In silico identification of potential inhibitors of acyl carrier protein reductase and acetyl CoA carboxylase of Plasmodium falciparum in antimalarial therapy

Malaria caused by Plasmodium falciparum, remains one of the most fatal parasitic diseases that has affected nearly a third of the world’s population. The major impediment to the treatment of malaria is the emergence of resistance of the P. falciparum parasite to current anti-malaria therapeutics such as Artemisinin (ART)-based combination therapy (ACT). This has resulted in countless efforts to develop novel therapeutics that will counter this resistance with the aim to control and eradicate the disease. The application of in silico modelling techniques has gained a lot of recognition in antimalarial research in recent times through the identification of biological components of the parasite for rational drug design. In this study we employed various in silico techniques such as the Virtual screening, molecular docking and molecular dynamic simulations to identify potential new inhibitors of biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase, two enzyme targets that play a crucial role in fatty acid synthesis in the Plasmodium parasite. Initially, nine hit compounds were identified for each of the two enzymes from the ZINCPharmer database. Subsequently, all hit compounds bind favourably to the active sites of the two enzymes as well as show excellent pharmacokinetic properties. Three 3) of the hits for the biotin acetyl-coenzyme A (CoA) carboxylase and six 6) of the enoyl-acyl carrier reductase showed good toxicity properties. The compounds were further evaluated based on the Molecular Dynamics simulation that confirmed the binding stability of the compounds to the targeted proteins. Overall, the lead compounds ZINC38980461, ZINC05378039, and ZINC15772056, were identified for acetyl-coenzyme A (CoA) carboxylase whiles ZINC94085628, ZINC93656835, ZINC94080670, ZINC1774609, ZINC94821232 and ZINC94919772 were identified as lead compounds for enoyl-acyl carrier reductase. The identified compounds can be developed as a treatment option for the malaria disease although, experimental validation is suggested for further evaluation of the work

Assessing the impact of differences in malaria transmission intensity on clinical and haematological indices in children with malaria.

BACKGROUND: Malaria control interventions have led to a decline in transmission intensity in many endemic areas, and resulted in elimination in some areas. This decline, however, will lead to delayed acquisition of protective immunity and thus impact disease manifestation and outcomes. Therefore, the variation in clinical and haematological parameters in children with malaria was assessed across three areas in Ghana with varying transmission intensities. METHODS: A total of 568 children between the ages of 2 and 14 years with confirmed malaria were recruited in hospitals in three areas with varying transmission intensities (Kintampo > Navrongo > Accra) and a comprehensive analysis of parasitological, clinical, haematological and socio-economic parameters was performed. RESULTS: Areas of lower malaria transmission tended to have lower disease severity in children with malaria, characterized by lower parasitaemias and higher haemoglobin levels. In addition, total white cell counts and percent lymphocytes decreased with decreasing transmission intensity. The heterozygous sickle haemoglobin genotype was protective against disease severity in Kintampo (P = 0.016), although this was not significant in Accra and Navrongo. Parasitaemia levels were not a significant predictor of haemoglobin level after controlling for age and gender. However, higher haemoglobin levels in children were associated with certain socioeconomic factors, such as having fathers who had any type of employment (P < 0.05) and mothers who were teachers (P < 0.05). CONCLUSIONS: The findings demonstrate significant differences in the haematological presentation and severity of malaria among areas with different transmission intensity in Ghana, indicating that these factors need to be considered in planning the management of the disease as the endemicity is expected to decline after control interventions

Comparison of genomic signatures of selection on Plasmodium falciparum between different regions of a country with high malaria endemicity.

BACKGROUND: Genome wide sequence analyses of malaria parasites from widely separated areas of the world have identified contrasting population structures and signatures of selection. To compare relatively closely situated but ecologically contrasting regions within an endemic African country, population samples of Plasmodium falciparum clinical isolates were collected in Ghana from Kintampo in the central forest-savannah area, and Navrongo in a drier savannah area ~350 km to the north with more seasonally-restricted transmission. Parasite DNA was sequenced and paired-end reads mapped to the P. falciparum reference genome. RESULTS: High coverage genome wide sequence data for 85 different clinical isolates enabled analysis of 121,712 single nucleotide polymorphisms (SNPs). The local populations had similar proportions of mixed genotype infections, similar SNP allele frequency distributions, and eleven chromosomal regions had elevated integrated haplotype scores (|iHS|) in both. A between-population Rsb metric comparing extended haplotype homozygosity indicated a stronger signal within Kintampo for one of these regions (on chromosome 14) and in Navrongo for two of these regions (on chromosomes 10 and 13). At least one gene in each of these identified regions is a potential target of locally varying selection. The candidates include genes involved in parasite development in mosquitoes, members of variant-expressed multigene families, and a leading vaccine-candidate target of immunity. CONCLUSIONS: Against a background of very similar population structure and selection signatures in the P. falciparum populations of Ghana, three narrow genomic regions showed evidence indicating local differences in historical timing or intensity of selection. Sampling of closely situated populations across heterogeneous environments has potential to refine the mapping of important loci under temporally or spatially varying selection

Predictors of fetal anemia and cord blood malaria parasitemia among newborns of HIV-positive mothers

Background: Malaria and HIV infections during pregnancy can individually or jointly unleash or confound pregnancy outcomes. Two of the probable outcomes are fetal anemia and cord blood malaria parasitemia. We determined clinical and demographic factors associated with fetal anemia and cord blood malaria parasitemia in newborns of HIV-positive women from two districts in Ghana. Results: We enrolled 1,154 antenatal attendees (443 HIV-positive and 711 HIV-negative) of which 66% were prospectively followed up at delivery. Maternal malaria parasitemia, and anemia rates among HIV+ participants at enrolment were 20.3% and 78.7% respectively, and 12.8% and 51.6% among HIV- participants. Multivariate linear and logistic regression models were used to study associations. Prevalence of fetal anemia (cord hemoglobin level < 12.5 g/dL) and cord parasitemia (presence of P. falciparum in cord blood at delivery) were 57.3% and 24.4% respectively. Factors found to be associated with fetal anemia were maternal malaria parasitemia and maternal anemia. Infant cord hemoglobin status at delivery was positively and significantly associated with maternal hemoglobin and gestational age whilst female gender of infant was negatively associated with cord hemoglobin status. Maternal malaria parasitemia status at recruitment and female gender of infant were positively associated with infant cord malaria parasitemia status. Conclusions: Our data show that newborns of women infected with HIV and/or malaria are at increased risk of anemia and also cord blood malaria parasitemia. Prevention of malaria infection during pregnancy may reduce the incidence of both adverse perinatal outcomes. © 2013 Laar et al.; licensee BioMed Central Ltd

Intrinsic multiplication rate variation and plasticity of human blood stage malaria parasites.

Pathogen multiplication rate is theoretically an important determinant of virulence, although often poorly understood and difficult to measure accurately. We show intrinsic asexual blood stage multiplication rate variation of the major human malaria parasite Plasmodium falciparum to be associated with blood-stage infection intensity in patients. A panel of clinical isolates from a highly endemic West African population was analysed repeatedly during five months of continuous laboratory culture, showing a range of exponential multiplication rates at all timepoints tested, mean rates increasing over time. All isolates had different genome sequences, many containing within-isolate diversity that decreased over time in culture, but increases in multiplication rates were not primarily attributable to genomic selection. New mutants, including premature stop codons emerging in a few isolates, did not attain sufficiently high frequencies to substantially affect overall multiplication rates. Significantly, multiplication rate variation among the isolates at each of the assayed culture timepoints robustly correlated with parasite levels seen in patients at clinical presentation, indicating innate parasite control of multiplication rate that contributes to virulence

James Abugri's Quick Files

The Quick Files feature was discontinued and it’s files were migrated into this Project on March 11, 2022. The file URL’s will still resolve properly, and the Quick Files logs are available in the Project’s Recent Activity

Ethical considerations for biobanking and use of genomics data in Africa: a narrative review

Abstract Background Biobanking and genomic research requires collection and storage of human tissue from study participants. From participants’ perspectives within the African context, this can be associated with fears and misgivings due to a myriad of factors including myths and mistrust of researchers. From the researchers angle ethical dilemmas may arise especially with consenting and sample reuse during storage. The aim of this paper was to explore these ethical considerations in the establishment and conduct of biobanking and genomic studies in Africa. Methods We conducted a narrative synthesis following a comprehensive search of nine (9) databases and grey literature. All primary research study designs were eligible for inclusion as well as both quantitative and qualitative evidence from peer reviewed journals, spanning a maximum of 20 years (2000–2020). It focused on research work conducted in Africa, even if data was stored or analysed outside the region. Results Of 2,663 title and abstracts screened, 94 full texts were retrieved and reviewed for eligibility. We included 12 studies (7 qualitative; 4 quantitative and one mixed methods). Ethical issues described in these papers related to community knowledge and understanding of biobanking and genomic research, regulation, and governance of same by research ethics committees, enrolment of participants, types of informed consents, data collection, storage, usage and sharing as well as material transfer, returning results and benefit sharing. ca. Biospecimen collection and storage is given in trust and participants expect confidentially of data and results generated. Most participants are comfortable with broad consent due to trust in researchers, though a few would like to be contacted for reconsenting in future studies, and this would depend on whether the new research is for good cause. Sharing data with external partners is welcome in some contexts but some research participants did not trust foreign researchers. Conclusion Biobanking and genomic studies are a real need in Africa. Linked to this are ethical considerations related to setting up and participation in biobanks as well as data storage, export, use and sharing. There is emerging or pre-existing consensus around the acceptability of broad consent as a suitable model of consent, the need for Africans to take the lead in international collaborative studies, with deliberate efforts to build capacity in local storage and analysis of samples and employ processes of sample collection and use that build trust of communities and potential study participants. Research ethics committees, researchers and communities need to work together to work together to adapt and use clearly defined ethical frameworks, guidelines, and policy documents to harmonize the establishment and running of biobanking and genomic research in Africa

Chemical Composition and Microbial Contaminants of Poha Beer: A Local Nonalcoholic Beverage in the Bolgatanga Municipality, Ghana

Microbial and physicochemical analysis was performed on randomly sampled Poha Beer manufactured and vended in the Bolgatanga Municipality, Ghana. Poha Beer as it is referred to in Dagbani, is a Tamarindus indica fruit extract, a local nonalcoholic beverage originally processed and sold by rural women of the Dagomba ethnic descend. Morphological examination of bacterial cultures, Gram staining, and biochemical confirmatory tests were used to detect the presence of microbial pathogens in 45 samples of Poha Beer. A refractometer, a flame photometer and an atomic absorption spectrometer were used for the elemental analysis. All Poha Beer samples obtained from the Bolgatanga Municipality were positive for yeast, E. coli, Enterobacter sp. and Bacillus cereus. Pb was not detected in any of the samples. Chemical components detected include Zn2+ (average, 0.154 mg/L), Cd2+ (0.056 mg/L), Na+ (1.723 mg/L), Ca2+ (2.262 mg/L) and K+ (3.96 mg/L). All samples were acidic with an average pH value of 3.55. The Brix value of samples, however, was between 9.0 and 11.4 % per 40 mL of Poha Beer. Therefore, Poha Beer processed and sold in the Bolgatanga Municipality is acidic and contains detrimental amounts of Cd2+ and bacterial pathogens which may render it unwholesome for human consumption

Analysis of Erythrocyte Invasion Mechanisms of Plasmodium falciparum Clinical Isolates Across 3 Malaria-Endemic Areas in Ghana.

BACKGROUND: Plasmodium falciparum invades human erythrocytes by using an array of ligands that interact with several receptors, including sialic acid (SA), complement receptor 1 (CR1), and basigin. We hypothesized that in malaria-endemic areas, parasites vary invasion pathways under immune pressure. Therefore, invasion mechanisms of clinical isolates collected from 3 zones of Ghana with different levels of endemicity (from lowest to highest, Accra, Navrongo, and Kintampo) were compared using standardized methods. METHODS: Blood samples were collected from children aged 2-14 years in whom malaria was diagnosed, and erythrocyte invasion phenotypes were determined using the enzymes neuraminidase, chymotrypsin, and trypsin, which differentially cleave receptors from the erythrocyte surface. In addition, antibodies against CR1 and basigin were used to determine the contributions of these receptors to invasion. Gene expression levels of P. falciparum invasion ligands were also examined. RESULTS: The parasites generally expressed SA-independent invasion phenotypes across the malaria-endemic areas, with parasites from Kintampo showing the highest invasion rates in neuraminidase-treated erythrocytes. CR1 was a major mediator of SA-independent invasion, while basigin was essential for both SA-dependent and SA-independent invasion mechanisms. Furthermore, expression of the basigin ligand PfRh5 was the best predictor of donor parasitemia. CONCLUSIONS: Erythrocyte invasion phenotypes expressed by P. falciparum are influenced by endemicity levels, and the PfRh5-basigin pathway is a potential vaccine target