scholarly journals Endogenous stimulus-powered antibiotic release from nanoreactors for a combination therapy of bacterial infections

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yang Wu ◽  
Zhiyong Song ◽  
Huajuan Wang ◽  
Heyou Han
Keyword(s):  
Hydrogen Peroxide ◽  
Fatty Acids ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Structural Integrity ◽  
Eutectic Mixture ◽  
Bacterial Toxin ◽  
Domino Effect ◽  
Antibiotic Release

Abstract The use of an endogenous stimulus instead of external trigger has an advantage for targeted and controlled release in drug delivery. Here, we report on cascade nanoreactors for bacterial toxin-triggered antibiotic release by wrapping calcium peroxide (CaO2) and antibiotic in a eutectic mixture of two fatty acids and a liposome coating. When encountering pathogenic bacteria in vivo these nanoreactors capture the toxins, without compromising their structural integrity, and the toxins form pores. Water enters the nanoreactors through the pores to react with CaO2 and produce hydrogen peroxide which decomposes to oxygen and drives antibiotic release. The bound toxins reduce the toxicity and also stimulate the body’s immune response. This works to improve the therapeutic effect in bacterially infected mice. This strategy provides a Domino Effect approach for treating infections caused by bacteria that secrete pore-forming toxins.

scholarly journals AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nathaniel B. Bone ◽  
Eugene J. Becker ◽  
Maroof Husain ◽  
Shaoning Jiang ◽  
Anna A. Zmijewska ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Inflammatory Responses ◽  
Abdominal Sepsis ◽  
Immune Defense ◽  
Bacterial Killing ◽  
Lung Infections ◽  
Sepsis Survivors ◽  
The Impact

AbstractMetabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Parkin, AMPK levels, and the effects of AMPK activators were investigated in human leukocytes from sepsis survivors as well as wild type and Park2−/− murine macrophages. In vivo, the impact of AMPK and Parkin was determined in mice subjected to polymicrobial intra-abdominal sepsis and secondary lung bacterial infections. Mice were treated with metformin during established immunosuppression. We showed that bacteria and mitochondria share mechanisms of autophagic killing/clearance triggered by sentinel events that involve depolarization of mitochondria and recruitment of Parkin in macrophages. Parkin-deficient mice/macrophages fail to form phagolysosomes and kill bacteria. This impairment of host defense is seen in the context of sepsis-induced immunosuppression with decreased levels of Parkin. AMPK activators, including metformin, stimulate Parkin-independent autophagy and bacterial killing in leukocytes from post-shock patients and in lungs of sepsis-immunosuppressed mice. Our results support a dual role of Parkin and AMPK in the clearance of dysfunctional mitochondria and killing of pathogenic bacteria, and explain the immunosuppressive phenotype associated Parkin and AMPK deficiency. AMPK activation appeared to be a crucial therapeutic target for the macrophage immunosuppressive phenotype and to reduce severity of secondary bacterial lung infections and respiratory failure.

scholarly journals TSPphg Lysin from the Extremophilic Thermus Bacteriophage TSP4 as a Potential Antimicrobial Agent against Both Gram-Negative and Gram-Positive Pathogenic Bacteria

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 192 ◽  
Author(s):  
Feng Wang ◽  
Xinyu Ji ◽  
Qiupeng Li ◽  
Guanling Zhang ◽  
Jiani Peng ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Infection Model ◽  
Bacterial Cells ◽  
Skin Damage ◽  
Gram Positive ◽  
Antibiotic Resistant ◽  
Gram Negative

New strategies against antibiotic-resistant bacterial pathogens are urgently needed but are not within reach. Here, we present in vitro and in vivo antimicrobial activity of TSPphg, a novel phage lysin identified from extremophilic Thermus phage TSP4 by sequencing its whole genome. By breaking down the bacterial cells, TSPphg is able to cause bacteria destruction and has shown bactericidal activity against both Gram-negative and Gram-positive pathogenic bacteria, especially antibiotic-resistant strains of Klebsiella pneumoniae, in which the complete elimination and highest reduction in bacterial counts by greater than 6 logs were observed upon 50 μg/mL TSPphg treatment at 37 °C for 1 h. A murine skin infection model further confirmed the in vivo efficacy of TSPphg in removing a highly dangerous and multidrug-resistant Staphylococcus aureus from skin damage and in accelerating wound closure. Together, our findings may offer a therapeutic alternative to help fight bacterial infections in the current age of mounting antibiotic resistance, and to shed light on bacteriophage-based strategies to develop novel anti-infectives.

scholarly journals Rv3723/LucA coordinates fatty acid and cholesterol uptake inMycobacterium tuberculosis

2017 ◽  
Author(s):  
Evgeniya V. Nazarova ◽  
Christine R. Montague ◽  
Thuy La ◽  
Kaley M. Wilburn ◽  
Neelima Sukumar ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Pathogenic Bacteria ◽  
Bacterial Virulence ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Uncharacterized Protein ◽  
Fatty Acid Transporter ◽  
Important Fatty Acid

AbstractPathogenic bacteria have evolved highly specialized systems to extract essential nutrients from their hosts andMycobacterium tuberculosis(Mtb) scavenges lipids (cholesterol and fatty acids) to maintain infection in mammals. While the uptake of cholesterol by Mtb is mediated by the Mce4 transporter, the route(s) of uptake of fatty acids remain unknown. Here, we demonstrate that an uncharacterized protein LucA, integrates the assimilation of both cholesterol and fatty acids in Mtb. LucA interacts with subunits of the Mce1 and Mce4 complexes to coordinate the activities of these nutrient transporters. We also demonstrate that Mce1 functions as an important fatty acid transporter in Mtb and we determine that the integration of cholesterol and fatty acid transport by LucA is required for full bacterial virulencein vivo. These data establish that fatty acid and cholesterol assimilation are inexorably linked in Mtb and reveals a key role for LucA in coordinating both transport activities.

scholarly journals A Toxin Involved inSalmonellaPersistence Regulates Its Activity by Acetylating Its Cognate Antitoxin, a Modification Reversed by CobB Sirtuin Deacetylase

mBio ◽  
2017 ◽  
Vol 8 (3) ◽  
Author(s):  
Chelsey M. VanDrisse ◽  
Anastacia R. Parks ◽  
Jorge C. Escalante-Semerena
Keyword(s):  
Protein Synthesis ◽  
Pathogenic Bacteria ◽  
Bacterial Toxin ◽  
Host Defenses ◽  
Mobility Shift ◽  
Reverse Transcription Pcr ◽  
Acetylation State ◽  
Host Infection

ABSTRACTBacterial toxin-antitoxin systems trigger the onset of a persister state by inhibiting essential cellular processes. The TacT toxin ofSalmonella entericais known to induce a persister state in macrophages through the acetylation of aminoacyl-tRNAs. Here, we show that the TacT toxin and the TacA antitoxin work as a complex that modulates TacT activity via the acetylation state of TacA. TacT acetylates TacA at residue K44, a modification that is removed by the NAD+-dependent CobB sirtuin deacetylase. TacA acetylation increases the activity of TacT, downregulating protein synthesis. TacA acetylation altered binding to its own promoter, although this did not changetacATexpression levels. These claims are supported by results fromin vitroprotein synthesis experiments used to monitor TacT activity,in vivogrowth analyses, electrophoretic mobility shift assays, and quantitative reverse transcription-PCR (RT-qPCR) analysis. TacT is the first example of a Gcn5-relatedN-acetyltransferase that modifies nonprotein and protein substrates.IMPORTANCEDuring host infection, pathogenic bacteria can modulate their physiology to evade host defenses. Some pathogens use toxin-antitoxin systems to modulate a state of self-toxicity that can decrease their cellular activity, triggering the onset of a persister state. The lower metabolic activity of persister cells allows them to escape host defenses and antibiotic treatments. Hence a better understanding of the mechanisms used by pathogens to ingress and egress the persister state is of relevance to human health.

scholarly journals BacFITBase: a database to assess the relevance of bacterial genes during host infection

2019 ◽  
Author(s):  
Javier Macho Rendón ◽  
Benjamin Lang ◽  
Gian Gaetano Tartaglia ◽  
Marc Torrent Burgas
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Well Being ◽  
Disability Adjusted Life ◽  
Life Years ◽  
Bacterial Fitness ◽  
Considerable Impact ◽  
Host Infection ◽  
Bacterial Genes

Abstract Bacterial infections have been on the rise world-wide in recent years and have a considerable impact on human well-being in terms of attributable deaths and disability-adjusted life years. Yet many mechanisms underlying bacterial pathogenesis are still poorly understood. Here, we introduce the BacFITBase database for the systematic characterization of bacterial proteins relevant for host infection aimed to enable the identification of new antibiotic targets. BacFITBase is manually curated and contains more than 90 000 entries with information on the contribution of individual genes to bacterial fitness under in vivo infection conditions in a range of host species. The data were collected from 15 different studies in which transposon mutagenesis was performed, including top-priority pathogens such as Acinetobacter baumannii and Campylobacter jejuni, for both of which increasing antibiotic resistance has been reported. Overall, BacFITBase includes information on 15 pathogenic bacteria and 5 host vertebrates across 10 different tissues. It is freely available at www.tartaglialab.com/bacfitbase.

scholarly journals Rv3723/LucA coordinates fatty acid and cholesterol uptake in Mycobacterium tuberculosis

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Evgeniya V Nazarova ◽  
Christine R Montague ◽  
Thuy La ◽  
Kaley M Wilburn ◽  
Neelima Sukumar ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Mycobacterium Tuberculosis ◽  
Fatty Acid ◽  
Pathogenic Bacteria ◽  
Fatty Acid Uptake ◽  
Bacterial Virulence ◽  
Acid Uptake ◽  
Uncharacterized Protein ◽  
Fatty Acid Transporter

Pathogenic bacteria have evolved highly specialized systems to extract essential nutrients from their hosts. Mycobacterium tuberculosis (Mtb) scavenges lipids (cholesterol and fatty acids) to maintain infections in mammals but mechanisms and proteins responsible for the import of fatty acids in Mtb were previously unknown. Here, we identify and determine that the previously uncharacterized protein Rv3723/LucA, functions to integrate cholesterol and fatty acid uptake in Mtb. Rv3723/LucA interacts with subunits of the Mce1 and Mce4 complexes to coordinate the activities of these nutrient transporters by maintaining their stability. We also demonstrate that Mce1 functions as a fatty acid transporter in Mtb and determine that facilitating cholesterol and fatty acid import via Rv3723/LucA is required for full bacterial virulence in vivo. These data establish that fatty acid and cholesterol assimilation are inexorably linked in Mtb and reveals a key function for Rv3723/LucA in in coordinating thetransport of both these substrates.

scholarly journals EFEKTIVITAS EKSTRAK ETANOL DAUN KIRINYUH (CHROMOLAENA ODORATA L) SEBAGAI ANTIBAKTERI SALMONELLA TYPHI DAN STAPHYLOCOCCUS AUREUS

2020 ◽  
Vol 2 (3) ◽  
pp. 158-168
Author(s):  
Fadia Fadia ◽  
Nurlailah Nurlailah ◽  
Tini Elyn Helmiah ◽  
Leka Lutpiatina
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Herbal Medicines ◽  
Ethanol Extract ◽  
Salmonella Typhi ◽  
Antibacterial Drug ◽  
Chromolaena Odorata ◽  
And Staphylococcus Aureus

        Salmonella typhi and Staphylococcus aureus are pathogenic bacteria that cause infectious diseases. Treatment of these diseases can be done by giving antibacterial drugs. One of the plants that can be used as an antibacterial drug is the leaves of Chromolaena odorata L. due to the presence of chemical compounds such as flavonoids, tannins, and saponins that have the potential as antibacterial. This study aims to determine the Minimum Inhibitory Concentration (MIC), and Minimum Bactericidal Concentration (MBC) ethanol extract of Chromolaena odorata L. leaves on the growth of Salmonella typhi and Staphylococcus aureus. This research is the initial stage of the development of herbal medicines to treat Salmonella typhi and Staphylococcus aureus infections. The study consisted of 5 treatments, namely concentrations of 20%, 40%, 60%, 80%, and 100% ethanol extract of Chromolaena odorata L. leaves with five repetitions. The antibacterial activity test was carried out by MIC and MBC methods. The research material uses leaves from Chromolaena odorata L. in the Sungai Besar area, Banjarbaru, South Kalimantan, Indonesia. The results showed that the average MIC yield of ethanol extract of Chromolaena odorata L. leaves against Salmonella typhi: 20% and Staphylococcus aureus: 20%. While the average yield of MBC values ​​against Salmonella typhi: 40% and Staphylococcus aureus: 40%. Based on the results obtained, it can be concluded that the ethanol extract of Chromolaena odorata L. leaves has an inhibitory effect on the growth of Salmonella typhi and Staphylococcus aureus. Chromolaena odorata L. leaves has potential as herbal medicine against bacterial infections but requires further research to determine its effect in vivo.

scholarly journals Prophage Lysin Ply30 Protects Mice from Streptococcus suis and Streptococcus equi subsp. zooepidemicus Infections

2015 ◽  
Vol 81 (21) ◽  
pp. 7377-7384 ◽  
Author(s):  
Fang Tang ◽  
Dezhi Li ◽  
Haojin Wang ◽  
Zhe Ma ◽  
Chengping Lu ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Streptococcus Suis ◽  
Swine Industry ◽  
Content Type ◽  
Antimicrobial Efficiency ◽  
Streptococcus Equi ◽  
Wide Ph Range

ABSTRACTStreptococcus suisandStreptococcus equisubsp.zooepidemicusare capable of infecting humans and various animals, causing significant problems for the worldwide swine industry. As antibiotic resistance has increased, lysosomal enzymes encoded by phages have shown potential for use against pathogenic bacteria. In this study, a novel bacteriophage lysin, Ply30, encoded by theS. suisprophage phi30c, was recombinantly expressed and purified. Ply30 showed high bacteriolysis activity onS. suisandS. equisubsp.zooepidemicus in vitro. The ratio of the optical density at 600 nm (OD600) with treatment versus the OD600with no treatment for most testedS. suisandS. equisubsp.zooepidemicusstrains decreased from 1 to <0.3 and <0.5, respectively, within 1 h. The results of plate viability assays showed that treated bacteria suffered a 1- to 2-log decrease in CFU within 1 h. The optimal concentration of Ply30 was 50 μg/ml, and the optimal pH was 7. Moreover, Ply30 maintained high activity over a wide pH range (pH 6 to 10). The MICs of Ply30 againstStreptococcusstrains ranged from 16 to 512 μg/ml.In vivo, a 2-mg dose of Ply30 protected 90% (9/10 mice) of mice from infection withS. equisubsp.zooepidemicusand 80% (8/10 mice) of mice from infection withS. suis. Seven days after lysin Ply30 treatment, bacterial loads were significantly decreased in all tested organs and blood compared with those at 1 h postinfection without Ply30 treatment. Ply30 showedin vitroandin vivoantimicrobial efficiency and protected mice against two kinds of bacterial infections, indicating that Ply30 may be an effective therapeutic against streptococci.

The Anti-infective Potential of Hydroalcoholic Extract of Phyllanthus emblica Seeds Against Selected Human-pathogenic Bacteria

2020 ◽  
Vol 20 (5) ◽  
pp. 672-692 ◽  
Author(s):  
Pooja Patel ◽  
Chinmayi Joshi ◽  
Vijay Kothari
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Seed Extract ◽  
Haemolytic Activity ◽  
Phyllanthus Emblica ◽  
Pathogenic Potential ◽  
Hydroalcoholic Extract ◽  
Infective Potential

Introduction: In the context of the global threat of antimicrobial resistance (AMR) among bacterial pathogens against conventional bactericidal antibiotics, investigation on complementary/ alternative approaches to manage bacterial infections is warranted. The present study aimed at investigating the anti-pathogenic potential of Phyllanthus emblica seed extract (PESE) against four different pathogenic bacteria. Methods: Hydroalcoholic extract of P. emblica seeds was tested for its possible in vitro quorummodulatory potential against Chromobacterium violaceum, Serratia marcescens, Pseudomonas aeruginosa, and Staphylococcus aureus through broth dilution assay. In vivo efficacy of PESE was assayed employing Caenorhabditis elegans as the model host for these four pathogens. Results: PESE was found to exert in vitro quorum-modulatory effect on C. violaceum, S. marcescens, P. aeruginosa, and S. aureus at ≥50 μg/mL. This extract could curb the haemolytic activity of all the four test bacteria by 23-65%, inhibit biofilm formation, and was also able to modulate their antibiotic susceptibility (AS) and catalase activity. Susceptibility of P. aeruginosa and S. aureus to lysis by human serum was enhanced under the influence of this extract by 23% and 49%, respectively. Repeated exposure of both these notorious pathogens to PESE did not induce resistance in them. In vivo assay confirmed the anti-virulence effect of this extract in the C. elegans host, wherein the nematode host challenged with the PESE-treated pathogenic bacteria scored better survival. PESE also displayed notable prebiotic potential by promoting the growth of three probiotic strains. Conclusion: To the best of our awareness, this is the first report on the quorum-modulatory potential of P. emblica seed extract, validating its anti-infective potential and prebiotic property.

scholarly journals Increased efficiency of Campylobacter jejuni N -oligosaccharyltransferase PglB by structure-guided engineering

Open Biology ◽  
2015 ◽  
Vol 5 (4) ◽  
pp. 140227 ◽  
Author(s):  
Julian Ihssen ◽  
Jürgen Haas ◽  
Michael Kowarik ◽  
Luzia Wiesli ◽  
Michael Wacker ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Three Dimensional ◽  
Homology Model ◽  
Functional Expression ◽  
Saturation Mutagenesis ◽  
Triple Mutant

Conjugate vaccines belong to the most efficient preventive measures against life-threatening bacterial infections. Functional expression of N -oligosaccharyltransferase ( N -OST) PglB of Campylobacter jejuni in Escherichia coli enables a simplified production of glycoconjugate vaccines in prokaryotic cells. Polysaccharide antigens of pathogenic bacteria can be covalently coupled to immunogenic acceptor proteins bearing engineered glycosylation sites. Transfer efficiency of PglB Cj is low for certain heterologous polysaccharide substrates. In this study, we increased glycosylation rates for Salmonella enterica sv. Typhimurium LT2 O antigen (which lacks N -acetyl sugars) and Staphylococcus aureus CP5 polysaccharides by structure-guided engineering of PglB. A three-dimensional homology model of membrane-associated PglB Cj , docked to the natural C. jejuni N -glycan attached to the acceptor peptide, was used to identify potential sugar-interacting residues as targets for mutagenesis. Saturation mutagenesis of an active site residue yielded the enhancing mutation N311V, which facilitated fivefold to 11-fold increased in vivo glycosylation rates as determined by glycoprotein-specific ELISA. Further rounds of in vitro evolution led to a triple mutant S80R-Q287P-N311V enabling a yield improvement of S. enterica LT2 glycoconjugates by a factor of 16. Our results demonstrate that bacterial N -OST can be tailored to specific polysaccharide substrates by structure-guided protein engineering.

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