum isolates collected in 2021 from northern Uganda, where resistance-associated PfK13 C469Y and A675V mutations have emerged, and eastern Uganda, where these mutations are uncommon. With the ex...

Malaria is the leading cause of disease burden in sub-Saharan Africa. In 2010, the East Africa International Center of Excellence for Malaria Research, also known as the Program for Resistance, Immunology, Surveillance, and Modeling of Malaria (PRISM), was established to provide a comprehensive approach to malaria surveillance in Uganda. We institu...

The Program for Resistance, Immunology, Surveillance, and Modeling of Malaria (PRISM) has been conducting malaria research in Uganda since 2010 to improve the understanding of the disease and measure the impact of population-level control interventions in the country. Here, we will summarize key research findings from a series of studies addressing...

Highly effective vector control can reduce malaria burden significantly, but individuals with parasitemia provide a potential reservoir for onward transmission. We performed an empirical, non-parametric simulation based on cohort data from Tororo District, Uganda—an area with historically high but recently reduced malaria transmission—to estimate t...

Background: Methods used to sample mosquitoes are important to consider when estimating entomologic metrics. Human landing catches (HLCs) are considered the gold standard for collecting malaria vectors. However, HLCs are labor intensive, can expose collectors to transmission risk, and are difficult to implement at scale. This study compared alterna...

Importance: Estimating the true burden of SARS-CoV-2 infection has been difficult in sub-Saharan Africa due to asymptomatic infections and inadequate testing capacity. Antibody responses from serologic surveys can provide an estimate of SARS-CoV-2 exposure at the population level. Objective: To estimate SARS-CoV-2 seroprevalence, attack rates, and...

The proteasome is a promising target for antimalarial chemotherapy. We assessed ex vivo susceptibilities of fresh Plasmodium falciparum isolates from eastern Uganda to seven proteasome inhibitors: two asparagine ethylenediamines, two macrocyclic peptides, and three peptide boronates; five had median IC50 values <100 nM. TDI8304, a macrocylic peptid...

Importance: Because transmission of ocular strains of Chlamydia trachomatis is greatest among preschool-aged children, limiting azithromycin distributions to this age group may conserve resources and result in less antimicrobial resistance, which is a potential advantage in areas with hypoendemic trachoma and limited resources. Objective: To det...

Malaria elimination urgently needs novel antimalarial therapies that transcend resistance, toxicity, and high costs. Our multicentric international collaborative team focuses on developing multistage antimalarials that exhibit novel mechanisms of action. Here, we describe the design, synthesis, and evaluation of a novel multistage antimalarial comp...

Background. Few data are available on COVID-19 outcomes among pregnant women in sub-Saharan Africa (SSA), where high-risk comorbidities are prevalent. We investigated the impact of pregnancy on SARS-CoV-2 infection and of SARS-CoV-2 infection on pregnancy to generate evidence for health policy and clinical practice. Methods. We conducted a 6-countr...

BACKGROUND: Few data are available on COVID-19 outcomes among pregnant women in sub-Saharan Africa (SSA), where high-risk comorbidities are prevalent. We investigated the impact of pregnancy on SARS-CoV-2 infection and of SARS-CoV-2 infection on pregnancy to generate evidence for health policy and clinical practice. METHODS: We conducted a 6-countr...

Coronavirus disease 2019 (COVID-19) in pregnancy is associated with excess maternal and infant morbidity and mortality in both African and higher-resource settings. Furthermore, mounting evidence demonstrates the safety and efficacy of COVID-19 vaccination for pregnant women and infants. However, national guidelines in many African countries are eq...

Background: Few data are available on COVID-19 outcomes among pregnant women in sub-Saharan Africa (SSA), where high-risk comorbidities are prevalent. We investigated the impact of pregnancy on SARS-CoV-2 infection and of SARS-CoV-2 infection on pregnancy to generate evidence for health policy and clinical practice. Methods: We conducted a 6-cou...

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasm...

Background Microscopic examination of Giemsa-stained blood films remains the reference standard for malaria parasite detection and quantification, but is undermined by difficulties in ensuring high-quality manual reading and inter-reader reliability. Automated parasite detection and quantification may address this issue. Methods A multi-centre, ob...

Malaria parasites continue to pose a concern. Drug resistance underlines the need for new structural cores that, when combined with existing antimalarial frameworks, can partially re-sensitize drug-resistant parasites to available antimalarial drugs, such as chloroquine (CQ). Herein, we used "covalent biotherapy" to design and synthesize a series o...

Introduction: Tororo District, in Eastern Uganda, experienced a dramatic decline in malaria burden following the implementation of indoor residual spraying of insecticide (IRS) in 2014; the adjacent Busia District did not receive IRS. Data from areas near the margins of IRS coverage are limited. In this study, measures of malaria transmission, infe...

We measured susceptibilities of Ugandan Plasmodium falciparum isolates assayed on the day of collection or after storage at 4°C. Samples were incubated with serial dilutions of 8 antimalarials, and susceptibilities were determined from 72-h growth inhibition assays. Storage was associated with decreased growth and lower 50% inhibitory concentration...

A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage Plasmodium falciparum (Pf) growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, e...

Piperaquine (PQ) is an antimalarial drug that is highly protein-bound. Variation in plasma protein contents may affect the pharmacokinetic (PK) exposure of unbound drug, leading to alteration of clinical outcomes. All published methods for determination of PQ in human plasma measure the total PQ including both bound and unbound PQ to plasma protein...

Malaria remains a prevalent infectious disease in developing countries. The first-line therapeutic options are based on combinations of fast-acting artemisinin derivatives and longer-acting synthetic drugs. However, the emergence of resistance to these first-line treatments represents a serious risk, and the discovery of new effective drugs is urge...