scholarly journals Coevolutionary phage training leads to greater bacterial suppression and delays the evolution of phage resistance

2021 ◽  
Vol 118 (23) ◽  
pp. e2104592118
Author(s):  
Joshua M. Borin ◽  
Sarit Avrani ◽  
Jeffrey E. Barrick ◽  
Katherine L. Petrie ◽  
Justin R. Meyer
Keyword(s):  
Single Step ◽  
Host Genome ◽  
Resistant Bacteria ◽  
Phage Resistance ◽  
Bacterial Populations ◽  
Antibiotic Resistant ◽  
Complete Resistance ◽  
Therapeutic Development ◽  
Transfer Of Information

The evolution of antibiotic-resistant bacteria threatens to become the leading cause of worldwide mortality. This crisis has renewed interest in the practice of phage therapy. Yet, bacteria’s capacity to evolve resistance may debilitate this therapy as well. To combat the evolution of phage resistance and improve treatment outcomes, many suggest leveraging phages’ ability to counter resistance by evolving phages on target hosts before using them in therapy (phage training). We found that in vitro, λtrn, a phage trained for 28 d, suppressed bacteria ∼1,000-fold for three to eight times longer than its untrained ancestor. Prolonged suppression was due to a delay in the evolution of resistance caused by several factors. Mutations that confer resistance to λtrn are ∼100× less common, and while the target bacterium can evolve complete resistance to the untrained phage in a single step, multiple mutations are required to evolve complete resistance to λtrn. Mutations that confer resistance to λtrn are more costly than mutations for untrained phage resistance. Furthermore, when resistance does evolve, λtrn is better able to suppress these forms of resistance. One way that λtrn improved was through recombination with a gene in a defunct prophage in the host genome, which doubled phage fitness. This transfer of information from the host genome is an unexpected but highly efficient mode of training phage. Lastly, we found that many other independently trained λ phages were able to suppress bacterial populations, supporting the important role training could play during phage therapeutic development.

scholarly journals Coevolutionary phage training leads to greater bacterial suppression and delays the evolution of phage resistance

2020 ◽  
Author(s):  
Joshua M. Borin ◽  
Sarit Avrani ◽  
Jeffrey E. Barrick ◽  
Katherine L. Petrie ◽  
Justin R. Meyer
Keyword(s):  
Phage Therapy ◽  
Single Step ◽  
Resistant Bacteria ◽  
Phage Resistance ◽  
Antibiotic Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Major Barrier ◽  
Complete Resistance ◽  
Transfer Of Information

AbstractThe evolution of antibiotic resistant bacteria threatens to become the leading cause of worldwide mortality. This crisis has renewed interest in the practice of phage therapy. Yet, bacteria’s capacity to evolve resistance is likely to debilitate this therapy as well. To combat the evolution of phage resistance and improve treatment outcomes, many have suggested leveraging phages’ ability to counter resistance by evolving phages on target hosts before using them in therapy (phage training). We found that during in vitro experiments, a phage trained for 28 days suppressed bacteria ∼1000-fold for 3-8 times longer than its untrained ancestor. This extension was due to a delay in the evolution of resistance. Several factors contributed to this prolonged suppression. Mutations that confer resistance to trained phages are ∼100× less common and, while the target bacterium can evolve complete resistance to the untrained phage in a single step, multiple mutations are required to evolve complete resistance to trained phages. Mutations that confer resistance to trained phages are more costly than mutations for untrained phage resistance. And when resistance does evolve, trained phages are better able to suppress these forms of resistance. One way the trained phage improved was through recombination with a gene in a defunct prophage in the host genome, which doubled phage fitness. This direct transfer of information encoded by the host but originating from a relict phage provides a previously unconsidered mode of training phage. Overall, we provide a case study for successful phage training and uncover mechanisms underlying its efficacy.Significance StatementThe evolution of antibiotic resistant bacteria threatens to claim over 10 million lives annually by 2050. This crisis has renewed interest in phage therapy, the use of bacterial viruses to treat infections. A major barrier to successful phage therapy is that bacteria readily evolve phage resistance. One idea proposed to combat resistance is “training” phages by using their natural capacity to evolve to counter resistance. Here, we show that training phages by coevolving them with their host for one month enhanced their capacity for suppressing bacterial growth and delayed the emergence of resistance. Enhanced suppression was caused by several mechanisms, suggesting that the coevolutionary training protocol produces a robust therapeutic that employs complementary modes of action.

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 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.

scholarly journals Antibiotic resistance in surface waters from a coastal lagoon of Southern Brazil under the impact of anthropogenic activities

2019 ◽  
Vol 14 (5) ◽  
pp. 1
Author(s):  
Belize Leite ◽  
Magda Antunes de Chaves ◽  
Athos Aramis Thopor Nunes ◽  
Louise Jank ◽  
Gertrudes Corção
Keyword(s):  
Antibiotic Resistance ◽  
Coastal Lagoon ◽  
Anthropogenic Activities ◽  
Class I ◽  
Systematic Evaluation ◽  
Resistant Bacteria ◽  
Bacterial Populations ◽  
Antibiotic Resistant ◽  
The Impact

Wastes arising from human activities can reach water bodies and contribute significantly to the presence of antibiotic resistant bacterial populations in aquatic environments. The objective of this study was to evaluate the cultivable antibiotic resistant bacterial populations from a coastal lagoon impacted by agriculture and urbanization activities. Water samples were collected in low and peak season and characterized regarding physicochemical variables, microbiological indicators and the presence of antimicrobial residues. In order to analyze the presence of resistant bacterial populations, the samples were grown in the presence of nalidixic acid, ceftazidime, imipenem and tetracycline. Genes associated with β-lactamic resistance (blaCTX-M-like, blaGES-like, blaOXA-51, blaOXA-23-like, blaSHV-like, blaTEM-like and blaSPM-1), class I integron and efflux systems (tetA, tetB, acrA, acrB, tolC, adeA, adeB, adeR, adeS, mexB, mexD, mexF and mexY) were analyzed by conventional in vitro amplification. Although antimicrobials residues were below the detection limit, resistant bacteria and resistance determinants - blaGES, class I integron, adeS, acrA, acrB, tolC, mexB, mexF - were present at almost all points, in both seasons and for all antimicrobials assessed. The high numbers of resistant bacteria counts observed after the antibiotic treatment were positively correlated to the urbanization effects on the Lagoon. Some resistant populations were even higher in the low season samples, indicating the importance of a systematic evaluation of antibiotic resistance on water resources.

scholarly journals Bacteriophages: the possible solution to treat infections caused by pathogenic bacteria

2017 ◽  
Vol 63 (11) ◽  
pp. 865-879 ◽  
Author(s):  
Ayman El-Shibiny ◽  
Salma El-Sahhar
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Phage Therapy ◽  
Multidrug Resistant ◽  
Clinical Applications ◽  
Western World ◽  
Resistant Bacteria ◽  
Vaccine Production ◽  
Bacterial Populations ◽  
Antibiotic Resistant

Since their discovery in 1915, bacteriophages have been used to treat bacterial infections in animals and humans because of their unique ability to infect their specific bacterial hosts without affecting other bacterial populations. The research carried out in this field throughout the 20th century, largely in Georgia, part of USSR and Poland, led to the establishment of phage therapy protocols. However, the discovery of penicillin and sulfonamide antibiotics in the Western World during the 1930s was a setback in the advancement of phage therapy. The misuse of antibiotics has reduced their efficacy in controlling pathogens and has led to an increase in the number of antibiotic-resistant bacteria. As an alternative to antibiotics, bacteriophages have become a topic of interest with the emergence of multidrug-resistant bacteria, which are a threat to public health. Recent studies have indicated that bacteriophages can be used indirectly to detect pathogenic bacteria or directly as biocontrol agents. Moreover, they can be used to develop new molecules for clinical applications, vaccine production, drug design, and in the nanomedicine field via phage display.

scholarly journals Mutant and Recombinant Phages Selected from In Vitro Coevolution Conditions Overcome Phage-Resistant Listeria monocytogenes

2020 ◽  
Vol 86 (22) ◽  
Author(s):  
Tracey Lee Peters ◽  
Yaxiong Song ◽  
Daniel W. Bryan ◽  
Lauren K. Hudson ◽  
Thomas G. Denes
Keyword(s):  
Listeria Monocytogenes ◽  
Host Range ◽  
Foodborne Pathogen ◽  
Resistant Bacteria ◽  
Phage Resistance ◽  
Short Term ◽  
Content Type ◽  
Life Threatening ◽  
The Impact

ABSTRACT Bacteriophages (phages) are currently available for use by the food industry to control the foodborne pathogen Listeria monocytogenes. Although phage biocontrols are effective under specific conditions, their use can select for phage-resistant bacteria that repopulate phage-treated environments. Here, we performed short-term coevolution experiments to investigate the impact of single phages and a two-phage cocktail on the regrowth of phage-resistant L. monocytogenes and the adaptation of the phages to overcome this resistance. We used whole-genome sequencing to identify mutations in the target host that confer phage resistance and in the phages that alter host range. We found that infections with Listeria phages LP-048, LP-125, or a combination of both select for different populations of phage-resistant L. monocytogenes bacteria with different regrowth times. Phages isolated from the end of the coevolution experiments were found to have gained the ability to infect phage-resistant mutants of L. monocytogenes and L. monocytogenes strains previously found to be broadly resistant to phage infection. Phages isolated from coinfected cultures were identified as recombinants of LP-048 and LP-125. Interestingly, recombination events occurred twice independently in a locus encoding two proteins putatively involved in DNA binding. We show that short-term coevolution of phages and their hosts can be utilized to obtain mutant and recombinant phages with adapted host ranges. These laboratory-evolved phages may be useful for limiting the emergence of phage resistance and for targeting strains that show general resistance to wild-type (WT) phages. IMPORTANCE Listeria monocytogenes is a life-threatening bacterial foodborne pathogen that can persist in food processing facilities for years. Phages can be used to control L. monocytogenes in food production, but phage-resistant bacterial subpopulations can regrow in phage-treated environments. Coevolution experiments were conducted on a Listeria phage-host system to provide insight into the genetic variation that emerges in both the phage and bacterial host under reciprocal selective pressure. As expected, mutations were identified in both phage and host, but additionally, recombination events were shown to have repeatedly occurred between closely related phages that coinfected L. monocytogenes. This study demonstrates that in vitro evolution of phages can be utilized to expand the host range and improve the long-term efficacy of phage-based control of L. monocytogenes. This approach may also be applied to other phage-host systems for applications in biocontrol, detection, and phage therapy.

scholarly journals In vitro Antimicrobial Activity of Acne Drugs Against Skin-Associated Bacteria

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Mark A. T. Blaskovich ◽  
Alysha G. Elliott ◽  
Angela M. Kavanagh ◽  
Soumya Ramu ◽  
Matthew A. Cooper
Keyword(s):  
Antimicrobial Activity ◽  
Resistant Bacteria ◽  
Microbial Infection ◽  
Antibiotic Resistant ◽  
Drug Resistant Bacteria ◽  
Cutibacterium Acnes ◽  
Common Skin ◽  
Sebum Production ◽  
Resistant Strains

Abstract Acne is a common skin affliction that involves excess sebum production and modified lipid composition, duct blockage, colonization by bacteria, and inflammation. Acne drugs target one or more of these steps, with antibiotics commonly used to treat the microbial infection for moderate to severe cases. Whilst a number of other acne therapies are purported to possess antimicrobial activity, this has been poorly documented in many cases. We conducted a comparative analysis of the activity of common topical acne drugs against the principal etiological agent associated with acne: the aerotolerant anaerobic Gram-positive organism Propionibacterium acnes (recently renamed as Cutibacterium acnes). We also assessed their impact on other bacteria that could also be affected by topical treatments, including both antibiotic-sensitive and antibiotic-resistant strains, using broth microdilution assay conditions. Drugs designated specifically as antibiotics had the greatest potency, but lost activity against resistant strains. The non-antibiotic acne agents did possess widespread antimicrobial activity, including against resistant strains, but at substantially higher concentrations. Hence, the antimicrobial activity of non-antibiotic acne agents may provide protection against a background of increased drug-resistant bacteria.

The Activity of Alkanna Species in vitro Culture and Intact Plant Extracts Against Antibiotic Resistant Bacteria

2019 ◽  
Vol 25 (16) ◽  
pp. 1861-1865 ◽  
Author(s):  
Naira Sahakyan ◽  
Margarit Petrosyan ◽  
Armen Trchounian
Keyword(s):  
Antibiotic Resistance ◽  
Antibacterial Agents ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Resistant Bacteria ◽  
Plant Origin ◽  
Bacterial Strains ◽  
Biotechnological Production ◽  
Antibiotic Resistant

Overcoming the antibiotic resistance is nowadays a challenge. There is still no clear strategy to combat this problem. Therefore, the urgent need to find new sources of antibacterial agents exists. According to some literature, substances of plant origin are able to overcome bacterial resistance against antibiotics. Alkanna species plants are among the valuable producers of these metabolites. But there is a problem of obtaining the standardized product. So, this review is focused on the discussion of the possibilities of biotechnological production of antimicrobial agents from Alkanna genus species against some microorganisms including antibiotic resistant bacterial strains.

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 A Study of Ethno-Veterinary Medicinal Plants and In Vitro Antimicrobial Activities Against Bovine Mastitis Isolated Bacterial Pathogens in Algeria

2019 ◽  
Vol 76 (2) ◽  
pp. 154
Author(s):  
Radhwane SAIDI ◽  
Nora MIMOUNE ◽  
Ratiba BAAZIZI ◽  
Mohamed Hocine BENAISSA ◽  
Djamel KHELEF ◽  
...  
Keyword(s):  
Medicinal Plants ◽  
Bovine Mastitis ◽  
Multidrug Resistant ◽  
Antimicrobial Activities ◽  
Economic Losses ◽  
Resistant Bacteria ◽  
Mentha Pulegium ◽  
Antibiotic Resistant ◽  
Marrubium Vulgare

Bovine mastitis is the most serious dairy problem in terms of economic losses to the dairy industry. In Algeria, dominates as one of the most prevalent diseases in dairy cattle among the dairy farms. Mastitis treatment with antibiotics leads to the development of antibiotic resistant strains and consumer health problem. Multidrug-resistant bacteria have become a major health issue. With new generations of virulence and resistant bacteria, we need to improve our understanding and produce novel techniques to control these pathogenic strains. In our study, the activity of several extracts from seven medicinal plants, namely Mentha pulegium, Lavandula dentate, Origanium sp, Marrubium vulgare, Salvia bicolor, Blackstonia perfoliata, and Phlomis crinita, traditionally used in Algeria was investigated against 26 methicillin resistant staphylococci and multi-resistant Escherichia coli. (E.coli) isolated from animals with mastitis manifestation by the disc diffusion method.Results revealed the potential of extracts of Salvia bicolor, Marrubium vulgare and Phlomis crinita as antibacterial agents against strains isolated from bovine mastitis and support the possible use of these phytotherapic agents in the clinical management of the disease. Further studies into their toxicity and phytochemistry are advocated.

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