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1.
J Am Chem Soc ; 144(44): 20137-20152, 2022 Nov 09.
Article in English | MEDLINE | ID: covidwho-2185542

ABSTRACT

Mucus hydrogels at biointerfaces are crucial for protecting against foreign pathogens and for the biological functions of the underlying cells. Since mucus can bind to and host both viruses and bacteria, establishing a synthetic model system that can emulate the properties and functions of native mucus and can be synthesized at large scale would revolutionize the mucus-related research that is essential for understanding the pathways of many infectious diseases. The synthesis of such biofunctional hydrogels in the laboratory is highly challenging, owing to their complex chemical compositions and the specific chemical interactions that occur throughout the gel network. In this perspective, we discuss the basic chemical structures and diverse physicochemical interactions responsible for the unique properties and functions of mucus hydrogels. We scrutinize the different approaches for preparing mucus-inspired hydrogels, with specific examples. We also discuss recent research and what it reveals about the challenges that must be addressed and the opportunities to be considered to achieve desirable de novo synthetic mucus hydrogels.


Subject(s)
Hydrogels , Mucus , Hydrogels/chemistry , Mucus/chemistry , Bacteria/metabolism
2.
Molecules ; 27(19)2022 Sep 24.
Article in English | MEDLINE | ID: covidwho-2066273

ABSTRACT

Lysozymes are hydrolytic enzymes characterized by their ability to cleave the ß-(1,4)-glycosidic bonds in peptidoglycan, a major structural component of the bacterial cell wall. This hydrolysis action compromises the integrity of the cell wall, causing the lysis of bacteria. For more than 80 years, its role of antibacterial defense in animals has been renowned, and it is also used as a preservative in foods and pharmaceuticals. In order to improve the antimicrobial efficacy of lysozyme, extensive research has been intended for its modifications. This manuscript reviews the natural antibiotic compound lysozyme with reference to its catalytic and non-catalytic mode of antibacterial action, lysozyme types, susceptibility and resistance of bacteria, modification of lysozyme molecules, and its applications in the food industry.


Subject(s)
Anti-Infective Agents , Muramidase , Animals , Anti-Bacterial Agents/pharmacology , Antiviral Agents , Bacteria/metabolism , Food Industry , Muramidase/chemistry , Peptidoglycan/metabolism , Pharmaceutical Preparations
3.
mBio ; 13(5): e0165022, 2022 10 26.
Article in English | MEDLINE | ID: covidwho-2053125

ABSTRACT

Bacteria have evolved many different signal transduction systems to sense and respond to changing environmental conditions. Signal integration is mainly achieved by signal recognition at extracytosolic ligand-binding domains (LBDs) of receptors. Hundreds of different LBDs have been reported, and our understanding of their sensing properties is growing. Receptors must function over a range of environmental pH values, but there is little information available on the robustness of sensing as a function of pH. Here, we have used isothermal titration calorimetry to determine the pH dependence of ligand recognition by nine LBDs that cover all major LBD superfamilies, of periplasmic solute-binding proteins, and cytosolic LBDs. We show that periplasmic LBDs recognize ligands over a very broad pH range, frequently stretching over eight pH units. This wide pH range contrasts with a much narrower pH response range of the cytosolic LBDs analyzed. Many LBDs must be dimeric to bind ligands, and analytical ultracentrifugation studies showed that the LBD of the Tar chemoreceptor forms dimers over the entire pH range tested. The pH dependences of Pseudomonas aeruginosa motility and chemotaxis were bell-shaped and centered at pH 7.0. Evidence for pH robustness of signaling in vivo was obtained by Förster Resonance Energy Transfer (FRET) measurements of the chemotaxis pathway responses in Escherichia coli. Bacteria have evolved several strategies to cope with extreme pH, such as periplasmic chaperones for protein refolding. The intrinsic pH resistance of periplasmic LBDs appears to be another strategy that permits bacteria to survive under adverse conditions. IMPORTANCE Demonstration of the pH robustness of extracytoplasmic sensing reveals a previously undescribed evolutionary mechanism that enables bacteria to monitor environmental changes under changing conditions. This mechanism includes the maintenance of the dimeric state of four-helixbundle ligand-binding domains (LBDs). The construction of biosensors is a rapidly growing field of research, and their use to monitor the progression of the COVID-19 pandemic has impressively demonstrated their usefulness. LBDs represent an enormous reservoir of binding modules that can be used to create novel biosensors. Among ligands recognized by LBDs are neurotransmitters, hormones, and quorum-sensing signals. The demonstration that extracytosolic LBDs bind their signals over a wide range of pH values will facilitate the design of biosensors that function under highly variable conditions of acidity and alkalinity.


Subject(s)
Bacterial Proteins , COVID-19 , Humans , Ligands , Bacterial Proteins/metabolism , Protein Binding , Pandemics , Chemotaxis , Bacteria/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Hormones/metabolism , Hydrogen-Ion Concentration
4.
PLoS One ; 17(8): e0269962, 2022.
Article in English | MEDLINE | ID: covidwho-1974307

ABSTRACT

Five endophytic bacterial isolates were studied to identify morphologically and biochemically, according to established protocols and further confirmed by 16S rDNA Sanger sequencing, as Priestia megaterium, Staphylococcus caprae, Neobacillus drentensis, Micrococcus yunnanensis, and Sphingomonas paucimobiliz, which were then tested for phytohormone, ammonia, and hydrolytic enzyme production. Antioxidant compounds total phenolic content (TPC), and total flavonoid content (TFC) were assessed by using bacterial crude extracts obtained from 24-hour shake-flask culture. Phylogenetic tree analysis of those identified isolates shared sequence similarities with the members of Bacillus, Micrococcus, Staphylococcus, and Pseudomonas species, and after GenBank submission, accession numbers for the nucleotide sequences were found to be MW494406, MW494408, MW494401, MW494402, and MZ021340, respectively. In silico analysis was performed to identify their bioactive genes and compounds in the context of bioactive secondary metabolite production with medicinal value, where nine significant bioactive compounds according to six different types of bioactive secondary metabolites were identified, and their structures, gene associations, and protein-protein networks were analyzed by different computational tools and servers, which were reported earlier with their antimicrobial, anti-infective, antioxidant, and anti-cancer capabilities. These compounds were then docked to the 3-chymotrypsin-like protease (3CLpro) of the novel SARS-COV-2. Docking scores were then compared with 3CLpro reference inhibitor (lopinavir), and docked compounds were further subjected to ADMET and drug-likeness analyses. Ligand-protein interactions showed that two compounds (microansamycin and aureusimine) interacted favorably with coronavirus 3CLpro. Besides, in silico analysis, we also performed NMR for metabolite detection whereas three metabolites (microansamycin, aureusimine, and stenothricin) were confirmed from the 1H NMR profiles. As a consequence, the metabolites found from NMR data aligned with our in-silico analysis that carries a significant outcome of this research. Finally, Endophytic bacteria collected from medicinal plants can provide new leading bioactive compounds against target proteins of SARS-COV-2, which could be an effective approach to accelerate drug innovation and development.


Subject(s)
COVID-19 , SARS-CoV-2 , Antioxidants/metabolism , Bacteria/metabolism , Humans , Molecular Docking Simulation , Phylogeny
5.
Nutrients ; 14(15)2022 Jul 25.
Article in English | MEDLINE | ID: covidwho-1957403

ABSTRACT

Natural resources, particularly plants and microbes, are an excellent source of bioactive molecules. Bromelain, a complex enzyme mixture found in pineapples, has numerous pharmacological applications. In a search for therapeutic molecules, we conducted an in silico study on natural phyto-constituent bromelain, targeting pathogenic bacteria and viral proteases. Docking studies revealed that bromelain strongly bound to food-borne bacterial pathogens and SARS-CoV-2 virus targets, with a high binding energy of -9.37 kcal/mol. The binding interaction was mediated by the involvement of hydrogen bonds, and some hydrophobic interactions stabilized the complex and molecular dynamics. Simulation studies also indicated the stable binding between bromelain and SARS-CoV-2 protease as well as with bacterial targets which are essential for DNA and protein synthesis and are required to maintain the integrity of membranous proteins. From this in silico study, it is also concluded that bromelain could be an effective molecule to control foodborne pathogen toxicity and COVID-19. So, eating pineapple during an infection could help to interfere with the pathogen attaching and help prevent the virus from getting into the host cell. Further, research on the bromelain molecule could be helpful for the management of COVID-19 disease as well as other bacterial-mediated diseases. Thus, the antibacterial and anti-SARS-CoV-2 virus inhibitory potentials of bromelain could be helpful in the management of viral infections and subsequent bacterial infections in COVID-19 patients.


Subject(s)
Ananas , COVID-19 , Antiviral Agents/pharmacology , Bacteria/metabolism , Bromelains/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases , Cysteine Endopeptidases , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , SARS-CoV-2 , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
6.
Front Immunol ; 13: 877533, 2022.
Article in English | MEDLINE | ID: covidwho-1938619

ABSTRACT

Infectious diseases are one of the leading causes of morbidity and mortality worldwide, affecting high-risk populations such as children and the elderly. Pathogens usually activate local immune responses at the site of infection, resulting in both protective and inflammatory responses, which may lead to local changes in the microbiota, metabolites, and the cytokine environment. Although some pathogens can disseminate and cause systemic disease, increasing evidence suggests that local infections can affect tissues not directly invaded. In particular, diseases occurring at distal mucosal barriers such as the lung and the intestine seem to be linked, as shown by epidemiological studies in humans. These mucosal barriers have bidirectional interactions based mainly on multiple signals derived from the microbiota, which has been termed as the gut-lung axis. However, the effects observed in such distal places are still incompletely understood. Most of the current research focuses on the systemic impact of changes in microbiota and bacterial metabolites during infection, which could further modulate immune responses at distal tissue sites. Here, we describe how the gut microbiota and associated metabolites play key roles in maintaining local homeostasis and preventing enteric infection by direct and indirect mechanisms. Subsequently, we discuss recent murine and human studies linking infectious diseases with changes occurring at distal mucosal barriers, with particular emphasis on bacterial and viral infections affecting the lung and the gastrointestinal tract. Further, we discuss the potential mechanisms by which pathogens may cause such effects, promoting either protection or susceptibility to secondary infection.


Subject(s)
Communicable Diseases , Gastrointestinal Microbiome , Microbiota , Pneumonia , Aged , Animals , Bacteria/metabolism , Child , Humans , Mice
7.
Int J Mol Sci ; 21(15)2020 Jul 27.
Article in English | MEDLINE | ID: covidwho-1934097

ABSTRACT

Microbial virulence factors encompass a wide range of molecules produced by pathogenic microorganisms, enhancing their ability to evade their host defenses and cause disease [...].


Subject(s)
Bacteria/metabolism , Bacteria/pathogenicity , Virulence Factors/metabolism , Humans , Virulence
8.
World J Microbiol Biotechnol ; 38(9): 158, 2022 Jul 12.
Article in English | MEDLINE | ID: covidwho-1930505

ABSTRACT

In this mini-review, after a brief introduction into the widespread antimicrobial use of silver ions and nanoparticles against bacteria, fungi and viruses, the toxicity of silver compounds and the molecular mechanisms of microbial silver resistance are discussed, including recent studies on bacteria and fungi. The similarities and differences between silver ions and silver nanoparticles as antimicrobial agents are also mentioned. Regarding bacterial ionic silver resistance, the roles of the sil operon, silver cation efflux proteins, and copper-silver efflux systems are explained. The importance of bacterially produced exopolysaccharides as a physiological (biofilm) defense mechanism against silver nanoparticles is also emphasized. Regarding fungal silver resistance, the roles of metallothioneins, copper-transporting P-type ATPases and cell wall are discussed. Recent evolutionary engineering (adaptive laboratory evolution) studies are also discussed which revealed that silver resistance can evolve rapidly in bacteria and fungi. The cross-resistance observed between silver resistance and resistance to other heavy metals and antibiotics in bacteria and fungi is also explained as a clinically and environmentally important issue. The use of silver against bacterial and fungal biofilm formation is also discussed. Finally, the antiviral effects of silver and the use of silver nanoparticles against SARS-CoV-2 and other viruses are mentioned. To conclude, silver compounds are becoming increasingly important as antimicrobial agents, and their widespread use necessitates detailed understanding of microbial silver response and resistance mechanisms, as well as the ecological effects of silver compounds. Figure created with BioRender.com.


Subject(s)
Anti-Infective Agents , Bacterial Infections , COVID-19 , Metal Nanoparticles , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/metabolism , Anti-Infective Agents/pharmacology , Bacteria/metabolism , Copper/metabolism , Humans , Ions/metabolism , Ions/pharmacology , SARS-CoV-2 , Silver/metabolism , Silver/pharmacology , Silver Compounds/metabolism , Silver Compounds/pharmacology
9.
Microb Drug Resist ; 28(8): 841-848, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1908719

ABSTRACT

Since the start of the COVID-19 pandemic, our reliance on disinfectants and sanitizers and the use thereof has grown. While this may protect human health, it may be selecting for antimicrobial-resistant microorganisms, including those that are not only capable of growth in the presence of disinfectants but also thrive using this as an energy source. Furthermore, there is a growing concern in emerging nosocomial pathogens, which have shown resistance to antibiotics and disinfectants. This rise in resistance has led to the investigation of various mechanisms behind resistance, such as biofilms, efflux pumps, and mobile genetic elements. Although many resistance mechanisms have been identified, it was discovered that some potentially pathogenic microbes could metabolize these compounds, which remains an avenue for further investigation. Investigating alternative metabolic pathways in microorganisms capable of growth using disinfectants as their sole carbon and energy source may provide insight into the metabolism of quaternary ammonium compound (QAC)-based antimicrobials. Many of the metabolic reactions proposed include hydroxylation, N-dealkylation, N-demethylation, and ß-oxidation of QACs. If clear metabolic pathways and reactions are elucidated, possible alternative approaches to QACs may be advised. Alternatively, this may provide opportunities for biodegradation of the compounds that adversely affect the environment.


Subject(s)
COVID-19 , Disinfectants , Anti-Bacterial Agents/pharmacology , Bacteria/genetics , Bacteria/metabolism , Disinfectants/pharmacology , Drug Resistance, Bacterial/genetics , Humans , Pandemics , Quaternary Ammonium Compounds/pharmacology
10.
Int J Mol Sci ; 23(10)2022 May 17.
Article in English | MEDLINE | ID: covidwho-1875644

ABSTRACT

The global utilization of single-use, non-biodegradable plastics, such as bottles made of polyethylene terephthalate (PET), has contributed to catastrophic levels of plastic pollution. Fortunately, microbial communities are adapting to assimilate plastic waste. Previously, our work showed a full consortium of five bacteria capable of synergistically degrading PET. Using omics approaches, we identified the key genes implicated in PET degradation within the consortium's pangenome and transcriptome. This analysis led to the discovery of a novel PETase, EstB, which has been observed to hydrolyze the oligomer BHET and the polymer PET. Besides the genes implicated in PET degradation, many other biodegradation genes were discovered. Over 200 plastic and plasticizer degradation-related genes were discovered through the Plastic Microbial Biodegradation Database (PMBD). Diverse carbon source utilization was observed by a microbial community-based assay, which, paired with an abundant number of plastic- and plasticizer-degrading enzymes, indicates a promising possibility for mixed plastic degradation. Using RNAseq differential analysis, several genes were predicted to be involved in PET degradation, including aldehyde dehydrogenases and several classes of hydrolases. Active transcription of PET monomer metabolism was also observed, including the generation of polyhydroxyalkanoate (PHA)/polyhydroxybutyrate (PHB) biopolymers. These results present an exciting opportunity for the bio-recycling of mixed plastic waste with upcycling potential.


Subject(s)
Microbial Consortia , Polyethylene Terephthalates , Bacteria/genetics , Bacteria/metabolism , Plasticizers , Plastics/metabolism
11.
Arch Razi Inst ; 77(2): 779-784, 2022 04.
Article in English | MEDLINE | ID: covidwho-1870227

ABSTRACT

The COVID-19 caused by the SARS-CoV-2 virus has an impact on all aspects of patient care. Since the onset of this disease pandemic in 2019, numerous studies have been published which have attempted to identify virus receptors in the upper respiratory tract, such as nasal, oropharynx, and lung and their role in coinfection of bacterial adherence. In this study, the level of m RNA for platelet-activating factor receptor (PAF-R) and angiotensin-converting enzyme 2 receptor (ACE2-R) were detected in the whole blood of COVID-19 patients and controlled by using real-time reverse transcription-polymerase chain reaction technique. The results of the expression level of the PAF-R gene were higher in patients (43 ± 12.5) than in the healthy control (40 ± 2.1). Moreover, the expression level of ACE2-R was significantly (0.0001) increased in patients (27.5±6.2), compared to the control group. In addition, there was an elevation of neutrophils (79.6±17.6%) and PAF-R level (43%) in COVID-19 patients in comparison to the control (40) with a positive correlation between these factors (r=0.8769, P=0.0001). Nasopharyngeal epithelial cells showed a higher adherence rate (86%) to both bacteria isolates (Streptococcus pneumonia and Staphylococcus aureus) in patients than in the control group. Increased expression of PAF-R and ACE2-R genes in COVID-19 patients and co-infected bacteria disease could be the factors for the SARS-CoV-2 virus to enter the cells of the host.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Animals , COVID-19/veterinary , SARS-CoV-2 , Neutrophils/metabolism , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Receptors, Virus/metabolism , Bacteria/genetics , Bacteria/metabolism , RNA
12.
Acta Crystallogr D Struct Biol ; 78(Pt 5): 647-657, 2022 May 01.
Article in English | MEDLINE | ID: covidwho-1831598

ABSTRACT

Sialic acids terminate many N- and O-glycans and are widely distributed on cell surfaces. There are a diverse range of enzymes which interact with these sugars throughout the tree of life. They can act as receptors for influenza and specific betacoronaviruses in viral binding and their cleavage is important in virion release. Sialic acids are also exploited by both commensal and pathogenic bacteria for nutrient acquisition. A common modification of sialic acid is 9-O-acetylation, which can limit the action of sialidases. Some bacteria, including human endosymbionts, employ esterases to overcome this modification. However, few bacterial sialic acid 9-O-acetylesterases (9-O-SAEs) have been structurally characterized. Here, the crystal structure of a 9-O-SAE from Phocaeicola vulgatus (PvSAE) is reported. The structure of PvSAE was determined to resolutions of 1.44 and 2.06 Šusing crystals from two different crystallization conditions. Structural characterization revealed PvSAE to be a dimer with an SGNH fold, named after the conserved sequence motif of this family, and a Ser-His-Asp catalytic triad. These structures also reveal flexibility in the most N-terminal α-helix, which provides a barrier to active-site accessibility. Biochemical assays also show that PvSAE deacetylates both mucin and the acetylated chromophore para-nitrophenyl acetate. This structural and biochemical characterization of PvSAE furthers the understanding of 9-O-SAEs and may aid in the discovery of small molecules targeting this class of enzyme.


Subject(s)
Acetylesterase , N-Acetylneuraminic Acid , Acetylation , Acetylesterase/chemistry , Acetylesterase/metabolism , Bacteria/metabolism , Bacteroides , Carboxylic Ester Hydrolases , Humans , N-Acetylneuraminic Acid/metabolism , Sialic Acids/metabolism
14.
Biomolecules ; 12(3)2022 02 23.
Article in English | MEDLINE | ID: covidwho-1760346

ABSTRACT

Prokaryotic Argonautes (pAgos) from mesophilic bacteria are attracting increasing attention for their genome editing potential. So far, it has been reported that KmAgo from Kurthia massiliensis can utilize DNA and RNA guide of any sequence to effectively cleave DNA and RNA targets. Here we find that three active pAgos, which have about 50% sequence identity with KmAgo, possess typical DNA-guided DNA target cleavage ability. Among them, RsuAgo from Rummeliibacillus suwonensis is mainly explored for which can cleave both DNA and RNA targets. Interestingly, RsuAgo-mediated RNA target cleavage occurs only with short guide DNAs in a narrow length range (16-20 nt), and mismatches between the guide and target sequence greatly affect the efficiency of RNA target cleavage. RsuAgo-mediated target cleavage shows a preference for a guide strand with a 5'-terminal A residue. Furthermore, we have found that RsuAgo can cleave double-stranded DNA in a low-salt buffer at 37 °C. These properties of RsuAgo provide a new tool for DNA and RNA manipulation at moderate temperatures.


Subject(s)
Argonaute Proteins , Bacterial Proteins , Argonaute Proteins/genetics , Bacteria/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , DNA/chemistry , Endonucleases , Planococcaceae , RNA
15.
Appl Microbiol Biotechnol ; 106(5-6): 1855-1878, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1702010

ABSTRACT

Microorganisms are remarkable producers of a wide diversity of natural products that significantly improve human health and well-being. Currently, these natural products comprise half of all the pharmaceuticals on the market. After the discovery of penicillin by Alexander Fleming 85 years ago, the search for and study of antibiotics began to gain relevance as drugs. Since then, antibiotics have played a valuable role in treating infectious diseases and have saved many human lives. New molecules with anticancer, hypocholesterolemic, and immunosuppressive activity have now been introduced to treat other relevant diseases. Smaller biotechnology companies and academic laboratories generate novel antibiotics and other secondary metabolites that big pharmaceutical companies no longer develop. The purpose of this review is to illustrate some of the recent developments and to show the potential that some modern technologies like metagenomics and genome mining offer for the discovery and development of new molecules, with different functions like therapeutic alternatives needed to overcome current severe problems, such as the SARS-CoV-2 pandemic, antibiotic resistance, and other emerging diseases. KEY POINTS: • Novel alternatives for the treatment of infections caused by bacteria, fungi, and viruses. • Second wave of efforts of microbial origin against SARS-CoV-2 and related variants. • Microbial drugs used in clinical practice as hypocholesterolemic agents, immunosuppressants, and anticancer therapy.


Subject(s)
Biological Products , COVID-19 , Anti-Bacterial Agents/metabolism , Bacteria/metabolism , Biological Products/therapeutic use , COVID-19/drug therapy , Humans , SARS-CoV-2
16.
Gut Microbes ; 14(1): 2018900, 2022.
Article in English | MEDLINE | ID: covidwho-1585291

ABSTRACT

Mounting evidence suggests that the gut-to-lung axis is critical during respiratory viral infections. We herein hypothesized that disruption of gut homeostasis during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may associate with early disease outcomes. To address this question, we took advantage of the Syrian hamster model. Our data confirmed that this model recapitulates some hallmark features of the human disease in the lungs. We further showed that SARS-CoV-2 infection associated with mild intestinal inflammation, relative alteration in intestinal barrier property and liver inflammation and altered lipid metabolism. These changes occurred concomitantly with an alteration of the gut microbiota composition over the course of infection, notably characterized by a higher relative abundance of deleterious bacterial taxa such as Enterobacteriaceae and Desulfovibrionaceae. Conversely, several members of the Ruminococcaceae and Lachnospiraceae families, including bacteria known to produce the fermentative products short-chain fatty acids (SCFAs), had a reduced relative proportion compared to non-infected controls. Accordingly, infection led to a transient decrease in systemic SCFA amounts. SCFA supplementation during infection had no effect on clinical and inflammatory parameters. Lastly, a strong correlation between some gut microbiota taxa and clinical and inflammation indices of SARS-CoV-2 infection severity was evidenced. Collectively, alteration of the gut microbiota correlates with disease severity in hamsters making this experimental model valuable for the design of interventional, gut microbiota-targeted, approaches for the control of COVID-19.Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; COVID-19, coronavirus disease 2019; SCFAs, short-chain fatty acids; dpi, day post-infection; RT-PCR, reverse transcription polymerase chain reaction; IL, interleukin. ACE2, angiotensin converting enzyme 2; TMPRSS2, transmembrane serine protease 2.


Subject(s)
COVID-19/microbiology , COVID-19/physiopathology , Disease Models, Animal , Gastrointestinal Microbiome , Mesocricetus , Animals , Bacteria/classification , Bacteria/isolation & purification , Bacteria/metabolism , COVID-19/drug therapy , COVID-19/pathology , Cricetinae , Fatty Acids, Volatile/administration & dosage , Fatty Acids, Volatile/metabolism , Humans , Male , SARS-CoV-2/physiology , Severity of Illness Index
17.
Rev Med Virol ; 31(5): 1-13, 2021 09.
Article in English | MEDLINE | ID: covidwho-1574011

ABSTRACT

Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is now pandemic. While most Covid-19 patients will experience mild symptoms, a small proportion will develop severe disease, which could be fatal. Clinically, Covid-19 patients manifest fever with dry cough, fatigue and dyspnoea, and in severe cases develop into acute respiratory distress syndrome (ARDS), sepsis and multi-organ failure. These severe patients are characterized by hyperinflammation with highly increased pro-inflammatory cytokines including IL-6, IL-17 and TNF-alpha as well as C-reactive protein, which are accompanied by decreased lymphocyte counts. Clinical evidence supports that gut microbiota dysregulation is common in Covid-19 and plays a key role in the pathogenesis of Covid-19. In this narrative review, we summarize the roles of intestinal dysbiosis in Covid-19 pathogenesis and posit that the associated mechanisms are being mediated by gut bacterial metabolites. Based on this premise, we propose possible clinical implications. Various risk factors could be causal for severe Covid-19, and these include advanced age, concomitant chronic disease, SARS-CoV-2 infection of enterocytes, use of antibiotics and psychological distress. Gut dysbiosis is associated with risk factors and severe Covid-19 due to decreased commensal microbial metabolites, which cause reduced anti-inflammatory mechanisms and chronic low-grade inflammation. The preconditioned immune dysregulation enables SARS-CoV-2 infection to progress to an uncontrolled hyperinflammatory response. Thus, a pre-existing gut microbiota that is diverse and abundant could be beneficial for the prevention of severe Covid-19, and supplementation with commensal microbial metabolites may facilitate and augment the treatment of severe Covid-19.


Subject(s)
Bacteria/metabolism , COVID-19/microbiology , Gastrointestinal Microbiome , Animals , Bacteria/classification , Bacteria/genetics , Bacteria/isolation & purification , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Cytokines/genetics , Cytokines/immunology , Dysbiosis/genetics , Dysbiosis/immunology , Dysbiosis/microbiology , Dysbiosis/virology , Humans , SARS-CoV-2/genetics , SARS-CoV-2/physiology
18.
mSphere ; 6(6): e0071121, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1546463

ABSTRACT

The COVID-19 pandemic has highlighted the need to identify additional antiviral small molecules to complement existing therapies. Although increasing evidence suggests that metabolites produced by the human microbiome have diverse biological activities, their antiviral properties remain poorly explored. Using a cell-based SARS-CoV-2 infection assay, we screened culture broth extracts from a collection of phylogenetically diverse human-associated bacteria for the production of small molecules with antiviral activity. Bioassay-guided fractionation uncovered three bacterial metabolites capable of inhibiting SARS-CoV-2 infection. This included the nucleoside analogue N6-(Δ2-isopentenyl)adenosine, the 5-hydroxytryptamine receptor agonist tryptamine, and the pyrazine 2,5-bis(3-indolylmethyl)pyrazine. The most potent of these, N6-(Δ2-isopentenyl)adenosine, had a 50% inhibitory concentration (IC50) of 2 µM. These natural antiviral compounds exhibit structural and functional similarities to synthetic drugs that have been clinically examined for use against COVID-19. Our discovery of structurally diverse metabolites with anti-SARS-CoV-2 activity from screening a small fraction of the bacteria reported to be associated with the human microbiome suggests that continued exploration of phylogenetically diverse human-associated bacteria is likely to uncover additional small molecules that inhibit SARS-CoV-2 as well as other viral infections. IMPORTANCE The continued prevalence of COVID-19 and the emergence of new variants has once again put the spotlight on the need for the identification of SARS-CoV-2 antivirals. The human microbiome produces an array of small molecules with bioactivities (e.g., host receptor ligands), but its ability to produce antiviral small molecules is relatively underexplored. Here, using a cell-based screening platform, we describe the isolation of three microbiome-derived metabolites that are able to prevent SARS-CoV-2 infection in vitro. These molecules display structural similarities to synthetic drugs that have been explored for the treatment of COVID-19, and these results suggest that the microbiome may be a fruitful source of the discovery of small molecules with antiviral activities.


Subject(s)
Antiviral Agents/pharmacology , Bacteria/metabolism , Culture Media/chemistry , Metabolic Networks and Pathways , Microbiota/physiology , SARS-CoV-2/drug effects , Symbiosis/physiology , Bacteria/chemistry , Bacteria/classification , Bacteria/growth & development , Biological Assay , Cell Line, Tumor , Culture Media/pharmacology , Humans , Molecular Docking Simulation , Protease Inhibitors/pharmacology , Protein Binding
19.
Elife ; 102021 01 26.
Article in English | MEDLINE | ID: covidwho-1513022

ABSTRACT

Humans have relied on sourdough starter microbial communities to make leavened bread for thousands of years, but only a small fraction of global sourdough biodiversity has been characterized. Working with a community-scientist network of bread bakers, we determined the microbial diversity of 500 sourdough starters from four continents. In sharp contrast with widespread assumptions, we found little evidence for biogeographic patterns in starter communities. Strong co-occurrence patterns observed in situ and recreated in vitro demonstrate that microbial interactions shape sourdough community structure. Variation in dough rise rates and aromas were largely explained by acetic acid bacteria, a mostly overlooked group of sourdough microbes. Our study reveals the extent of microbial diversity in an ancient fermented food across diverse cultural and geographic backgrounds.


Sourdough bread is an ancient fermented food that has sustained humans around the world for thousands of years. It is made from a sourdough 'starter culture' which is maintained, portioned, and shared among bread bakers around the world. The starter culture contains a community of microbes made up of yeasts and bacteria, which ferment the carbohydrates in flour and produce the carbon dioxide gas that makes the bread dough rise before baking. The different acids and enzymes produced by the microbial culture affect the bread's flavor, texture and shelf life. However, for such a dependable staple, sourdough bread cultures and the mixture of microbes they contain have scarcely been characterized. Previous studies have looked at the composition of starter cultures from regions within Europe. But there has never been a comprehensive study of how the microbial diversity of sourdough starters varies across and between continents. To investigate this, Landis, Oliverio et al. used genetic sequencing to characterize the microbial communities of sourdough starters from the homes of 500 bread bakers in North America, Europe and Australasia. Bread makers often think their bread's unique qualities are due to the local environment of where the sourdough starter was made. However, Landis, Oliverio et al. found that geographical location did not correlate with the diversity of the starter cultures studied. The data revealed that a group of microbes called acetic acid bacteria, which had been overlooked in past research, were relatively common in starter cultures. Moreover, starters with a greater abundance of this group of bacteria produced bread with a strong vinegar aroma and caused dough to rise at a slower rate. This research demonstrates which species of bacteria and yeast are most commonly found in sourdough starters, and suggests geographical location has little influence on the microbial diversity of these cultures. Instead, the diversity of microbes likely depends more on how the starter culture was made and how it is maintained over time.


Subject(s)
Bacteria/metabolism , Bread/microbiology , Food Microbiology , Microbiota , Acetic Acid/metabolism
20.
Toxins (Basel) ; 12(4)2020 04 02.
Article in English | MEDLINE | ID: covidwho-1453289

ABSTRACT

Bacterial toxins play a key role in the pathogenesis of lung disease. Based on their structural and functional properties, they employ various strategies to modulate lung barrier function and to impair host defense in order to promote infection. Although in general, these toxins target common cellular signaling pathways and host compartments, toxin- and cell-specific effects have also been reported. Toxins can affect resident pulmonary cells involved in alveolar fluid clearance (AFC) and barrier function through impairing vectorial Na+ transport and through cytoskeletal collapse, as such, destroying cell-cell adhesions. The resulting loss of alveolar-capillary barrier integrity and fluid clearance capacity will induce capillary leak and foster edema formation, which will in turn impair gas exchange and endanger the survival of the host. Toxins modulate or neutralize protective host cell mechanisms of both the innate and adaptive immunity response during chronic infection. In particular, toxins can either recruit or kill central players of the lung's innate immune responses to pathogenic attacks, i.e., alveolar macrophages (AMs) and neutrophils. Pulmonary disorders resulting from these toxin actions include, e.g., acute lung injury (ALI), the acute respiratory syndrome (ARDS), and severe pneumonia. When acute infection converts to persistence, i.e., colonization and chronic infection, lung diseases, such as bronchitis, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) can arise. The aim of this review is to discuss the impact of bacterial toxins in the lungs and the resulting outcomes for pathogenesis, their roles in promoting bacterial dissemination, and bacterial survival in disease progression.


Subject(s)
Bacteria/pathogenicity , Bacterial Infections/microbiology , Bacterial Toxins/metabolism , Lung/microbiology , Respiratory Tract Infections/microbiology , Adaptive Immunity , Animals , Bacteria/immunology , Bacteria/metabolism , Bacterial Infections/immunology , Bacterial Infections/metabolism , Bacterial Infections/pathology , Disease Progression , Host-Pathogen Interactions , Humans , Immunity, Innate , Lung/immunology , Lung/metabolism , Lung/pathology , Respiratory Tract Infections/immunology , Respiratory Tract Infections/metabolism , Respiratory Tract Infections/pathology , Signal Transduction
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