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Introduction
Publications
Publications (478)
The emergence of Plasmodium parasite resistance to current front-line antimalarial treatments poses a serious threat to global malaria control and highlights the necessity for the development of therapeutics with novel targets and mechanisms of action. Plasmepsins IX and X (PMIX/PMX) have been recognised as highly promising targets in Plasmodium du...
Screening published transcriptomes, we have discovered 75 RNA viruses that infect 27 species of parasitic nematodes, responsible for >1.5 billion infections in people and animals. Our analysis shows extensive diversity and a conserved global spread of virus/nematode associations across multiple continents suggesting an ancestral acquisition event a...
Mycobacterium tuberculosis cytochrome bd quinol oxidase (cyt bd), the alternative terminal oxidase of the respiratory chain, has been identified as playing a key role during chronic infection and presents a putative target for the development of novel antitubercular agents. Here, we report confirmation of successful heterologous expression of M. tu...
Antimalarials targeting the ubiquinol-oxidation (Qo) site of the Plasmodium falciparum bc1 complex, such as atovaquone, have become less effective due to the rapid emergence of resistance linked to point mutations in the Qo site. Recent findings showed a series of 2-aryl quinolones mediate inhibitions of this complex by binding to the ubiquinone-re...
Significance
Lymphatic filariasis caused by Wuchereria bancrofti , Brugia malayi , and Brugia timori affects 51 million people, leading to severe physical and mental disabilities. A mutualistic symbiosis between these filarial nematodes and Wolbachia bacteria has been exploited as a new curative treatment. Epidemiological modeling of anti- Wolbachi...
A key element for the prevention and management of COVID-19 is the development of effective therapeutics. Drug combination strategies of repurposed drugs offer several advantages over monotherapies, including the potential to achieve greater efficacy, the potential to increase the therapeutic index of drugs and the potential to reduce the emergence...
Anti-Wolbachia therapy has been identified as a viable treatment for combating filarial diseases. Phenotypic screening revealed a series of pyrazolopyrimidine hits with potent anti-Wolbachia activity. This paper focuses on the exploration of the SAR for this chemotype, with improvement of metabolic stability and solubility profiles using medicinal...
The mutualistic association between Wolbachia endosymbionts and their filarial nematode hosts has been exploited as a validated drug target delivering macrofilaricidal outcomes. Limitations of existing antibiotics to scale-up have driven the search for new drugs, which are effective in shorter regimens of 7 days or less. Here, we review the last 14...
A key element to the prevention and management of the COVID-19 pandemic is the development of effective therapeutics. Drug combination strategies of repurposed drugs offer a number of advantages to monotherapies including the potential to achieve greater efficacy, the potential to increase the therapeutic index of drugs and the potential to reduce...
The rapidly growing COVID-19 pandemic is the most serious global health crisis since the "Spanish flu" of 1918. There is currently no proven effective drug treatment or prophylaxis for this coronavirus infection. While developing safe and effective vaccines is one of the key focuses, a number of existing antiviral drugs are being evaluated for thei...
Background:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic by the World Health Organisation and urgent treatment and prevention strategies are needed. Many clinical trials have been initiated with existing medications, but assessments of the expected plasma and lung exposures at the selected doses...
There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS‐CoV‐2. However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, EC90 values...
Many papers are emerging that describe the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, no comprehensive evaluation of these molecules in the context of the achievable plasma pharmacokinetics after administration of approved doses and schedules to humans has been conducted....
The rapid detection of β-lactamases (Blas) and effective screening of Bla inhibitors are critically important and urgent for solving antibiotic resistance and improving precision medicine. Here a novel fluorescent probe CDC-559 was designed and synthesized, which can be used for the selective and direct detection of AmpC Blas. More importantly, it...
The elimination of filarial diseases such as onchocerciasis and lymphatic filariasis is hampered by the lack of a macrofilaricidal–adult worm killing–drug. In the present study, we tested the in vivo efficacy of AN11251, a boron-pleuromutilin that targets endosymbiotic Wolbachia bacteria from filarial nematodes and compared its efficacy to doxycycl...
Background : Malaria during pregnancy is a major health risk for both the mother and the foetus. Pregnancy has been shown to influence the pharmacokinetics of a number of different antimalarial drugs. This might lead to an under-exposure in these patients which could increase the risk of treatment failure and the development of drug resistance. The...
Clinical studies of new anti-tubercular drugs are costly and time consuming. Owing to the extensive TB treatment periods, the ability to identify drug candidates based on their predicted clinical efficacy is vital to accelerate the pipeline of new therapies. Recent failures of pre-clinical models in predicting the activity of fluoroquinolones under...
In high-transmission regions, we expect parasite lineages within complex malaria infections to be unrelated due to parasite inoculations from different mosquitoes. This project was designed to test this prediction. We generated 485 single-cell genome sequences from fifteen P. falciparum malaria patients from Chikhwawa, Malawi-an area of intense tra...
BACKGROUND:
Ivermectin is being considered for mass drug administration for malaria, due to its ability to kill mosquitoes feeding on recently treated individuals. In a recent trial, 3-day courses of 300 and 600 mcg/kg/day were shown to kill Anopheles mosquitoes for at least 28 days post-treatment when fed patients' venous blood using membrane fee...
Depletion of Wolbachia endosymbionts of human pathogenic filariae using 4-6 weeks of doxycycline treatment can lead to permanent sterilization and adult filarial death. We investigated the anti-Wolbachia drug candidate ABBV-4083 in the Litomosoides sigmodontis rodent model to determine Wolbachia depletion kinetics with different regimens. Wolbachia...
Primaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action is unclear. Here, we demonstrate that hydroxylated-PQ metabolites (OH-PQm) are responsible for efficacy against liver and sexual transmission stages of Plasmodium falciparum. The antimalarial activity of PQ against liver stages depend...
Increasing rifampicin (RIF) dosages could significantly reduce tuberculosis (TB) treatment durations. Understanding the pharmacokinetic-pharmacodynamics (PK–PD) of increasing RIF dosages could inform clinical regimen selection. We used intracellular PD modelling (PDi) to predict clinical outcomes, primarily time to culture conversion, of increasing...
The Anti-Wolbachia (A·WOL) consortium at the Liverpool School of Tropical Medicine (LSTM) has partnered with the Global High-Throughput Screening (HTS) Centre at AstraZeneca to create the first anthelmintic HTS for neglected tropical diseases (NTDs). The A·WOL consortium aims to identify novel macrofilaricidal drugs targeting the essential bacteria...
There is an urgent global need for a safe macrofilaricide drug to accelerate elimination of the neglected tropical diseases onchocerciasis and lymphatic filariasis. From an anti-infective compound library, the macrolide veterinary antibiotic, tylosin A, was identified as a hit against Wolbachia . This bacterial endosymbiont is required for filarial...
Background : Malaria during pregnancy is a major health risk for both the mother and the foetus. Pregnancy has been shown to influence the pharmacokinetics of a number of different antimalarial drugs. This might lead to an under-exposure in these patients which could increase the risk of treatment failure and the development of drug resistance. The...
Author summary
The Wolbachia bacterium lives symbiotically within the filarial worms that cause onchocerciasis and lymphatic filariasis. In the absence of these bacteria juvenile worms cannot mature, females are unable to reproduce, and the worm life-span is significantly shortened. Thus, anti-Wolbachia therapy would seem to be an ideal approach to...
A series of pleuromutilins modified by introduction of a boron-containing heterocycle on C(14) of the polycyclic core are described. These analogs were found to be potent anti-Wolbachia antibiotics, and as such, may be useful in the treatment of filarial infections caused by Onchocherca volvulus, resulting in Onchocerciasis or river blindness, or W...
The Onchocerca ochengi adult implant and Brugia malayi microfilariemic Severe-Combined Immunodeficient (SCID) mouse models are validated screens to measure macrofilaricidal and microfilaricidal activities of candidate onchocerciasis drugs. The purpose of this study was to assess whether 5 daily sub-cutaneous (s.c.) injections of standard flubendazo...
Results of compartmental PK analysis as determined from PK modelling of FBZ exposure data.
(DOCX)
Significance
Onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) are neglected tropical diseases that cause severe disability and affect more than 157 million people globally. Current control efforts are hindered by the lack of a safe macrofilaricidal drug that can eliminate the parasitic adult nematodes safely. A clinically v...
Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont, Wolbachia, for survival and fecundity, making Wolbachia a promising therapeutic target. Here we perform a high-throughput screen of AstraZeneca’s 1.3 million in-house compound library and identify 5 novel chemotypes with faster in vitro kill rates (<2 da...
Background:
Poor response to TB therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic parameters can be affected by comorbidities or the interaction of drugs with food.
Objectives:
This study aimed to determine the effect of food intake upon pharmacokinetics of rifampicin and isoniazid in a Peruvian p...
A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.
Tuberculosis (TB) treatment is long and complex, typically involving a combination of drugs taken for 6 months. Improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to TB drug development is the lack of predictive pre-clinical tools. To address this deficiency, we have adopted a new high-content...
A series of N⁴-benzylamine-N²-isopropyl-quinazoline-2,4-diamine derivatives has been synthesized and tested for antibacterial activity against five bacterial strains. Twelve different substituents on the N⁴-benzylamine group have been investigated along with replacement of the quinazoline core (with either a benzothiophene or regioisomeric pyridopy...
Significance
Filarial nematode infections, caused by Wuchereria bancrofti , Brugia malayi (elephantiasis), and Onchocerca volvulus (river blindness) infect 150 million of the world’s poorest populations and cause profound disability. Standard treatments require repetitive, long-term, mass drug administrations and have failed to interrupted transmis...
Lymphatic filariasis and onchocerciasis are two important neglected tropical diseases (NTDs) that cause severe disability. Control efforts are hindered by the lack of a safe macrofilaricidal drug. Targeting the Wolbachia bacterial endosymbionts in these parasites with doxycycline leads to a macrofilaricidal outcome, but protracted treatment regimen...
It has been estimated that in 2013 there were approximately 198 million cases of malaria (with an uncertainty range of 124–283 million) and an estimated 584,000 deaths (with an uncertainty range of 367,000–755,000), with the majority of deaths amongst African children under 5 years of age [1]. As a result of global efforts, including in transmissio...
Supplementary Figures, Supplementary Tables, Supplementary Notes, Supplementary Methods and Supplementary References
K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecu...
A High-throughput screen (HTS) was undertaken against the respiratory chain dehydrogenase component, NADH:menaquinone oxidoreductase (Ndh) of Mycobacterium tuberculosis (Mtb). 11,000 compounds were selected for the HTS based on the known phenothiazine Ndh inhibitors, trifluoperazine and thioridazine. Combined HTS (11,000 compounds) and in-house scr...
Piperaquine combined with dihydroartemisinin is one of the artemisinin derivative combination therapies, which can replace artesunate-mefloquine in treating uncomplicated falciparum malaria in Thailand. The aim of this study was to determine the in vitro sensitivity of Thai Plasmodium falciparum isolates against piperaquine and the influence of the...
Unlabelled:
Each year, millions of African children receive praziquantel (PZQ) by mass drug administration (MDA) to treat schistosomiasis at a standard single dose of 40 mg/kg of body weight, a direct extrapolation from studies of adults. A higher dose of 60 mg/kg is also acceptable for refractory cases. We conducted the first PZQ pharmacokinetic...
Adverse events that were self-reported (A) or observed by pediatrician (B). Download
An efficient route to the synthesis of potent antimalarial aryloxy 1,2,4,5-tetraoxanes is described that permits parallel synthesis for Structure–Activity Relationship (SAR) investigations. Brief details of the in vitro and in vivo antimalarial evaluation are included which enables identification of antimalarial leads for further development. Also...
In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross-resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4-trioxolane activity based pro...
Background:
Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual pa...
Background
Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual pati...
Additional file 2: Figure S1. Relationship between gametocytaemia on enrolment and baseline haemoglobin concentration, parasitaemia and patient age. The predicted probability of gametocyte carriage at enrolment is plotted from the multivariate model; the line indicates the best fit, the shaded area the 95 % CI. Only patients from studies with gamet...
Additional file 3: Table S2. Independent risk factors for the prevalence of gametocytaemia at enrolment in children aged 1–5 years. Logistic multivariable analysis by region with prevalence of gametocytaemia at enrolment as dependent variable. Nobs, Number of observations; Npos, Number of positive observations. The relationship between gametocyte p...
Additional file 8: Table S7. Sensitivity analysis: variation in model coefficients after exclusion of individual studies. 1 Estimates as obtained in the final multivariate models and listed in main tables. 2 RSD, Relative standard deviation was calculated as a ratio of standard deviation to mean of the estimates (odds ratio or hazard ratio) calcula...
Additional file 9: Figure S2. Development of gametocytaemia after treatment evaluated in patients with no gametocytaemia on enrolment and full 28-day follow-up. A: Development of gametocytaemia by artemisinin combination therapy. B: Development of gametocytaemia by treatment outcome. (TIF 284 kb)
Additional file 4: Table S3. The effect of treatment dosing on the appearance of gametocytaemia in participants without microscopically detected gametocytaemia before treatment (time to gametocytaemia) and clearance of gametocytaemia in participants with gametocytaemia at enrolment (time to clearance). All analyses of time to clearance are adjusted...
Additional file 7: Table S6. Factors associated with the development of gametocytaemia after enrolment in individuals who were gametocyte-free before treatment with artemisinin combination therapy. Cox regression model for time to gametocytaemia. Only patients with complete 28-day follow-up are included. (DOC 35 kb)
Additional file 1: Table S1. Overview of all included studies. 1 The sensitivity of microscopy methods was classified into one of four categories: 1 = studies in which slides were specifically read for gametocytes, reviewing at least 100 microscopic high power fields or against ≥ 1000 white blood cells (WBC); 2 = microscopists specifically instruct...
Additional file 5: Table S4. Factors associated with the clearance of gametocytaemia after enrolment in individuals who were gametocytaemic before treatment with artemisinin combination therapy. Nobs, Number of observations; N cleared, Number of patients with day of clearance of gametocytaemia recorded. Derived haemoglobin, conversion from haematoc...
Additional file 6: Table S5. Risk of bias in individual studies included in the analysis. ACT, Artemisinin combination therapy. 1 For trials with non-ACTs, data were only analysed for gametocytaemia on enrolment and regimens, arms, randomization, concealment of treatment, sequence generation and treatment blinding are given as not applicable (NA)....
Supplementary
Supplementary
Tuberculosis (TB) remains one of the world’s major health burdens with 9.6 million new infections globally. Though considerable progress has been made in reduction of TB incidence and mortality, there is a continuous need for lower cost, simpler and more robust means of diagnosis. One method that may fulfil these requirements is in the area of brea...
Primaquine (PQ), an 8-aminoquinoline, is considered a tissue schizonticide drug for radical cure in vivax and ovale malaria, with minimal impact on asexual erythrocytic stages at therapeutic concentrations. Tafenoquine (TQ), a new 8-aminoquinoline analog of PQ, is active against both malaria parasite tissue and blood stages and is being promoted as...
In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross-resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4-trioxolane activity based pro...
In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross-resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4-trioxolane activity based pro...
Lymphatic filariasis and onchocerciasis are parasitic helminth diseases, which cause severe morbidities such as elephantiasis, skin disease and blindness, presenting a major public health burden in endemic communities. The anti-Wolbachia consortium (A·WOL: http://www.a-wol.com/) has identified a number of registered antibiotics that target the endo...
Lymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial nematodes responsible for LF (Brugia malayi, Wuchereria bancrofti) or onchocerciasis (Onchocerca volvulus) is doxycycline. The target of doxycycline is t...
Significance
The mechanism of action of the artemisinin (ART) class of antimalarial drugs, the most important antimalarial drug class in use today, remains controversial, despite more than three decades of intensive research. We have developed an unbiased chemical proteomic approach using a suite of ART activity-based protein profiling probes to id...
Objectives:
Low rifampicin plasma concentrations can lead to treatment failure and increased risk of developing drug resistant tuberculosis. The objectives of this study were to: Characterise the population-PK of rifampicin in Malawian children and adults with tuberculosis; Simulate exposures under revised WHO dosing guidelines that aim to reduce...
Lymphocytes are implicated in immunity and pathogenesis of severe malaria. Since lymphocyte subsets vary with age, assessment
of their contribution to different etiologies can be difficult. We immunophenotyped peripheral blood from Malawian children
presenting with cerebral malaria, severe malarial anemia and uncomplicated malaria (n=113), and heal...
The award of the Nobel Prize to Dr Bill Campbell and Professor Satoshi Ōmura for their role in the discovery of avermectin and Professor Youyou Tu for her work on the development of artemisinin has been universally welcomed by the International Health community for what the Nobel Committee described as 'The discoveries of Avermectin and Artemisinin...
Stoppt Malaria! Phänotyp-Screening von Malariaparasiten, Hit-Identifizierung und effiziente Leitstrukturoptimierung lieferten den präklinischen Wirkstoffkandidaten DDD107498 gegen Malaria. Die Verbindung hat das Potenzial zur Malariaheilung per einmaliger Gabe und zeigt ein einzigartiges Aktivitätsspektrum gegen das Leber-, Blut- und Moskito-Stadiu...
Putting a stop to malaria: Phenotypic screening against malaria parasites, hit identification, and efficient lead optimization have delivered the preclinical candidate antimalarial DDD107498. This molecule is distinctive in that it has potential for use as a single-dose cure for malaria and shows a unique broad spectrum of activity against the live...
Background:
Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference...
Limited data address the impact of HIV co-infection on the pharmacokinetics of anti-tuberculosis drugs in Sub-Saharan Africa. 47 Malawian adults underwent rich pharmacokinetic sampling at 0-0.5-1-2-3-4-6-8 and 24 hours post-dose. 51% were male; mean age was 34 years. 65% were HIV-positive with a mean CD4 count of 268 cells/μL. Anti-tuberculosis dru...
Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan Afri...
References of all clinical trials and their study designs
Maps showing locations of published clinical efficacy studies and the studies included in the pooled analysis
Transmission classification
Additional tables and figures
Authors and contributions
