scholarly journals Hitchhiking with Nature: Snake Venom Peptides to Fight Cancer and Superbugs

Toxins ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 255 ◽  
Author(s):  
Clara Pérez-Peinado ◽  
Sira Defaus ◽  
David Andreu
Keyword(s):  
Therapeutic Potential ◽  
State Of The Art ◽  
Resistant Bacteria ◽  
Snake Venoms ◽  
Antibiotic Resistant ◽  
Anticancer Peptides ◽  
Therapeutic Development ◽  
Drug Leads

For decades, natural products in general and snake venoms (SV) in particular have been a rich source of bioactive compounds for drug discovery, and they remain a promising substrate for therapeutic development. Currently, a handful of SV-based drugs for diagnosis and treatment of various cardiovascular disorders and blood abnormalities are on the market. Likewise, far more SV compounds and their mimetics are under investigation today for diverse therapeutic applications, including antibiotic-resistant bacteria and cancer. In this review, we analyze the state of the art regarding SV-derived compounds with therapeutic potential, focusing on the development of antimicrobial and anticancer drugs. Specifically, information about SV peptides experimentally validated or predicted to act as antimicrobial and anticancer peptides (AMPs and ACPs, respectively) has been collected and analyzed. Their principal activities both in vitro and in vivo, structures, mechanisms of action, and attempts at sequence optimization are discussed in order to highlight their potential as drug leads.

scholarly journals Characterization and Therapeutic Potential of Bacteriophage-Encoded Polysaccharide Depolymerases with β Galactosidase Activity against Klebsiella pneumoniae K57 Capsular Type

Antibiotics ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 732
Author(s):  
Nikolay V. Volozhantsev ◽  
Anna M. Shpirt ◽  
Alexander I. Borzilov ◽  
Ekaterina V. Komisarova ◽  
Valentina M. Krasilnikova ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Therapeutic Potential ◽  
Resistant Bacteria ◽  
Capsular Type ◽  
Antibiotic Resistant ◽  
Promising Tool ◽  
Hip Infection ◽  
Immune Attack ◽  
Hydrolytic Mechanism

Bacteriophages and phage enzymes are considered as possible alternatives to antibiotics in the treatment of infections caused by antibiotic-resistant bacteria. Due to the ability to cleave the capsular polysaccharides (CPS), one of the main virulence factors of Klebsiella pneumoniae, phage depolymerases, has potential in the treatment of K. pneumoniae infections. Here, we characterized in vivo two novel phage-encoded polysaccharide depolymerases as therapeutics against clinical isolates of K. pneumoniae. The depolymerases Dep_kpv79 and Dep_kpv767 encoded by Klebsiella phages KpV79 (Myoviridae; Jedunavirus) and KpV767 (Autographiviridae, Studiervirinae, Przondovirus), respectively, were identified as specific β-galactosidases that cleave the K. pneumoniae K57 type CPS by the hydrolytic mechanism. They were found to be highly effective at combating sepsis and hip infection caused by K. pneumoniae in lethal mouse models. Here, 80–100% of animals were protected against death by a single dose (e.g., 50 μg/mouse) of the enzyme injected 0.5 h after infection by K. pneumoniae strains of the K57 capsular type. The therapeutic effect of the depolymerases is because they strip the capsule and expose the underlying bacterium to the immune attack such as complement-mediated killing. These data provide one more confirmation that phage polysaccharide depolymerases represent a promising tool for antimicrobial therapy.

scholarly journals Phage steering of antibiotic-resistance evolution in the bacterial pathogen, Pseudomonas aeruginosa

2020 ◽  
Vol 2020 (1) ◽  
pp. 148-157 ◽  
Author(s):  
James Gurney ◽  
Léa Pradier ◽  
Joanne S Griffin ◽  
Claire Gougat-Barbera ◽  
Benjamin K Chan ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Bacterial Pathogen ◽  
Antibiotic Sensitivity ◽  
Resistant Bacteria ◽  
Phage Resistance ◽  
Antibiotic Resistant ◽  
Trade Off

Abstract Background and objectives Antimicrobial resistance is a growing global concern and has spurred increasing efforts to find alternative therapeutics. Bacteriophage therapy has seen near constant use in Eastern Europe since its discovery over a century ago. One promising approach is to use phages that not only reduce bacterial pathogen loads but also select for phage resistance mechanisms that trade-off with antibiotic resistance—so called ‘phage steering’. Methodology Recent work has shown that the phage OMKO1 can interact with efflux pumps and in so doing select for both phage resistance and antibiotic sensitivity of the pathogenic bacterium Pseudomonas aeruginosa. We tested the robustness of this approach to three different antibiotics in vitro (tetracycline, erythromycin and ciprofloxacin) and one in vivo (erythromycin). Results We show that in vitro OMKO1 can reduce antibiotic resistance of P. aeruginosa (Washington PAO1) even in the presence of antibiotics, an effect still detectable after ca.70 bacterial generations in continuous culture with phage. Our in vivo experiment showed that phage both increased the survival times of wax moth larvae (Galleria mellonella) and increased bacterial sensitivity to erythromycin. This increased antibiotic sensitivity occurred both in lines with and without the antibiotic. Conclusions and implications Our study supports a trade-off between antibiotic resistance and phage sensitivity. This trade-off was maintained over co-evolutionary time scales even under combined phage and antibiotic pressure. Similarly, OMKO1 maintained this trade-off in vivo, again under dual phage/antibiotic pressure. Our findings have implications for the future clinical use of steering in phage therapies. Lay Summary: Given the rise of antibiotic-resistant bacterial infection, new approaches to treatment are urgently needed. Bacteriophages (phages) are bacterial viruses. The use of such viruses to treat infections has been in near-continuous use in several countries since the early 1900s. Recent developments have shown that these viruses are not only effective against routine infections but can also target antibiotic resistant bacteria in a novel, unexpected way. Similar to other lytic phages, these so-called ‘steering phages’ kill the majority of bacteria directly. However, steering phages also leave behind bacterial variants that resist the phages, but are now sensitive to antibiotics. Treatment combinations of these phages and antibiotics can now be used to greater effect than either one independently. We evaluated the impact of steering using phage OMKO1 and a panel of three antibiotics on Pseudomonas aeruginosa, an important pathogen in hospital settings and in people with cystic fibrosis. Our findings indicate that OMKO1, either alone or in combination with antibiotics, maintains antibiotic sensitivity both in vitro and in vivo, giving hope that phage steering will be an effective treatment option against antibiotic-resistant bacteria.

In Vitro and In Vivo Efficacy of Catheters Impregnated With Antiseptics or Antibiotics: Evaluation of the Risk of Bacterial Resistance to the Antimicrobials in the Catheters

2001 ◽  
Vol 22 (10) ◽  
pp. 640-646 ◽  
Author(s):  
Lester A. Sampath ◽  
Suhas M. Tambe ◽  
Shanta M. Modak
Keyword(s):  
Bacterial Resistance ◽  
Test Organism ◽  
Similar Efficacy ◽  
Resistant Bacteria ◽  
Antibiotic Resistant ◽  
In Vivo Efficacy ◽  
Development Of Resistance ◽  
Zones Of Inhibition

AbstractObjective:To compare the efficacy of a new antiseptic catheter containing silver sulfadiazine and chlorhexidine on the external surface and chlorhexidine in the lumens to an antibiotic catheter impregnated with minocycline and rifampin on its external and luminal surfaces.Design:Experimental trial.Methods:Antimicrobial spectrum of catheters was determined by zones of inhibition. Resistance to luminal colonization was tested in vitro by locking catheter lumens withStaphylococcus epidermidisorStaphylococcus aureusculture after 7 days of perfusion. In vitro development of resistance to the antiseptic or antibiotic combination used in catheters was investigated. In vivo efficacy was tested (rat subcutaneous model) by challenge with sensitive or antibiotic-resistant bacteria.Results:Antiseptic and antibiotic catheters exhibited broad-spectrum action. However, antibiotic catheters were not effective againstCandidaspecies andPseudomonas aeruginosa.Both catheters prevented luminal colonization. Compared to controls, both test catheters resisted colonization when challenged withS aureus7 and 14 days' postimplant (P<.05).Repeated in vitro exposure ofS epidermidisculture to the antibiotic and antiseptic combinations led to small increases in the minimum inhibitory concentration (15 times and 2 times, respectively). Unlike the antibiotic catheter, the in vitro and in vivo activity of the antiseptic catheter was unaffected by the resistance profile of the test organism. Antiseptic catheters were more effective than antibiotic catheters in preventing colonization by rifampin-resistantS epidermidisin vivo (P<.05).Conclusions:Antiseptic and antibiotic catheters exhibit similar efficacy; however, when challenged with a rifampin-resistant strain, the antibiotic catheter appeared to be more susceptible to colonization than the antiseptic device.

scholarly journals New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

2016 ◽  
Vol 60 (6) ◽  
pp. 3717-3729 ◽  
Author(s):  
Jourdan A. Andersson ◽  
Eric C. Fitts ◽  
Michelle L. Kirtley ◽  
Duraisamy Ponnusamy ◽  
Alex G. Peniche ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Bacterial Pathogens ◽  
Bactericidal Effect ◽  
Resistant Bacteria ◽  
Content Type ◽  
Broad Applicability ◽  
Approved Drugs ◽  
Fda Approved Drugs

Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulentYersinia pestisCO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventingY. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy inin vitroscreens, were chosen for further evaluation in a murine model of pneumonic plague to delineate ifin vitroefficacy could be translatedin vivo. Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect onY. pestisand having no modulating effect on crucialY. pestisvirulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified fromin vitroscreens, the therapeutic potential of TFP, the most efficacious drugin vivo, was evaluated in murine models ofSalmonella entericaserovar Typhimurium andClostridium difficileinfections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens.

scholarly journals Silver i-motifs and their antibacterial activity

2021 ◽  
Author(s):  
Jessica Bratt
Keyword(s):  
Antibacterial Activity ◽  
Therapeutic Potential ◽  
Bacterial Load ◽  
Therapeutic Benefit ◽  
In Vivo Studies ◽  
Resistant Bacteria ◽  
Drug Resistant Bacteria ◽  
Low Concentrations

<p>The spread of antibiotic resistance and the emergence of multi-drug resistant bacteria is a major threat to public health. This study investigated a unique cytosine rich DNA structure, the i-Motif to deliver soluble Ag+ as a novel antimicrobial agent (AgiMs). AgiMs were evaluated in vitro against P. aeruginosa and A. baumannii strains. AgiMs displayed significant antibacterial activity against both P. aeruginosa and A. baumannii (median MIC: 0.875 µM and 0.75 µM, respectively) by rapid, bactericidal and concentration-dependent effect. Low concentrations of AgiMs showed efficacy against PAO1 20-h biofilms, resulting in 57% reduction in biomass (5 x MIC). A single dose of AgiMs extended survival of G. Mellonella larvae, with the therapeutic benefit paralleled in the reduction of internal bacterial load. Synergistic interactions were observed with the combination of AgiMs and tobramycin, a common antibiotic used to treat P. aeruginosa infections; indicating the potential for AgiMs to reinstate the potency of current antibiotics. This silver-based agent might be an alternative to the failing antibiotic regimes for MDR resistant infections. Further in vitro and in vivo studies are warranted to confirm the therapeutic potential. </p>

scholarly journals In Vitro Tests for Assessing the Neutralizing Ability of Snake Antivenoms: Toward the 3Rs Principles

2021 ◽  
Vol 11 ◽  
Author(s):  
José María Gutiérrez ◽  
Mariángela Vargas ◽  
Álvaro Segura ◽  
María Herrera ◽  
Mauren Villalta ◽  
...  
Keyword(s):  
State Of The Art ◽  
Toxicity Tests ◽  
In Vitro Tests ◽  
Enzyme Assays ◽  
Snake Venoms ◽  
Experimental Animals ◽  
Functional Assays ◽  
3Rs Principle

There is an urgent need to strengthen the implementation of the 3Rs principle (Replacement, Reduction and Refinement) in the use of experimental animals in toxinological research and in the assessment of the neutralizing efficacy of snake antivenoms. This is a challenging task owing to the inherent complexity of snake venoms. The state of the art on this topic is hereby reviewed, with emphasis on the studies in which a correlation has been observed between in vivo toxicity tests and in vitro surrogate assays, particularly in the study of lethal activity of venoms and its neutralization. Correlations have been described with some venoms-antivenoms when using: (a) enzyme immunoassays, (b) hemagglutination, (c) enzyme assays (proteinase, phospholipase A2), (d) in vitro coagulant effect on plasma, (e) cell culture assays for cytotoxicity, (f) functional assays for assessing neurotoxicity in vitro, (g) use of hens’ eggs, and (h) antivenomics. Additionally, the routine introduction of analgesia in these assays and the design of more ‘humane’ protocols for the lethality test are being pursued. It is expected that the next years will witness a growing awareness of the relevance of the 3Rs principles in antivenom testing, and that new in vitro alternatives and more ‘humane’ experimental designs will emerge in this field.

scholarly journals THE POSSIBILITIES OF USING PHAGE THERAPY IN DENTISTRY

2018 ◽  
Vol 22 (2) ◽  
pp. 107-110
Author(s):  
Maria Vladimirovna Kuchmina ◽  
A. Yu Turkina ◽  
Yu. O Paramonov
Keyword(s):  
Bacterial Cell ◽  
Phage Therapy ◽  
Periodontal Diseases ◽  
Resistant Bacteria ◽  
Clinical Use ◽  
Antibiotic Resistant ◽  
Domestic Literature ◽  
Advantages And Disadvantages

The article is devoted to the possibilities of using bacteriophages in dentistry. The main characteristics of bacteriophages and mechanisms of their interaction with a bacterial cell as well as the data of microbiological studies and the results of clinical use of bacteriophages in periodontal diseases are discussed. Bacteriophages have been shown to be effective against periodontopathogenic microorganisms, including antibiotic resistant bacteria in vitro and in vivo. There were reflected the advantages and disadvantages of phage therapy, the main of which for today is a small experience of clinical use of this method. Objective. To analyze the data of foreign and domestic literature and publications in the field of phagotherapy effectiveness in dentistry.

scholarly journals PredictingIn VivoEfficacy of Therapeutic Bacteriophages Used To Treat Pulmonary Infections

2013 ◽  
Vol 57 (12) ◽  
pp. 5961-5968 ◽  
Author(s):  
Marine Henry ◽  
Rob Lavigne ◽  
Laurent Debarbieux
Keyword(s):  
Mouse Lung ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Bacteriophage Therapy ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Personalized Approach ◽  
First Time

ABSTRACTThe potential of bacteriophage therapy to treat infections caused by antibiotic-resistant bacteria has now been well established using various animal models. While numerous newly isolated bacteriophages have been claimed to be potential therapeutic candidates on the basis ofin vitroobservations, the parameters used to guide their choice among billions of available bacteriophages are still not clearly defined. We made use of a mouse lung infection model and a bioluminescent strain ofPseudomonas aeruginosato compare the activitiesin vitroandin vivoof a set of nine different bacteriophages (PAK_P1, PAK_P2, PAK_P3, PAK_P4, PAK_P5, CHA_P1, LBL3, LUZ19, and PhiKZ). For seven bacteriophages, a good correlation was found betweenin vitroandin vivoactivity. While the remaining two bacteriophages were activein vitro, they were not sufficiently activein vivounder similar conditions to rescue infected animals. Based on the bioluminescence recorded at 2 and 8 h postinfection, we also define for the first time a reliable index to predict treatment efficacy. Our results showed that the bacteriophages isolated directly on the targeted host were the most efficientin vivo, supporting a personalized approach favoring an optimal treatment.

scholarly journals Evaluation of Phage Therapy in the Context of Enterococcus faecalis and Its Associated Diseases

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 366 ◽  
Author(s):  
Bolocan ◽  
Upadrasta ◽  
Bettio ◽  
Clooney ◽  
Draper ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Antimicrobial Agents ◽  
Phage Therapy ◽  
Domain Architecture ◽  
The Body ◽  
In Vivo Studies ◽  
Resistant Bacteria ◽  
Antibiotic Resistant

Bacteriophages (phages) or bacterial viruses have been proposed as natural antimicrobial agents to fight against antibiotic-resistant bacteria associated with human infections. Enterococcus faecalis is a gut commensal, which is occasionally found in the mouth and vaginal tract, and does not usually cause clinical problems. However, it can spread to other areas of the body and cause life-threatening infections, such as septicemia, endocarditis, or meningitis, in immunocompromised hosts. Although E. faecalis phage cocktails are not commercially available within the EU or USA, there is an accumulated evidence from in vitro and in vivo studies that have shown phage efficacy, which supports the idea of applying phage therapy to overcome infections associated with E. faecalis. In this review, we discuss the potency of bacteriophages in controlling E. faecalis, in both in vitro and in vivo scenarios. E. faecalis associated bacteriophages were compared at the genome level and an attempt was made to categorize phages with respect to their suitability for therapeutic application, using orthocluster analysis. In addition, E. faecalis phages have been examined for the presence of antibiotic-resistant genes, to ensure their safe use in clinical conditions. Finally, the domain architecture of E. faecalis phage-encoded endolysins are discussed.

scholarly journals Silver i-motifs and their antibacterial activity

2021 ◽  
Author(s):  
Jessica Bratt
Keyword(s):  
Antibacterial Activity ◽  
Therapeutic Potential ◽  
Bacterial Load ◽  
Therapeutic Benefit ◽  
In Vivo Studies ◽  
Resistant Bacteria ◽  
Drug Resistant Bacteria ◽  
Low Concentrations

<p>The spread of antibiotic resistance and the emergence of multi-drug resistant bacteria is a major threat to public health. This study investigated a unique cytosine rich DNA structure, the i-Motif to deliver soluble Ag+ as a novel antimicrobial agent (AgiMs). AgiMs were evaluated in vitro against P. aeruginosa and A. baumannii strains. AgiMs displayed significant antibacterial activity against both P. aeruginosa and A. baumannii (median MIC: 0.875 µM and 0.75 µM, respectively) by rapid, bactericidal and concentration-dependent effect. Low concentrations of AgiMs showed efficacy against PAO1 20-h biofilms, resulting in 57% reduction in biomass (5 x MIC). A single dose of AgiMs extended survival of G. Mellonella larvae, with the therapeutic benefit paralleled in the reduction of internal bacterial load. Synergistic interactions were observed with the combination of AgiMs and tobramycin, a common antibiotic used to treat P. aeruginosa infections; indicating the potential for AgiMs to reinstate the potency of current antibiotics. This silver-based agent might be an alternative to the failing antibiotic regimes for MDR resistant infections. Further in vitro and in vivo studies are warranted to confirm the therapeutic potential. </p>

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