Structure-based design, and development of amidinyl, amidoximyl and hydroxamic acid based organic molecules as novel antimalarial drug candidates.

Malaria remains a significant global health concern causing numerous fatalities and the emergence of antimalarial drug resistance highlights the urgent need for novel therapeutic options with innovative mechanisms of action and targets. This study aimed to design potential inhibitors of Plasmodium falciparum 6-pyruvoyltetrahydropterin synthase (PfPTPS), synthesize them, and experimentally validate their efficacy as antimalarial agents. A structure-based approach was employed to design a series of novel derivatives, including amidinyl, amidoximyl and hydroxamic acid analogs (1c, 1d, 2b, and 3b), with a focus on their ability to bind to the Zn2+ present in the active site of PfPTPS. The syntheses of these compounds were accomplished through various multi-step synthetic pathways and their structural identities were confirmed using 1H and 13C NMR spectra, mass spectra, and elemental analysis. The compounds were screened for their antiplasmodial activity against the NF54 strain of P. falciparum and in vitro cytotoxicity testing was performed using L-6 cells. The in vivo acute toxicity of the compounds was evaluated in mice. Docking studies of the compounds with the 3D structure of PfPTPS revealed their strong binding affinities, with compound 3b exhibiting notable metal-acceptor interaction with the Zn2+ in the protein binding pocket thereby positioning it as a lead compound for PfPTPS inhibition. The in vitro antiplasmodial studies revealed moderate efficacies against the Pf NF54 strain, particularly compounds 1d and 3b which displayed IC50 < 0.2 µM. No significant cytotoxicity was noted on the L-6 rat cell line. Moreover, in vivo studies suggested that compound 3b exhibited both safety and efficacy in treating rodent malaria. The identified lead compound in this study represents a possible candidate for antimalarial drug development and can be further explored in the search for alternative antifolate drugs to combat the malaria menace.

Screening, isolation and biotechnological potentials of foodborne Lactobacillus fermentum strains MT903311 and MT903312.

Vitamins are an essential food source with excellent roles in the cellular metabolism and other essential nutrients required in food intake but cannot be synthesized by humans. There have been reports of some lactic acid bacteria (LAB) abilities with probiotic activities to produce food-grade vitamins. Our study aimed to investigate lactic acid bacteria (LAB) possessing antimicrobial activities and extracellular production of folate from different Nigerian fermented foods. LAB was assayed for their antimicrobial activities against clinical isolates of Escherichia coli and Salmonella typhimurium and their extracellular production of essential vitamins. Among the 43 isolates of LAB, two strains of Lactobacillus fermentum showed the highest inhibitions against the test bacteria and demonstrated the highest concentrations of extracellular vitamins production. The range of vitamins produced at 24 h was between 12.23 and 801.79 µg/ml, while the highest vitamin production of 801.79 and 310.55 µg/ml was observed for folate and vitamin B12 respectively, the lowest production was for B1+B2. Consistent vitamin production was typical with only L. fermentum MT903311 and L. fermentum MT903312, so were their antimicrobial activities. The L. fermentum strains isolated in this study could be exploited and applied in food products to substitute synthetic vitamin enrichment and fortification.

Evaluation of Efflux-Mediated Resistance and Biofilm formation in Virulent Pseudomonas aeruginosa Associated with Healthcare Infections.

Pseudomonas aeruginosa is a significant pathogen identified with healthcare-associated infections. The present study evaluates the role of biofilm and efflux pump activities in influencing high-level resistance in virulent P. aeruginosa strains in clinical infection. Phenotypic resistance in biotyped Pseudomonas aeruginosa (n = 147) from diagnosed disease conditions was classified based on multiple antibiotic resistance (MAR) indices and analysed with logistic regression for risk factors. Efflux pump activity, biofilm formation, and virulence factors were analysed for optimal association in Pseudomonas infection using receiver operation characteristics (ROC). Age-specificity (OR [CI] = 0.986 [0.946-1.027]), gender (OR [CI] = 1.44 [0.211-9.827]) and infection sources (OR [CI] = 0.860 [0.438-1.688]) were risk variables for multidrug resistance (MDR)-P. aeruginosa infection (p < 0.05). Biofilm formers caused 48.2% and 18.5% otorrhea and wound infections (95% CI = 0.820-1.032; p = 0.001) respectively and more than 30% multidrug resistance (MDR) strains demonstrated high-level efflux pump activity (95% CI = 0.762-1.016; p = 0.001), protease (95% CI = 0.112-0.480; p = 0.003), lipase (95% CI = 0.143-0.523; p = 0.001), and hemolysin (95% CI = 1.109-1.780; p = 0.001). Resistance relatedness of more than 80% and 60% to cell wall biosynthesis inhibitors (ceftazidime, ceffproxil, augumentin, ampicillin) and, DNA translational and transcriptional inhibitors (gentamicin, ciprofloxacin, ofloxacin, nitrofurantoin) were observed (p < 0.05). Strong efflux correlation (r = 0.85, p = 0.034) with MDR strains, with high predictive performances in efflux pump activity (ROC-AUC 0.78), biofilm formation (ROC-AUC 0.520), and virulence hierarchical-clustering. Combine activities of the expressed efflux pump and biofilm formation in MDR-P. aeruginosa pose risk to clinical management and infection control.

The Human Microbiome and Its Impacts on Health.

The human microbiome comprises bacteria, archaea, viruses, and eukaryotes which reside within and outside our bodies. These organisms impact human physiology, both in health and in disease, contributing to the enhancement or impairment of metabolic and immune functions. Micro-organisms colonise various sites on and in the human body, where they adapt to specific features of each niche. Facultative anaerobes are more dominant in the gastrointestinal tract, whereas strict aerobes inhabit the respiratory tract, nasal cavity, and skin surface. The indigenous organisms in the human body are well adapted to the immune system, due to the biological interaction of the organisms with the immune system over time. An alteration in the intestinal microbial community plays a major role in human health and disease pathogenesis. These alterations result from lifestyle and the presence of an underlying disease. Dysbiosis increases host susceptibility to infection, and the nature of which depends on the anatomical site involved. The unique diversity of the human microbiota accounts for the specific metabolic activities and functions of these micro-organisms within each body site. It is therefore important to understand the microbial composition and activities of the human microbiome as they contribute to health and disease.

Data set on Rapid Diagnostic Tests (RDTs) and microscopy for diagnosing plasmodium falciparum and plasmodium vivax.

The World Heal Organization (WHO) has identified malaria diagnosis as being pivotal to eradicating the disease by 2030 as stipulated in the Sustainable Development Goals (SDG). The data presented here was obtained from outpatients of a hospital in the South Western Region of Nigeria from November 2016 to May 2017. The data contains malaria incidence amongst asymptomatic and symptomatic outpatients in the period under review. Malaria incidence was obtained using two diagnostic test kits, Bioline SD (HRP-2) and ACON (HRP-2/Aldolase) alongside Microscopy as gold standard. Specificity, Sensitivity and Kappa statistic of each test device is presented in the tables herewith. Data presented here could be used alongside other data sources to assess the state of malaria diagnostics.

In vitro studies on the sensitivity pattern of Plasmodium falciparum to anti-malarial drugs and local herbal extracts.

BACKGROUND: The resistance of human malaria parasites to anti-malarial compounds has become considerable concern, particularly in view of the shortage of novel classes of anti-malarial drugs. One way to prevent resistance is by using new compounds that are not based on existing synthetic antimicrobial agents. RESULTS: Sensitivity of 100 Plasmodium falciparum isolates to chloroquine, quinine, amodiaquine, mefloquine, sulphadoxine/pyrimethamine, artemisinin, Momordica charantia ('Ejirin') Diospyros monbuttensis ('Egun eja') and Morinda lucida ('Oruwo') was determined using the in vitro microtest (Mark III) technique to determine the IC50 of the drugs. All the isolates tested were sensitive to quinine, mefloquine and artesunate. Fifty-one percent of the isolates were resistant to chloroquine, 13% to amodiaquine and 5% to sulphadoxine/pyrimethamine. Highest resistance to chloroquine (68.9%) was recorded among isolates from Yewa zone while highest resistance to amodiaquine (30%) was observed in Ijebu zone. Highest resistance to sulphadoxine/pyrimethamine was recorded in Yewa and Egba zones, respectively. A positive correlation was observed between the responses to artemisinin and mefloquine (P<0.05), artemisinin and quinine (P<0.05) and quinine and mefloquine (P<0.05). A negative correlation was observed between the responses to chloroquine and mefloquine (P>0.05). Highest anti-plasmodial activity was obtained with the ethanolic extract of D. monbuttensis (IC50 = 3.2 nM) while the lowest was obtained from M. lucida (IC50 = 25 nM). CONCLUSIONS: Natural products isolated from plants used in traditional medicine, which have potent anti-plasmodial action in vitro, represent potential sources of new anti-malarial drugs.