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1.
Elife ; 102021 07 19.
Article in English | MEDLINE | ID: covidwho-1513059

ABSTRACT

The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failures across Southeast Asia. In Africa, K13-propeller genotyping confirms the emergence of the R561H mutation in Rwanda and highlights the continuing dominance of wild-type K13 elsewhere. Using gene editing, we show that R561H, along with C580Y and M579I, confer elevated in vitro ART resistance in some African strains, contrasting with minimal changes in ART susceptibility in others. C580Y and M579I cause substantial fitness costs, which may slow their dissemination in high-transmission settings, in contrast with R561H that in African 3D7 parasites is fitness neutral. In Cambodia, K13 genotyping highlights the increasing spatio-temporal dominance of C580Y. Editing multiple K13 mutations into a panel of Southeast Asian strains reveals that only the R561H variant yields ART resistance comparable to C580Y. In Asian Dd2 parasites C580Y shows no fitness cost, in contrast with most other K13 mutations tested, including R561H. Editing of point mutations in ferredoxin or mdr2, earlier associated with resistance, has no impact on ART susceptibility or parasite fitness. These data underline the complex interplay between K13 mutations, parasite survival, growth and genetic background in contributing to the spread of ART resistance.


Subject(s)
Artemisinins/pharmacology , Drug Resistance/drug effects , Drug Resistance/genetics , Mutation , Plasmodium falciparum/drug effects , Plasmodium falciparum/genetics , Protozoan Proteins/genetics , Africa , Antimalarials/pharmacology , Asia , Cambodia , Humans , Malaria, Falciparum/epidemiology , Malaria, Falciparum/parasitology , Molecular Epidemiology
3.
Eur J Pharmacol ; 908: 174374, 2021 Oct 05.
Article in English | MEDLINE | ID: covidwho-1322083

ABSTRACT

The efficacy of corticosteroids and its use for the treatment of SARS-CoV-2 infections is controversial. In this study, using data sets of SARS-CoV-2 infected lung tissues and nasopharyngeal swabs, as well as in vitro experiments, we show that SARS-CoV-2 infection significantly downregulates DUSP1 expression. This downregulation of DUSP1 could be the mechanism regulating the enhanced activation of MAPK pathway as well as the reported steroid resistance in SARS-CoV-2 infection. Moreover, chloroquine, an off labeled COVID-19 drug is able to induce DUSP1 and attenuate MAPK pathway; and is expected to improve sensitivity to steroid treatment. However, further mechanistic studies are required to confirm this effect.


Subject(s)
COVID-19/drug therapy , Chloroquine/pharmacology , Dual Specificity Phosphatase 1/genetics , Glucocorticoids/pharmacology , p38 Mitogen-Activated Protein Kinases/metabolism , Adult , Aged , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Cells, Cultured , Chloroquine/therapeutic use , Datasets as Topic , Down-Regulation/drug effects , Drug Resistance/drug effects , Drug Resistance/genetics , Drug Synergism , Dual Specificity Phosphatase 1/metabolism , Fibroblasts , Glucocorticoids/therapeutic use , Healthy Volunteers , Humans , Lung/cytology , Lung/pathology , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Middle Aged , Nasopharynx/virology , Off-Label Use , Primary Cell Culture , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity
4.
Molecules ; 26(8)2021 Apr 15.
Article in English | MEDLINE | ID: covidwho-1302425

ABSTRACT

Malaria is one of the most life-threatening infectious diseases and constitutes a major health problem, especially in Africa. Although artemisinin combination therapies remain efficacious to treat malaria, the emergence of resistant parasites emphasizes the urgent need of new alternative chemotherapies. One strategy is the repurposing of existing drugs. Herein, we reviewed the antimalarial effects of marketed antibiotics, and described in detail the fast-acting antibiotics that showed activity in nanomolar concentrations. Antibiotics have been used for prophylaxis and treatment of malaria for many years and are of particular interest because they might exert a different mode of action than current antimalarials, and can be used simultaneously to treat concomitant bacterial infections.


Subject(s)
Antimalarials/therapeutic use , Drug Repositioning/methods , Animals , Anti-Bacterial Agents/therapeutic use , Drug Resistance/genetics , Humans , Malaria/physiopathology , Plasmodium falciparum/genetics , Plasmodium falciparum/pathogenicity
5.
BMC Res Notes ; 13(1): 497, 2020 Oct 27.
Article in English | MEDLINE | ID: covidwho-895028

ABSTRACT

OBJECTIVE: Nigeria bears 25% of global malaria burden despite concerted efforts towards its control and elimination. The emergence of drug resistance to first line drugs, artemisinin combination therapies (ACTs), indicates an urgent need for continuous molecular surveillance of drug resistance especially in high burden countries where drug interventions are heavily relied on. This study describes mutations in Plasmodium falciparum genes associated with drug resistance in malaria; Pfk13, Pfmdr1, PfATPase6 and Pfcrt in isolates obtained from 83 symptomatic malaria patients collected in August 2014, aged 1-61 years old from South-west Nigeria. RESULTS: Two Pfmdr1, N86 and Y184 variants were present at a prevalence of 56% and 13.25% of isolates respectively. There was one synonymous (S679S) and two non-synonymous (M699V, S769M) mutations in the PATPase6 gene, while Pfcrt genotype (CVIET), had a prevalence of 45%. The Pfk13 C580Y mutant allele was suspected by allelic discrimination in two samples with mixed genotypes although this could not be validated with independent isolation or additional methods. Our findings call for robust molecular surveillance of antimalarial drug resistance markers in west Africa especially with increased use of antimalarial drugs as prophylaxis for Covid-19.


Subject(s)
Artemether, Lumefantrine Drug Combination/therapeutic use , Calcium-Transporting ATPases/genetics , Malaria, Falciparum/drug therapy , Membrane Transport Proteins/genetics , Multidrug Resistance-Associated Proteins/genetics , Mutation , Plasmodium falciparum/drug effects , Protozoan Proteins/genetics , Adolescent , Adult , Antimalarials/therapeutic use , Artemisinins/therapeutic use , COVID-19 , Child , Child, Preschool , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Drug Resistance/genetics , Female , Gene Expression , Genotype , Humans , Infant , Malaria, Falciparum/epidemiology , Malaria, Falciparum/parasitology , Middle Aged , Molecular Epidemiology , Nigeria/epidemiology , Pandemics/prevention & control , Plasmodium falciparum/genetics , Plasmodium falciparum/growth & development , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control
6.
Curr Opin Pharmacol ; 54: 72-81, 2020 10.
Article in English | MEDLINE | ID: covidwho-778682

ABSTRACT

Kawasaki disease is an acute childhood self-limited vasculitis, causing the swelling or inflammation of medium-sized arteries, eventually leading to cardiovascular problems such as coronary artery aneurysms. Acetylsalicylic acid combined with intravenous immunoglobulin (IVIG) is the standard treatment of Kawasaki disease (KD). However, a rising number of IVIG resistant cases were reported with severe disease complications such as the KD Shock Syndrome or KD-Macrophage activation syndrome. Recent reports have depicted the overlapped number of children with SARS-CoV-2 and KD, which was called multisystem inflammatory syndrome. Simultaneously, the incidence rate of KD-like diseases are increased after the outbreak of COVID-19, suggesting the virus may be associated with KD. New intervention is important to overcome the problem of IVIG treatment resistance. This review aims to introduce the current pharmacological intervention and possible resistance genes for the discovery of new drug for IVIG resistant KD.


Subject(s)
Drug Resistance/genetics , Immunoglobulins, Intravenous/therapeutic use , Mucocutaneous Lymph Node Syndrome/drug therapy , Mucocutaneous Lymph Node Syndrome/genetics , COVID-19/epidemiology , COVID-19/genetics , COVID-19/virology , Comorbidity , Humans , Mucocutaneous Lymph Node Syndrome/epidemiology , Mucocutaneous Lymph Node Syndrome/virology , SARS-CoV-2/pathogenicity
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