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The Journal of Antimicrobial... Jul 2021To evaluate Plasmodium malariae susceptibility to current and lead candidate antimalarial drugs.
OBJECTIVES
To evaluate Plasmodium malariae susceptibility to current and lead candidate antimalarial drugs.
METHODS
We conducted cross-sectional screening and detection of all Plasmodium species malaria cases, which were nested within a longitudinal prospective study, and an ex vivo assessment of efficacy of a panel of antimalarials against P. malariae and Plasmodium falciparum, both PCR-confirmed mono-infections. Reference compounds tested included chloroquine, lumefantrine, artemether and piperaquine, while candidate antimalarials included the imidazolopiperazine GNF179, a close analogue of KAF156, and the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691.
RESULTS
We report a high frequency (3%-15%) of P. malariae infections with a significant reduction in ex vivo susceptibility to chloroquine, lumefantrine and artemether, which are the current frontline drugs against P. malariae infections. Unlike these compounds, potent inhibition of P. malariae and P. falciparum was observed with piperaquine exposure. Furthermore, we evaluated advanced lead antimalarial compounds. In this regard, we identified strong inhibition of P. malariae using GNF179, a close analogue of KAF156 imidazolopiperazines, which is a novel class of antimalarial drug currently in clinical Phase IIb testing. Finally, in addition to GNF179, we demonstrated that the Plasmodium PI4K-specific inhibitor KDU691 is highly inhibitory against P. malariae and P. falciparum.
CONCLUSIONS
Our data indicated that chloroquine, lumefantrine and artemether may not be suitable for the treatment of P. malariae infections and the potential of piperaquine, as well as new antimalarials imidazolopiperazines and PI4K-specific inhibitor, for P. malariae cure.
Topics: Antimalarials; Artemisinins; Cross-Sectional Studies; Humans; Malaria, Falciparum; Mali; Plasmodium falciparum; Plasmodium malariae; Prospective Studies
PubMed: 34021751
DOI: 10.1093/jac/dkab133 -
Annual Review of Microbiology Sep 2020African apes harbor at least twelve species, some of which have been a source of human infection. It is now well established that emerged following the transmission of... (Review)
Review
African apes harbor at least twelve species, some of which have been a source of human infection. It is now well established that emerged following the transmission of a gorilla parasite, perhaps within the last 10,000 years, while emerged earlier from a parasite lineage that infected humans and apes in Africa before the Duffy-negative mutation eliminated the parasite from humans there. Compared to their ape relatives, both human parasites have greatly reduced genetic diversity and an excess of nonsynonymous mutations, consistent with severe genetic bottlenecks followed by rapid population expansion. A putative new species widespread in chimpanzees, gorillas, and bonobos places the origin of in Africa. Here, we review what is known about the origins and evolutionary history of all human-infective species, the time and circumstances of their emergence, and the diversity, host specificity, and zoonotic potential of their ape counterparts.
Topics: Animals; DNA, Protozoan; Evolution, Molecular; Genetic Variation; Gorilla gorilla; Hominidae; Humans; Malaria; Pan troglodytes; Phylogeny; Plasmodium; Plasmodium falciparum; Zoonoses
PubMed: 32905751
DOI: 10.1146/annurev-micro-020518-115628 -
Critical Reviews in Microbiology Feb 2021is often reported as a benign malaria parasite. There are limited data on its biology and disease burden in sub-Saharan Africa (sSA) possibly due to the unavailability... (Review)
Review
is often reported as a benign malaria parasite. There are limited data on its biology and disease burden in sub-Saharan Africa (sSA) possibly due to the unavailability of specific and affordable tools for routine diagnosis and large epidemiology studies. In addition, occurs at low parasite densities and in co-infections with other species, predominately . The paucity of data on infections limits the capacity to accurately determine its contribution to malaria and the effect of control interventions against on its prevalence. Here, we summarise the current knowledge on epidemiology in sSA - overall prevalence ranging from 0-32%, as detected by different diagnostic methods; seroprevalence ranging from 0-56% in three countries (Mozambique, Benin and Zimbabwe), and explore the future application of next-generation sequencing technologies as a tool for enriching genomic epidemiology. This will provide insights into important adaptive mechanisms of this neglected non-falciparum species, including antimalarial drug resistance, local and regional parasite transmission patterns and genomic signatures of selection. Improved diagnosis and genomic surveillance of non-falciparum malaria parasites in Africa would be helpful in evaluating progress towards elimination of all human species.
Topics: Africa; Animals; Antibodies, Protozoan; Biomedical Research; Humans; Malaria; Neglected Diseases; Plasmodium malariae
PubMed: 33507842
DOI: 10.1080/1040841X.2020.1838440 -
The Journal of Infectious Diseases Mar 2020
Topics: Humans; Malaria; Plasmodium malariae; Plasmodium ovale
PubMed: 30855671
DOI: 10.1093/infdis/jiz103 -
Frontiers in Microbiology 2022Malaria elimination includes neglected human malaria parasites spp., and . Biological features such as association with low-density infection and the formation of... (Review)
Review
Malaria elimination includes neglected human malaria parasites spp., and . Biological features such as association with low-density infection and the formation of hypnozoites responsible for relapse make their elimination challenging. Studies on these parasites rely primarily on clinical samples due to the lack of long-term culture techniques. With improved methods to enrich parasite DNA from clinical samples, whole-genome sequencing of the neglected malaria parasites has gained increasing popularity. Population genomics of more than 2200 global isolates has improved our knowledge of parasite biology and host-parasite interactions, identified vaccine targets and potential drug resistance markers, and provided a new way to track parasite migration and introduction and monitor the evolutionary response of local populations to elimination efforts. Here, we review advances in population genomics for neglected malaria parasites, discuss how the rich genomic information is being used to understand parasite biology and epidemiology, and explore opportunities for the applications of malaria genomic data in malaria elimination practice.
PubMed: 36160257
DOI: 10.3389/fmicb.2022.984394 -
Current Pediatric Reviews 2023The fifth malaria parasite causing malaria- Plasmodium knowlesi (Pk), is not a novel emergent species but was an undiagnosed species before the availability of molecular... (Review)
Review
The fifth malaria parasite causing malaria- Plasmodium knowlesi (Pk), is not a novel emergent species but was an undiagnosed species before the availability of molecular methods as a tool from diagnostics and sometimes confused with morphologically similar human malaria parasite P. malariae or P. falciparum. Now it is well-distributed species in Southeast Asia, especially in Malaysia. Since 2004, cases of Pk malaria are continuously being reported in adults. Though adult age, forest-related activities and a recent visit to forested areas are well-known factors, childhood did not remain untouched by this disease. Few pieces of research and reports in the literature indicate that Infection in children is uncomplicated, but this may be attributed to the scarcity of data and research in this field. Pk malaria in pregnant females and infants are being well reported, so this indicates that the problem is not only restricted to known factors related to the disease, but we should think out of the box and take action before the disease takes the form of significant health burden on the human population as P. vivax and P. falciparum species did in the past. With the reports in literature of Pk malaria in pregnancy and early infancy, the possibility of congenital and neonatal malaria also cannot be denied. So more and more research is needed to understand Pk malaria in the pediatric population clearly. So this running review covers the problem status, demographic profile, clinical and haematological features, diagnosis, management and outcome of Pk malaria in paediatric group worldwide. This review also discusses the gaps in our present knowledge of the real problem status, prevention, control, diagnosis and management of Pk malaria, particularly in this age group.
Topics: Adult; Infant; Infant, Newborn; Pregnancy; Female; Child; Humans; Malaria; Malaysia; Asia, Southeastern; Plasmodium knowlesi
PubMed: 35366778
DOI: 10.2174/1573396318666220401110835 -
Microorganisms Jan 2022Cysteine proteases belonging to the falcipain (FP) family play a pivotal role in the biology of malaria parasites and have been extensively investigated as potential...
Cysteine proteases belonging to the falcipain (FP) family play a pivotal role in the biology of malaria parasites and have been extensively investigated as potential antimalarial drug targets. Three paralogous FP-family cysteine proteases of , termed malapains 2-4 (MP2-4), were identified in PlasmoDB. The three MPs share similar structural properties with the FP-2/FP-3 subfamily enzymes and exhibit a close phylogenetic lineage with vivapains (VXs) and knowpains (KPs), FP orthologues of and . Recombinant MP-2 and MP-4 were produced in a bacterial expression system, and their biochemical properties were characterized. Both recombinant MP-2 and MP-4 showed enzyme activity across a broad range of pH values with an optimum activity at pH 5.0 and relative stability at neutral pHs. Similar to the FP-2/FP-3 subfamily enzymes in other species, recombinant MP-2 and MP-4 effectively hydrolyzed hemoglobin at acidic pHs. They also degraded erythrocyte cytoskeletal proteins, such as spectrin and band 3, at a neutral pH. These results imply that MP-2 and MP-4 are redundant hemoglobinases of and may also participate in merozoite egression by degrading erythrocyte cytoskeletal proteins. However, compared with other FP-2/FP-3 enzymes, MP-2 showed a strong preference for arginine at the P2 position. Meanwhile, MP-4 showed a primary preference for leucine at the P2 position but a partial preference for phenylalanine. These different substrate preferences of MPs underscore careful consideration in the design of optimized inhibitors targeting the FP-family cysteine proteases of human malaria parasites.
PubMed: 35056641
DOI: 10.3390/microorganisms10010193 -
The Journal of Infectious Diseases Apr 2024
Topics: Humans; Plasmodium ovale; Plasmodium malariae; Malaria; Plasmodium
PubMed: 38243611
DOI: 10.1093/infdis/jiae015 -
Trends in Parasitology Feb 2023Plasmodium malariae is a 'neglected malaria parasite' in as much as the amount of research conducted on it pales into insignificance when compared to that pertaining to... (Review)
Review
Plasmodium malariae is a 'neglected malaria parasite' in as much as the amount of research conducted on it pales into insignificance when compared to that pertaining to Plasmodium falciparum and Plasmodium vivax, its more notorious and pathogenic cousins. There has, however, been an increase in interest in this parasite over the past decade. Principally, this is because of the increasing use of sensitive molecular detection techniques that have revealed a wider than previously recorded prevalence in some regions (particularly in Africa), and high numbers of chronic, asymptomatic infections.
Topics: Animals; Humans; Malaria; Parasites; Plasmodium malariae; Plasmodium falciparum; Plasmodium vivax
PubMed: 36517330
DOI: 10.1016/j.pt.2022.11.008