Figure - available from: Bioinformatics and Biology Insights
This content is subject to copyright.
Source publication
Diarrhoeal disease kills about 1.5 million human beings per year across the continents. The enterotoxigenic Escherichia coli (ETEC) pathotype has been noted as a major cause of diarrheal disease in human and livestock. The aim of this study is to identify broad-spectrum molecular targets in bacteria and broad-spectrum lead compounds (functional inh...
Citations
... Moreover, it also improving the DNA translation, RNA transcription, protein replication, and controlling cell proliferation [62]. Secondly, a multi-subunits enzyme, DNA polymerase III (Pol III) responsible for the replication of bacterial genome, with actual DNA synthesis, carried out by Pol III α subunit [63]. While putative deacetylase BC1534 protein of B. cereus is an enzyme which exhibits deacetylase activity with the N-acetyl moiety of the N-acetylglucosamine, diacetylchitobiose, and triacetylchitotriose [64]. ...
... While putative deacetylase BC1534 protein of B. cereus is an enzyme which exhibits deacetylase activity with the N-acetyl moiety of the N-acetylglucosamine, diacetylchitobiose, and triacetylchitotriose [64]. Since these selected enzymes are pivotal for bacterial survival, these are as the key targets of antibacterial agents [62,63]. Oleandomycin being macrolide antibiotic inhibits protein synthesis by binding to the 50s subunit of ribosome by interfering with translocation of amino acids to protein synthesis machinery during translation. ...
Lactic acid bacteria are known to produce numerous antibacterial metabolites that are active against various pathogenic microbes. In this study, bioactive metabolites from the cell free supernatant of Loigolactobacillus coryniformis BCH-4 were obtained by liquid-liquid extraction, using ethyl acetate, followed by fractionation, using silica gel column chromatography. The collected F23 fraction effectively inhibited the growth of pathogenic bacteria (Escherichia coli, Bacillus cereus, and Staphylococcus aureus) by observing the minimum inhibitory concentration (MIC) and minimum bactericidal concentrations (MBC). The evaluated values of MIC were 15.6 ± 0.34, 3.9 ± 0.59, and 31.2 ± 0.67 μg/mL and MBC were 15.6 ± 0.98, 7.8 ± 0.45, and 62.5 ± 0.23 μg/mL respectively, against the above-mentioned pathogenic bacteria. The concentration of F23 fraction was varying from 1000 to 1.9 μg/mL. Furthermore, the fraction also exhibited sustainable biofilm inhibition. Using the Electrospray Ionization Mass Spectrometry (ESI-MS/MS), the metabolites present in the bioactive fraction (F23), were identified as phthalic acid, myristic acid, mangiferin, 16-hydroxylpalmatic acid, apigenin, and oleandomycin. By using in silico approach, docking analysis showed good interaction of identified metabolites and receptor proteins of pathogenic bacteria. The present study suggested Loigolactobacillus coryniformis BCH-4, as a promising source of natural bioactive metabolites which may receive great benefit as potential sources of drugs in the pharmacological sector.
... which is active against gametocytes as well as recalcitrant parasitic forms of malaria, and therefore useful for preventing vivax and ovale relapse [70]. None of these four compounds has any previously documented antibacterial activity (in vivo or in vitro) against Gram negative bacteria, however, Ugboko et al (2019) in an in silico screen and analysis of broad-spectrum molecular targets and lead compounds for potential anti-diarrhoea agents reported MMV687800 as one of the compounds with predicted activity against potential targets for diarrhoea disease among twenty five other compounds [71]. Low et al (2017) in a screen to identify TB active compounds against nontuberculous Mycobacterium additionally retrieved MMV687800 as an M. avium-specific main hits among five other MMV compounds [72] and Hennessey et al (2018) also reported MMV687800 among seven MMV compounds as an inhibitor with dual efficacy against Giardia lamblia and Cryptosporidium parvum in a pathogen box screen [73]. ...
... which is active against gametocytes as well as recalcitrant parasitic forms of malaria, and therefore useful for preventing vivax and ovale relapse [70]. None of these four compounds has any previously documented antibacterial activity (in vivo or in vitro) against Gram negative bacteria, however, Ugboko et al (2019) in an in silico screen and analysis of broad-spectrum molecular targets and lead compounds for potential anti-diarrhoea agents reported MMV687800 as one of the compounds with predicted activity against potential targets for diarrhoea disease among twenty five other compounds [71]. Low et al (2017) in a screen to identify TB active compounds against nontuberculous Mycobacterium additionally retrieved MMV687800 as an M. avium-specific main hits among five other MMV compounds [72] and Hennessey et al (2018) also reported MMV687800 among seven MMV compounds as an inhibitor with dual efficacy against Giardia lamblia and Cryptosporidium parvum in a pathogen box screen [73]. ...
Background
Enteroaggregative 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.
Methodology
We used 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 25 other EAEC strains. 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 findings
In 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 potent antibiofilm activity at concentrations at least 10-fold lower than those reported for 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.
Conclusions
This study identified five compounds, not previously described as anti-adhesins or Gram-negative antibacterials, with significant EAEC antibiofilm activity. Molecule, MMV687800 targets the EAEC Aap. In vitro small-molecule inhibition of EAEC colonization opens a way to new therapeutic approaches against EAEC infection.
... which is active against gametocytes as well as 460 recalcitrant parasitic forms of malaria, and therefore useful for preventing vivax and ovale 461 relapse [70]. None of these four compounds has any previously documented antibacterial 462 activity (in vivo or in vitro) against Gram negative bacteria, however, Ugboko et al (2019) in 463 an in silico screen and analysis of broad-spectrum molecular targets and lead compounds for 464 potential anti-diarrhoea agents reported MMV687800 as one of the compounds with 465 predicted activity against potential targets for diarrhoea disease among twenty five other 466 compounds [71]. Low et al (2017) in screen to identify TB active compounds against 467 nontuberculous Mycobacterium additionally retrieved MMV687800 as an M. avium-specific 468 (which was not certified by peer review) is the author/funder. ...
... which is active against gametocytes as well as 460 recalcitrant parasitic forms of malaria, and therefore useful for preventing vivax and ovale 461 relapse [70]. None of these four compounds has any previously documented antibacterial 462 activity (in vivo or in vitro) against Gram negative bacteria, however, Ugboko et al (2019) in 463 an in silico screen and analysis of broad-spectrum molecular targets and lead compounds for 464 potential anti-diarrhoea agents reported MMV687800 as one of the compounds with 465 predicted activity against potential targets for diarrhoea disease among twenty five other 466 compounds [71]. Low et al (2017) in screen to identify TB active compounds against 467 nontuberculous Mycobacterium additionally retrieved MMV687800 as an M. avium-specific 468 (which was not certified by peer review) is the author/funder. ...
Background
Enteroaggregative 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.
Methodology
We 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 findings
In 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.
Conclusions
This 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 summary
Diarrhoea 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.
... The human body serves as a host to billions of microorganisms (bacteria, viruses, fungi, and protozoa) with a large functional diversity that surpasses the human gene pool, which can bring health outcome Diarrhoea, a gastrointestinal disease which has been consistently caused over one million childhood mortality per year worldwide (Ugboko et al., 2019). The occurrence of childhood mortality in developing countries due to diarrhoea disease is between 9%-34% (WHO, 2015). ...
... Enterotoxigenic Escherichia coli (ETEC) remains a major cause of diarrhoea-associated mortality and morbidity of infants, young adults and adults in endemic areas (Lamberti et al., 2014). Bioinformatics and metagenomic studies of diarrhoea have reported the presence of E. coli, C. jejuni, Clostridium di cile, Helicobacter pylori, Salmonella typhi, Shigella exneri and Vibrio cholera (Loman et al., 2013;Ugboko et al., 2019), while existing viruses can serve as causative agents of diarrhoea, such as noroviruses, rotaviruses, astroviruses, sapovirus, and enteric adenoviruses (Dycke et al., 2018). Chronic diarrhea is often a critical problem for patients infected with the human immunode ciency virus (HIV), where it decreases response to antiretroviral therapy and quality of life in general (Old eld, 2002). ...
In this study, 16S rRNA of diarrhoea microbial cluster was investigated computationally. The phylogeny, two-and three-dimensional structures, molecular docking and dynamics simulations were carried out. The result showed that Escherichia coli, Campylobacter jejuni, Campylobacter upsaliensis, Streptococcus lutetiensis 033, Streptococcus infantarius, Enterococcus ratti, Helicobacter sp. 'feline isolate, Helicobacter canadensis, Anaerobiospirillum sp. B0101, Anaerobiospirillum sp. 3J102 as well as uncultured bacterium (Prevotella) and unidenti ed bacterium (Lactobacillus) were involved in diarrhoea infection. Optimal secondary structure alignment from ClustalO has a minimum free energy (MFE) of-764.31 kcal/mol while that Aligner has MFE of-592.43 kcal/mol. The free energies from molecular docking reveal possible e cacy in the order of doxycycline > metacycline > streptomycin > rolitetracycline > tetracycline > tigecycline. Out of 17 antibiotics used in this study, chlortetracycline and minocycline have high a nity for methyltransferase KsgA (PDB ID: 3TPZ), kanamycin has almost equal a nity for both enzymes, while the remaining 14 antibiotic compounds have high a nity for pseudouridine synthase RsuA (PDB ID: 1KSV). The modelled three-dimensional structure of 16S rRNA bind to 1KSV and 3TPZ with free energy of-367.52 kcal/mol and-371.55 kcal/mol respectively. Moreover, the active site nucleotide residues were found to have direct interaction with amino acid residues in the active site of the enzymes. This study provides insight on the mechanism of action of antibiotics that targeted 16S rRNA by inhibition of key enzymes that involve in protein synthesis.
... To this end, synthetic molecules can be used as alternative antimotility agents. The current focus of this field is on the design of new molecules using in silico molecular modeling approaches based on available chemical structures of natural molecules (Mondal et al. 2015;Ugboko et al. 2019). Molecules designed using such approaches can be used as templates to synthesize new potent antimotility molecules as well. ...
The initial colonization of the host organism by commensal, probiotic, and pathogenic Escherichia coli strains is an important step in the development of infections and biofilms. Sensing and colonization of host cell surfaces are governed by flagellar and fimbriae/pili appendages, respectively. Biofilm formation confers great advantages on pathogenic E. coli cells such as protection against the host immune system, antimicrobial agents, and several environmental stress factors. The transition from planktonic to sessile physiological states involves several signaling cascades and factors responsible for the regulation of flagellar motility in E. coli cells. These regulatory factors have thus become important targets to control pathogenicity. Hence, attenuation of flagellar motility is considered a potential therapy against pathogenic E. coli. The present review describes signaling pathways and proteins involved in direct or indirect regulation of flagellar motility. Furthermore, application strategies for antimotility natural or synthetic compounds are discussed also.
... The molecular docking simulations were carried out using the method of Ugboko et al. (2019). Briefly, 5 SARS-CoV proteins (2-O-ribose methyltransferase, 3-chymotrypsin-like protease, RNA-dependent RNA polymerase, papain-like protease and helicase) were selected from literatures Chen et al., 2020;Tong, 2009) and 2 human proteins (DNA-PK and CK2a) were identified from expression network. ...
... The structures of these proteins were obtained from PDB database (www.rcsb.org/pdb) in pdb format and 3DLigandSite server (http://www.sbg.bio.ic.ac.uk/3dligandsite/advanced.cgi, Wass et al., 2010), was used to predict the active site amino acid residues of the protein targets. The structures of selected 10 predicted drugs from the expression network Lamb et al., 2006), five (5) drugs for repurposing as anti-nCoV (Pang et al., 2020;Hosseini & Amanlou, 2020;Gordon et al., 2020;Ugboko et al., 2019;De Clercq, 2006) and seventeen (17) selected phytochemicals from 9 medicinal plants (selected from Table 1, based on overall constituents including ellagic acid and caffeic acid which are key inhibitors of multifunctional proteins in the human host of SARS-CoV-2), were obtained from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/) in sdf format and were converted to pdb format using PyMol v2.0.7. The crystal structure of the seven (7) (Decroly et al., 2011;Hou et al., 2012) using the same docking parameter that were setup earlier in this study. ...
The novel coronavirus of 2019 (nCoV-19) has become a pandemic, affecting over 205 nations with over 7,410,000 confirmed cases which has resulted to over 418,000 deaths worldwide. This study aimed to identify potential therapeutic compounds and phytochemicals of medicinal plants that have potential to modulate the expression network of genes that are involve in SARS-CoV-2 pathology in human host and to understand the dynamics key proteins involved in the virus-host interactions. The method used include gene network analysis, molecular docking, and sequence and structure dynamics simulations. The results identified DNA-dependent protein kinase (DNA-PK) and Protein kinase CK2 as key players in SARS-CoV-2 lifecycle. Among the predicted drugs compounds, clemizole, monorden, spironolactone and tanespimycin showed high binding energies; among the studied repurposing compounds, remdesivir, simeprevir and valinomycin showed high binding energies; among the predicted acidic compounds, acetylursolic acid and hardwickiic acid gave high binding energies; while among the studied anthraquinones and glycosides compounds, ellagitannin and friedelanone showed high binding energies against 3-Chymotrypsin-like protease (3CLpro), Papain-like protease (PLpro), helicase (nsp13), RNA-dependent RNA polymerase (nsp12), 2’-O-ribose methyltransferase (nsp16) of SARS-CoV-2 and DNA-PK and CK2alpha in human. The order of affinity for CoV proteins is 5Y3E > 6NUS > 6JYT > 2XYR > 3VB6. Finally, medicinal plants with phytochemicals such as caffeine, ellagic acid, quercetin and their derivatives could possibly remediate COVID-19.
Communicated by Ramaswamy H. Sarma
... The molecular docking simulations were carried out using the method of Ugboko et al. (2019). Briefly, 5 SARS-CoV proteins (2-O-ribose methyltransferase, 3-chymotrypsin-like protease, RNA-dependent RNA polymerase, papain-like protease and helicase) were selected from literatures Chen et al., 2020;Tong, 2009) and 2 human proteins (DNA-PK and CK2a) were identified from expression network. ...
... The structures of these proteins were obtained from PDB database (www.rcsb.org/pdb) in pdb format and 3DLigandSite server (http://www.sbg.bio.ic.ac.uk/3dligandsite/advanced.cgi, Wass et al., 2010), was used to predict the active site amino acid residues of the protein targets. The structures of selected 10 predicted drugs from the expression network Lamb et al., 2006), five (5) drugs for repurposing as anti-nCoV (Pang et al., 2020;Hosseini & Amanlou, 2020;Gordon et al., 2020;Ugboko et al., 2019;De Clercq, 2006) and seventeen (17) selected phytochemicals from 9 medicinal plants (selected from Table 1, based on overall constituents including ellagic acid and caffeic acid which are key inhibitors of multifunctional proteins in the human host of SARS-CoV-2), were obtained from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/) in sdf format and were converted to pdb format using PyMol v2.0.7. The crystal structure of the seven (7) (Decroly et al., 2011;Hou et al., 2012) using the same docking parameter that were setup earlier in this study. ...
ABSTRACT
The novel coronavirus of 2019 (nCoV-19) has become a pandemic, affecting over 205 nations with
over 7,410,000 confirmed cases which has resulted to over 418,000 deaths worldwide. This study
aimed to identify potential therapeutic compounds and phytochemicals of medicinal plants that have
potential to modulate the expression network of genes that are involve in SARS-CoV-2 pathology in
human host and to understand the dynamics key proteins involved in the virus-host interactions. The
method used include gene network analysis, molecular docking, and sequence and structure dynamics
simulations. The results identified DNA-dependent protein kinase (DNA-PK) and Protein kinase CK2 as
key players in SARS-CoV-2 lifecycle. Among the predicted drugs compounds, clemizole, monorden,
spironolactone and tanespimycin showed high binding energies; among the studied repurposing compounds,
remdesivir, simeprevir and valinomycin showed high binding energies; among the predicted
acidic compounds, acetylursolic acid and hardwickiic acid gave high binding energies; while among
the studied anthraquinones and glycosides compounds, ellagitannin and friedelanone showed high
binding energies against 3-Chymotrypsin-like protease (3CLpro), Papain-like protease (PLpro), helicase
(nsp13), RNA-dependent RNA polymerase (nsp12), 2’-O-ribose methyltransferase (nsp16) of SARS-CoV-2
and DNA-PK and CK2alpha in human. The order of affinity for CoV proteins is 5Y3E > 6NUS > 6JYT >
2XYR > 3VB6. Finally, medicinal plants with phytochemicals such as caffeine, ellagic acid, quercetin
and their derivatives could possibly remediate COVID-19.
ARTICLE HISTORY
Received 3 June 2020
Accepted 7 July 2020
KEYWORDS
SARS-CoV-2; COVID-19;
gene expression network;
drug discovery; molecular
docking and
dynamics simulation
... The molecular docking simulations were carried out using the method of Ugboko et al. (2019). Briefly, 5 SARS-CoV proteins (2-O-ribose methyltransferase, 3-chymotrypsin-like protease, RNA-dependent RNA polymerase, papain-like protease and helicase) were selected from literatures Chen et al., 2020;Tong, 2009) and 2 human proteins (DNA-PK and CK2a) were identified from expression network. ...
... The structures of these proteins were obtained from PDB database (www.rcsb.org/pdb) in pdb format and 3DLigandSite server (http://www.sbg.bio.ic.ac.uk/3dligandsite/advanced.cgi, Wass et al., 2010), was used to predict the active site amino acid residues of the protein targets. The structures of selected 10 predicted drugs from the expression network Lamb et al., 2006), five (5) drugs for repurposing as anti-nCoV (Pang et al., 2020;Hosseini & Amanlou, 2020;Gordon et al., 2020;Ugboko et al., 2019;De Clercq, 2006) and seventeen (17) selected phytochemicals from 9 medicinal plants (selected from Table 1, based on overall constituents including ellagic acid and caffeic acid which are key inhibitors of multifunctional proteins in the human host of SARS-CoV-2), were obtained from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/) in sdf format and were converted to pdb format using PyMol v2.0.7. The crystal structure of the seven (7) (Decroly et al., 2011;Hou et al., 2012) using the same docking parameter that were setup earlier in this study. ...
... The molecular docking simulations were carried out using the method of Ugboko et al. (2019). Briefly, 5 SARS-CoV proteins (2-O-ribose methyltransferase, 3-chymotrypsin-like protease, RNA-dependent RNA polymerase, papain-like protease and helicase) were selected from literatures Chen et al., 2020;Tong, 2009) and 2 human proteins (DNA-PK and CK2a) were identified from expression network. ...
... The structures of these proteins were obtained from PDB database (www.rcsb.org/pdb) in pdb format and 3DLigandSite server (http://www.sbg.bio.ic.ac.uk/3dligandsite/advanced.cgi, Wass et al., 2010), was used to predict the active site amino acid residues of the protein targets. The structures of selected 10 predicted drugs from the expression network Lamb et al., 2006), five (5) drugs for repurposing as anti-nCoV (Pang et al., 2020;Hosseini & Amanlou, 2020;Gordon et al., 2020;Ugboko et al., 2019;De Clercq, 2006) and seventeen (17) selected phytochemicals from 9 medicinal plants (selected from Table 1, based on overall constituents including ellagic acid and caffeic acid which are key inhibitors of multifunctional proteins in the human host of SARS-CoV-2), were obtained from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/) in sdf format and were converted to pdb format using PyMol v2.0.7. The crystal structure of the seven (7) (Decroly et al., 2011;Hou et al., 2012) using the same docking parameter that were setup earlier in this study. ...
... The molecular docking simulations were carried out using the method of Ugboko et al. (2019). Briefly, 5 SARS-CoV proteins (2-O-ribose methyltransferase, 3-chymotrypsin-like protease, RNA-dependent RNA polymerase, papain-like protease and helicase) were selected from literatures Chen et al., 2020;Tong, 2009) and 2 human proteins (DNA-PK and CK2a) were identified from expression network. ...
... The structures of these proteins were obtained from PDB database (www.rcsb.org/pdb) in pdb format and 3DLigandSite server (http://www.sbg.bio.ic.ac.uk/3dligandsite/advanced.cgi, Wass et al., 2010), was used to predict the active site amino acid residues of the protein targets. The structures of selected 10 predicted drugs from the expression network Lamb et al., 2006), five (5) drugs for repurposing as anti-nCoV (Pang et al., 2020;Hosseini & Amanlou, 2020;Gordon et al., 2020;Ugboko et al., 2019;De Clercq, 2006) and seventeen (17) selected phytochemicals from 9 medicinal plants (selected from Table 1, based on overall constituents including ellagic acid and caffeic acid which are key inhibitors of multifunctional proteins in the human host of SARS-CoV-2), were obtained from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/) in sdf format and were converted to pdb format using PyMol v2.0.7. The crystal structure of the seven (7) (Decroly et al., 2011;Hou et al., 2012) using the same docking parameter that were setup earlier in this study. ...
