scholarly journals Characterization of Cetacean Proline-Rich Antimicrobial Peptides Displaying Activity against ESKAPE Pathogens

2020 ◽  
Vol 21 (19) ◽  
pp. 7367
Author(s):  
Riccardo Sola ◽  
Mario Mardirossian ◽  
Bertrand Beckert ◽  
Laura Sanghez De Luna ◽  
Dennis Prickett ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Mechanism Of Action ◽  
In Vitro Cytotoxicity ◽  
Peptide Transporter ◽  
Cetacean Species ◽  
Activity Spectrum ◽  
Low Cytotoxicity ◽  
Eskape Pathogens ◽  
Bacterial Protein Synthesis

Proline-rich antimicrobial peptides (PrAMPs) may be a valuable weapon against multi-drug resistant pathogens, combining potent antimicrobial activity with low cytotoxicity. We have identified novel PrAMPs from five cetacean species (cePrAMPs), and characterized their potency, mechanism of action and in vitro cytotoxicity. Despite the homology between the N-terminal of cePrAMPs and the bovine PrAMP Bac7, some differences emerged in their sequence, activity spectrum and mode of action. CePrAMPs with the highest similarity with the Bac7(1-35) fragment inhibited bacterial protein synthesis without membrane permeabilization, while a second subgroup of cePrAMPs was more membrane-active but less efficient at inhibiting bacterial translation. Such differences may be ascribable to differences in presence and positioning of Trp residues and of a conserved motif seemingly required for translation inhibition. Unlike Bac7(1-35), which requires the peptide transporter SbmA for its uptake, the activity of cePrAMPs was mostly independent of SbmA, regardless of their mechanism of action. Two peptides displayed a promisingly broad spectrum of activity, with minimal inhibiting concentration MIC ≤ 4 µM against several bacteria of the ESKAPE group, including Pseudomonas aeruginosa and Enterococcus faecium. Our approach has led us to discover several new peptides; correlating their sequences and mechanism of action will provide useful insights for designing optimized future peptide-based antibiotics.

In-Vitro Cytotoxicity and Clinical Correlates of MRSA Bacteremia

2021 ◽  
Author(s):  
Thomas H. McConville ◽  
Eloise D. Austin ◽  
Wenjing Geng ◽  
Qiuhu Shi ◽  
Divya Balasubramanian ◽  
...  
Keyword(s):  
Cell Model ◽  
Bloodstream Infections ◽  
Toxin Production ◽  
In Vitro Cytotoxicity ◽  
Comorbidity Burden ◽  
Observational Cohort ◽  
Low Cytotoxicity ◽  
High Cytotoxicity ◽  
Poor Outcomes

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections are associated with significant morbidity and mortality. MRSA secretes a number of virulence factors and pore-forming toxins that enable tissue invasion. Prior studies have found associations between decreased toxin production and poor outcomes in invasive MRSA infection, particularly in pneumonia. In this retrospective observational cohort study of MRSA bacteremia in adult patients 2007-2015, we examined whether cytotoxicity was associated with 30-day mortality. Isolates were obtained from 776 patients and screened for cytotoxicity in a human HL-60 cell model, antimicrobial susceptibility and spa type, and clinical data were abstracted from charts. We did not find an association between low cytotoxic activity and 30-day mortality in univariate logistic regression analyses. There was a difference in distribution of the genotypes across cytotoxicity phenotypes, with spa -CC008 accounting for a larger proportion of isolates in the high cytotoxicity group. Isolates with a skin and soft tissue primary infective site had a higher median cytotoxicity. There was no association between cytotoxicity and host factors such as age or comorbidity burden. The isolates in our study came from heterogeneous primary sites of infection and were predominantly from spa -CC002 and spa -CC008 lineages, so it is possible that findings in prior studies reflect a different distribution in genotypes and clinical syndromes. Overall, in this large study of cytotoxicity of MRSA bloodstream isolates, we did not find the low cytotoxicity phenotype to be predictive of poor outcomes in MRSA bacteremia.

scholarly journals Targeting Mycobacterium tuberculosis and Other Microbial Pathogens Using Improved Synthetic Antibacterial Peptides

2013 ◽  
Vol 57 (5) ◽  
pp. 2295-2303 ◽  
Author(s):  
Santiago Ramón-García ◽  
Ralf Mikut ◽  
Carol Ng ◽  
Serge Ruden ◽  
Rudolf Volkmer ◽  
...  
Keyword(s):  
Amino Acids ◽  
Mycobacterium Tuberculosis ◽  
Antimicrobial Peptides ◽  
Fungal Pathogens ◽  
Antimicrobial Activities ◽  
Microbial Pathogens ◽  
Cationic Antimicrobial Peptides ◽  
Content Type ◽  
Activity Spectrum ◽  
Low Cytotoxicity

ABSTRACTThe lack of effective therapies for treating tuberculosis (TB) is a global health problem. WhileMycobacterium tuberculosisis notoriously resistant to most available antibiotics, we identified synthetic short cationic antimicrobial peptides that were active at low micromolar concentrations (less than 10 μM). These small peptides (averaging 10 amino acids) had remarkably broad spectra of antimicrobial activities against both bacterial and fungal pathogens and an indication of low cytotoxicity. In addition, their antimicrobial activities displayed various degrees of species specificity that were not related to taxonomy. For example,Candida albicansandStaphylococcus aureuswere the best surrogates to predict peptide activity againstM. tuberculosis, whileMycobacterium smegmatiswas a poor surrogate. Principle component analysis of activity spectrum profiles identified unique features associated with activity againstM. tuberculosisthat reflect their distinctive amino acid composition; active peptides were more hydrophobic and cationic, reflecting increased tryptophan with compensating decreases in valine and other uncharged amino acids and increased lysine. These studies provide foundations for development of cationic antimicrobial peptides as potential new therapeutic agents for TB treatment.

In vitro cytotoxicity of co-exposure to superparamagnetic iron oxide and solid lipid nanoparticles

2020 ◽  
pp. 074823372097738
Author(s):  
Okunola A Alabi ◽  
Adny H Silva ◽  
Michele P Rode ◽  
Carine dal Pizzol ◽  
Angela Machado de Campos ◽  
...  
Keyword(s):  
Iron Oxide ◽  
Solid Lipid Nanoparticles ◽  
Superparamagnetic Iron Oxide ◽  
Lipid Nanoparticles ◽  
In Vitro Cytotoxicity ◽  
Ros Generation ◽  
Solid Lipid ◽  
Viability Assay ◽  
Low Cytotoxicity

Increased production and use of different types of nanoparticles (NPs) in the last decades has led to increased environmental release of these NPs with potential detrimental effects on both the environment and public health. Information is scarce in the literature on the cytotoxic effect of co-exposure to many NPs as this concern is relatively recent. Thus, in this study, we hypothesized scenarios of cell’s co-exposure to two kinds of NPs, solid lipid nanoparticles (SLNs) and superparamagnetic iron oxide nanoparticles (SPIONs), to assess the potential cytotoxicity of exposure to NPs combination. Cytotoxicity of SPIONs, SLNs, and their 1:1 mixture (MIX) in six tumor and six non-tumor cell lines was investigated. The mechanisms underlining the induced cytotoxicity were studied through cell cycle analysis, detection of reactive oxygen species (ROS), and alterations in mitochondrial membrane potential (ΔΨM). Double staining with acridine orange and ethidium bromide was also used to confirm cell morphology alterations. The results showed that SPIONs induced low cytotoxicity compared to SLNs. However, the mixture of SPIONs and SLNs showed synergistic, antagonistic, and additive effects based on distinct tests such as viability assay, ROS generation, ΔΨM, and DNA damage, depending on the cell line. Apoptosis triggered by ROS and disturbances in ΔΨM are the most probable related mechanisms of action. As was postulated, there is possible cytotoxic interaction between the two kinds of NPs.

scholarly journals Intraperitoneal treatment with antimicrobial peptide rescues mice from a pulmonaryFrancisellainfection

2019 ◽  
Author(s):  
Monique L. van Hoek ◽  
Akanksha Kaushal ◽  
Barney M. Bishop ◽  
Stephanie M. Barksdale
Keyword(s):  
Antibacterial Activity ◽  
Antimicrobial Peptides ◽  
Cyclic Peptide ◽  
Virulent Strain ◽  
Multi Drug Resistance ◽  
Beta Lactam ◽  
Beta Lactam Antibiotics ◽  
Peptide Derivatives ◽  
Low Cytotoxicity

AbstractOur long-term goal is to identify new antimicrobial peptides that might be effective against pneumonicFrancisellainfection in mice. Previously, our group searched the peptidome of the American alligator for novel cationic antimicrobial peptides and identified a naturally-occurring C-terminal fragment of apolipoprotein C-1, which we called Apo6. This peptide was found to have antibacterial activity against the ESKAPE pathogens, including those exhibiting multi-drug resistance. In this work, we tested Apo6 and synthetic derivatives for antibacterial activity againstFrancisella tularensisincluding the virulent strainF. tularensisSchuS4.Francisellais inherently highly resistant to the cyclic peptide polymyxin antibiotics and beta-lactam antibiotics. We found that our synthetic peptide derivatives (called GATR peptides), designed with increased hydrophobicity and charge, had generally strongerin vitroantimicrobial activity againstFrancisellathan the parent peptide Apo6. The GATR peptides had a greater effect on the bacterial membrane than the Apo6 peptide and were able to bindFrancisellaLPS, suggesting their mechanism of action againstFrancisella. Cytotoxicity experiments showed low cytotoxicity for most of the GATR peptides, and whole organism toxicity studies in the waxworm allowed us to down-select to two our lead peptides, GATR-3 and GATR-6. These peptides were tested in a murine pulmonary tularemia model. We found that the GATR-3 peptide rescued 50-60% of mice from lethal tularemia infection when administered systemically through the intraperitoneal route. This peptide is a candidate for further pre-clinical studies for a potential peptide-based approach to tularemia.

scholarly journals Engineered Cationic Antimicrobial Peptides To Overcome Multidrug Resistance by ESKAPE Pathogens

2014 ◽  
Vol 59 (2) ◽  
pp. 1329-1333 ◽  
Author(s):  
Berthony Deslouches ◽  
Jonathan D. Steckbeck ◽  
Jodi K. Craigo ◽  
Yohei Doi ◽  
Jane L. Burns ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Antimicrobial Peptides ◽  
De Novo ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Resistant Bacteria ◽  
Clinical Settings ◽  
Eskape Pathogens ◽  
Antibiotic Peptides

ABSTRACTMultidrug resistance constitutes a threat to the medical achievements of the last 50 years. In this study, we demonstrated the abilities of twode novoengineered cationic antibiotic peptides (eCAPs), WLBU2 and WR12, to overcome resistance from 142 clinical isolates representing the most common multidrug-resistant (MDR) pathogens and to display a lower propensity to select for resistant bacteriain vitrocompared to that with colistin and LL37. The results warrant an exploration of eCAPs for use in clinical settings.

scholarly journals Mechanism of Action of the Novel Aminomethylcycline Antibiotic Omadacycline

2013 ◽  
Vol 58 (3) ◽  
pp. 1279-1283 ◽  
Author(s):  
Michael P. Draper ◽  
S. Weir ◽  
A. Macone ◽  
J. Donatelli ◽  
C. A. Trieber ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Mechanism Of Action ◽  
Tetracycline Resistance ◽  
The Novel ◽  
Content Type ◽  
Biophysical Studies ◽  
Bacterial Protein Synthesis ◽  
Ribosomal Protection Protein ◽  
Ribosomal Protection

ABSTRACTOmadacycline is a novel first-in-class aminomethylcycline with potent activity against important skin and pneumonia pathogens, including community-acquired methicillin-resistantStaphylococcus aureus(MRSA), β-hemolytic streptococci, penicillin-resistantStreptococcus pneumoniae,Haemophilus influenzae, andLegionella. In this work, the mechanism of action for omadacycline was further elucidated using a variety of models. Functional assays demonstrated that omadacycline is active against strains expressing the two main forms of tetracycline resistance (efflux and ribosomal protection). Macromolecular synthesis experiments confirmed that the primary effect of omadacycline is on bacterial protein synthesis, inhibiting protein synthesis with a potency greater than that of tetracycline. Biophysical studies with isolated ribosomes confirmed that the binding site for omadacycline is similar to that for tetracycline. In addition, unlike tetracycline, omadacycline is activein vitroin the presence of the ribosomal protection protein Tet(O).

scholarly journals Synthesis and Comparative Characterization of Different Microparticles used as Biomaterials in Dentistry

2021 ◽  
Vol 58 (2) ◽  
pp. 192-200
Author(s):  
Sergiu Alexandru Tofan ◽  
Cristian Olteanu ◽  
Camelia Szuhanek ◽  
ramona Amina Popovici ◽  
Magda Mihaela Luca ◽  
...  
Keyword(s):  
Living System ◽  
In Vitro Cytotoxicity ◽  
Functional Requirements ◽  
Clinical Evaluations ◽  
Polymeric Microparticles ◽  
Great Availability ◽  
Low Cytotoxicity ◽  
Materials Used

A biomaterial must be biologically compatible, mechanical, functional, corrosion resistant and easily adapt to clinical and laboratory technologies. Dental biomaterials are materials used to replace a part of a living system or to work closely with living tissue. Many scientific articles present different polymeric biocomposites with possible application in dentistry and this is a proof of the opportunity of a research in a field in full ascent and with great availability in the promotion of materials destined to �work under biological constraint� and which must also meet the functional requirements of a dental implant. The objectives of this research were to obtain and to comparatively evaluate different polymeric microparticles that can be used in dentistry. The samples based on poly(lactic-co-glycolic acid) and respectively polyurethane microparticles were characterized by pH and Zetasizer measurements, and in vitro cytotoxicity assays. The results indicate the obtaining of particles with a neutral pH, medium homogeneity, and with different tendencies to form agglomerations. Their low cytotoxicity, tested on the primary human gingival fibroblasts by MTT and LDH techniques, indicates that these microparticles are safe to be tested in further clinical evaluations.

scholarly journals Sinorhizobium meliloti functions required for resistance to antimicrobial NCR peptides and bacteroid differentiation

2020 ◽  
Author(s):  
Quentin Nicoud ◽  
Quentin Barrière ◽  
Nicolas Busset ◽  
Mickaël Bourge ◽  
Romain Le Bars ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Sinorhizobium Meliloti ◽  
Peptide Transporter ◽  
Nitrogen Fixing ◽  
Nodule Bacteria ◽  
Toxic Activity ◽  
Large Numbers ◽  
Peptide Uptake ◽  
Broad Specificity

AbstractLegumes of the Medicago genus form symbiosis with the bacterium Sinorhizobium meliloti and develop root nodules housing large numbers of the intracellular symbionts. Members of the Nodule-specific Cysteine Rich peptide (NCRs) family induce the endosymbionts into a terminal differentiated state. Individual cationic NCRs are antimicrobial peptides that have the capacity to kill the symbiont but the nodule cell environment prevents killing. Moreover, the bacterial broad-specificity peptide uptake transporter BacA and exopolysaccharides contribute to protect the endosymbionts against the toxic activity of NCRs. Here, we show that other S. meliloti functions participate in the protection of the endosymbionts, including an additional broad-specificity peptide uptake transporter encoded by the yejABEF genes, lipopolysaccharide modifications mediated by lpsB and lpxXL as well as rpoH1, encoding a stress sigma factor. Mutants in these genes show in vitro a strain-specific increased sensitivity profile against a panel of NCRs and form nodules in which bacteroid differentiation is affected. The lpsB mutant nodule bacteria do not differentiate, the lpxXL and rpoH1 mutants form some seemingly fully differentiated bacteroids although most of the nodule bacteria are undifferentiated, while the yejABEF mutants form hypertrophied but nitrogen-fixing bacteroids. The nodule bacteria of all the mutants have a strongly enhanced membrane permeability, which is dependent on the transport of NCRs to the endosymbionts. Our results suggest that S. meliloti relies on a suite of functions including peptide transporters, the bacterial envelope structures and stress response regulators to resist the stressful assault of NCR peptides in the nodule cells.ImportanceThe nitrogen fixing symbiosis of legumes with rhizobium bacteria has a predominant ecological role in the nitrogen cycle and has the potential to provide the nitrogen required for plant growth in agriculture. The host plants allow the rhizobia to colonize specific symbiotic organs, the nodules, in large numbers in order to produce sufficient reduced nitrogen for the plant needs. Some legumes, including Medicago spp., produce massively antimicrobial peptides to keep this large bacterial population in check. These peptides, known as NCRs, have the potential to kill the rhizobia but in nodules, they only inhibit the division of the bacteria, which maintain a high nitrogen fixing activity. In this study, we show that the tempering of the antimicrobial activity of the NCR peptides in the Medicago symbiont Sinorhizobium meliloti is multifactorial and requires the YejABEF peptide transporter, the lipopolysaccharide outer membrane and the stress regulator RpoH1.

scholarly journals Robust Copper Metal–Organic Framework-Embedded Polysiloxanes for Biomedical Applications: Its Antibacterial Effects on MRSA and In Vitro Cytotoxicity

Nanomaterials ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 719
Author(s):  
Kihak Gwon ◽  
Youngmee Kim ◽  
Hyunjun Cho ◽  
Seonhwa Lee ◽  
So-Hyeon Yang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Metal Organic Framework ◽  
In Vitro Cytotoxicity ◽  
Disease Treatment ◽  
Metal Organic ◽  
Bactericidal Activities ◽  
Low Cytotoxicity ◽  
Phosphate Buffered Saline ◽  
Organic Framework

Polysiloxanes (PSs) have been widely utilized in the industry as lubricants, varnishes, paints, release agents, adhesives, and insulators. In addition, their applications have been expanded to include the development of new biomedical materials. To modify PS for application in therapeutic purposes, a flexible antibacterial Cu-MOF (metal–organic framework) consisting of glutarate and 1,2-bis(4-pyridyl)ethane ligands was embedded in PS via a hydrosilylation reaction of vinyl-terminated and H-terminated PSs at 25 °C. The bactericidal activities of the resulting Cu-MOF-embedded PS (PS@Cu-MOF) and the control polymer (PS) were tested against Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus. PS@Cu-MOF exhibited more than 80% bactericidal activity toward the tested bacteria at a concentration of 100 μg⋅mL−1 and exhibited a negligible cytotoxicity toward mouse embryonic fibroblasts at the same concentration. Release tests of the Cu(II) ion showed PS@Cu-MOF to be particularly stable in a phosphate-buffered saline solution. Furthermore, its physical and thermal properties, including the phase transition, rheological measurements, swelling ratio, and thermogravimetric profile loss, were similar to those of the control polymer. Moreover, the low cytotoxicity and bactericidal activities of PS@Cu-MOF render it a promising candidate for use in medicinal applications, such as in implants, skin-disease treatment, wound healing, and drug delivery.

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