Biology subjects

Olubiyi, O. O.

Publications and source records attributed to Olubiyi, O. O..

3 recordsLinked to original sources

bioRxiv2021

Antibiofilm agents with therapeutic potential against enteroaggregative Escherichia coli

BackgroundEnteroaggregative Escherichia coli (EAEC) is a predominant but neglected enteric pathogen implicated in infantile diarrhoea and nutrient malabsorption. There are no non-antibiotic approaches to dealing with persistent infection by these exceptional colonizers, which form copious biofilms. We screened the Medicines for Malaria Venture Pathogen Box for chemical entities that inhibit EAEC biofilm formation. MethodologyWe used two EAEC strains, 042 and MND005E, in a medium-throughput crystal violet-based antibiofilm screen. Hits were confirmed in concentration-dependence, growth kinetic and time course assays and activity spectra were determined against a panel of genome-sequenced EAEC. Antibiofilm activity against isogenic EAEC mutants, molecular docking simulations and comparative genomic analysis were used to identify the mechanism of action of one hit. Principal findingsIn all, five compounds (1.25%) reproducibly inhibited biofilm accumulation by at least one strain by 30-85% while inhibiting growth by under 10%. Hits exhibited at least 10-fold greater antibiofilm activity than nitazoxanide, the only known EAEC biofilm inhibitor. Reflective of known EAEC heterogeneity, only one hit was active against both screen isolates, but three hits showed broad antibiofilm activity against a larger panel of strains. Mechanism of action studies point to the EAEC anti-aggregation protein (Aap), dispersin, as the target of compound MMV687800. ConclusionsThis study identified five compounds not previously described as anti-adhesins or Gram-negative antibacterials with significant and specific EAEC antibiofilm activity. One molecule, MMV687800, targets the EAEC Aap. In vitro small-molecule inhibition of EAEC colonization opens a way to new therapeutic approaches to preventing and treating EAEC infection. Author summaryDiarrhoea accounts for over half a million deaths in children under five annually. It additionally contributes to childhood malnutrition as well as growth and development deficiencies, particularly in low-income countries. Enteroaggregative Escherichia coli (EAEC) causes diarrhoea that is often persistent and can also contribute to growth deficiencies in young children. EAEC is a neglected pathogen that is often resistant to antimicrobial drugs. Small molecules that block EAEC colonization may hold the key to interfering with EAEC disease without promoting antimicrobial resistance. We screened the Medicines for Malaria Ventures Pathogen Box for chemicals that can interfere with EAEC biofilm formation, a key colonization indicator. Our screen identified five biofilm-inhibiting molecules that did not interfere with bacterial viability and therefore are unlikely to exert strong pressure for resistance. Molecular biology and computational investigations point to the EAEC anti-aggregative protein, also known as dispersin, as a possible target for one of these hit molecules. Optimizing EAEC antibiofilm hits will create templates that can be employed for resolving EAEC diarrhoea and related infections.

microbiology↗

bioRxiv2021

Hoslundia opposita and other Nigerian plants inhibit sickle hemoglobin polymerization and prevent erythrocyte sickling: a virtual screening-guided identification of bioactive plants.

In sickle cell disease, a hereditary hemoglobinopathy, clinically observed disease presentations are the endpoint of a point mutation involving the substitution of glutamic acid with valine at the position 6 of the beta globin chain. With about 4.4 million people globally being affected, and another 43 million people bearing the sickle cell trait, several research efforts have been made to discover new and affordable treatment and possibly cure for the disease. Africa is endowed with a large flora population and traditional healers and citizens have over time depended on the use of herbs in folkloric medicine for different ailments including sickle cell disease (SCD). Such native knowledge has often formed the basis for different research exploration into the anti-sickling activities of selected African plants. These plants that have been so far investigated for their anti-sickling properties represent about 0.05 % of the 45,000 plant species enriching the flora landscape in Sub-Saharan Africa. Some of these have yielded potent anti-sickling profiles. In the current work we seek to achieve a more extensive search of the African plant diversity with anti-sickling properties: for this we have adopted a hybrid computational-cum-experimental protocol that employed computer-aided drug design (CADD) means for identifying plants with at least one constituent capable of interacting with the sickle hemoglobin, followed by extractive procedures and anti-sickling experiments for validating the predictions. Over two thousand (or 2,000) African natural products, representing over 200 plant species, were first virtually screened against the crystal structure of the dimerized human sickle hemoglobin. The natural products with the best computed sickle hemoglobin interaction energetics were found to belong to five plant species including Catharanthus roseus, Rauvolfia vomitoria, Hoslundia opposita, Lantana camara and Euphorbia hirta. The leaves of these plants were each collected subsequently and subjected to standard processing and extraction procedures. Using both HbSS polymerization inhibition and sickling reversal tests significant reductions in polymerization of erythrocyte hemolysate of the HbSS genotype were observed with the methanolic extracts of the plants, as well as sickling reversal levels of up to 68.50 % (H. opposita) was observed.

bioinformatics↗

bioRxiv2020

IN SILICO SCREENING AND MOLECULAR DYNAMIC SIMULATION STUDIES OF POTENTIAL SMALL MOLECULE IMMUNOMODULATORS OF THE KIR2DS2 RECEPTOR

The World Health Organization reports that cancer is one of the most common causes of death worldwide and it accounted for an estimated 9.6 million deaths in 2018. As compared with chemotherapy or radiotherapy, immunotherapy offers a safer, less stressful and selective strategy in the destruction of cancer cells. The killer cell immunoglobulin-like receptor 2DS2 (KIR2DS2) expressed on Natural Killer (NK) cells are involved in signal transduction processes that produce pro-inflammatory cytokines and directly destroy cancer and virally infected cells. The aim of this study is to identify small molecules from natural products that have strong binding affinity with KIR2DS2 and possible bioactivity. A library of small molecule natural compounds obtained from edible African plants was used for in Silico molecular docking simulations of KIR2DS2 (PDBID: 1m4k) using Pyrx. An arbitrary docking score [≥] -7.0 kcal/mol was chosen as cut off value. Screening for drug-likeness and ligand efficiency was based on the molecular descriptors of the compounds as provided by Pubchem. Further screening for saturation, molar refractivity, promiscuity, pharmacokinetic properties, and bioactivity was done using SWISSADME, PKCSM, and Molinspiration respectively. The molecular dynamic simulation and analyses was done using the Galaxy webserver which uses the GROMACS software. Analyses of molecular dynamic simulation were done using Galaxy and MDWEB webservers. Gibberellin A20 and A29 were obtained as the lead compounds and they show better promise as drug candidates for KIR2DS2 than the standard. It is recommended that the immuno-stimulatory effect of the lead compounds on KIR2DS2 be further investigated.

bioinformatics↗