SILVER

Saving Dogs from Infection: The Discovery of Darobactin connecting to MRSP in dogs

I analyzed the effectiveness of the new treatment Darobactin for MRSP in dogs and how this would play in to the overall development of the antibiotic and also in human and animal health.
Eden Xu
Grade 7

Problem

Is the new antibiotic Darobactin an effective treatment for methicillin-resistant staphylococcus pseudintermedius (and the bacteria it causes) in dogs?

 

Method

none - research project

Research

  • Bacteria that can cause more infections in diseases in dogs and humans
  • Methicillin-resistant Staphylococcus pseudintermedius:
  • Antibiotic resistant bacteria
  • Commonly found on the skin, mouth, nose, or gastrointestinal tract
  • ~50% of dogs are colonized with S. pseudintermedius
  • An additional 6-9  % are colonized with MRSP
  • Usually not harmful on its own, but can create opportunity for secondary infections
  • Also, if the pet is immunocompromised, or has a compromised immune system, it can affect them more severely 
  • MRSP commonly causes skin/ear infections, especially if the skin has been damaged (i.e. scratched or affected by allergies)
  • MRSP has also emerged as a clinically important pathogen and resistance to several classes of antimicrobials, such as tetracyclines and a few others
  • MRSP is an opportunistic bacteria, so the skin must be damaged by something in order for it to cause an infection

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  • MRSP is artificially selected to be resistant to majority of antibiotics
    • Spreads fast within dogs
    • zoonotic disease, meaning that it can be spread from animals to humans, but very rare transmission occurring
      • very capable of spreading through dogs, less likely cats
      • This bacteria is not well adapted to cause disease in people, rather better adapted to animals, mainly dogs
        • Although dog owners may be exposed to this bacteria on a regular basis, this is not a major concern
          • Infections happen from direct contact with the bacteria from an inorganic object or other infected animal(s)
        • Recurrent antibiotic exposure can lead to resistant bacteria in the pet

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  • Occurs when disease-causing bacteria develop the ability to resist some antibiotics 
    • From frequent and/or inappropriate use of antibiotics as treatment
      • Bacteria is not killed by antibiotics, rather, they continue to grow
    • Currently increasing in certain bacteria that are important in canine and human  health
      •  Leads to infections that are difficult/impossible to treat 
        • Public health concerns - transmission
  • One of the biggest human/veterinary health challenges of our time
    • Some regions/populations may have greater issues with this, because of current antimicrobial use and lack of regulations
      • Inattention to antibiotic use guidelines may also be a factor
    • Have been identified in many species
      • Individuals who are immunocompromised are at greatest risk for this

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The Gram Test / Gram’s Method of Staining

  • way to classify bacteria
    • The Gram Test is staining the cell walls of the separate bacteria
      • two (main) classifications; Gram-positive and Gram-negative

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Peptidoglycan is a particular layer in the cell walls of the bacteria, and the place where action of beta-lactam antibiotics such as penicillins and cephalosporins do their job

Gram positive

  • thicker cell wall
  • More peptidoglycan
  • This bacteria is easier to defeat because of its cell wall
  • An example of a Gram-positive bacteria would be bacterial pneumonia

Gram negative

  • bacteria that reacts differently to the stain 
  • The cell wall of these bacteria is thinner
  • Less peptidoglycan 
  • Harder to combat because there is not as much peptidoglycan, leaving less space for the antibiotics to do their job
  • An example of a Gram-negative bacteria would be bacterial meningitis

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Darobactin

  • New antibiotic
  • First discovered by Professor Till Schäberle
    • Discovered at the Institute of Insecticidal Biotechnology on November 21, 2019 
    • found to create a possible cure for antibiotic resistant (gram-negative) bacteria
    • Achieved because scientists found a new chemical inside a new species of insect that could help battle bacteria – called nematode
    • Last antibiotic that can cure gram-negative bacteria was developed in the 1960s
    • Aiming to cure gram-negative bacteria that are resistant to common antibiotics

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Data

  • A ScienceDirect Study selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority 
  • Mortality, health-care burden, community burden, prevalence of resistance, 10 year trend of resistance, transmissibility, preventability in the community setting and healthcare setting, treatability, and pipeline
  • Stratified priority list into three tiers
  • Critical, high and medium priority
  •  Using 33rd percentile of the bacterium's total scores as cutoff
  • Highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant enterococcus faecium and methicillin-resistant staphylococcus aureus
  • Of the bacteria normally responsible for community-acquired infections, bacteria such as clarithromycin-resistant Helicobacter pylori and Salmonella typhi were included in the high-priority tier
  • This study shows that the antibiotic resistant bacteria should be top priority

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  • You cannot prevent exposure of your pets / yourself to MRSP - It is carried by many healthy animals / people
  • One study found MRSP in 4.5% of healthy dogs and 1.2% of healthy cats
  • More recent studies indicate a greater percentage of healthy dogs and cats now carry MRSP
  • MRSP infections appear to be increasing substantially in animals (particularly dogs)
    • Also very large increases in MRSP skin infections 
      • Infections after surgery are also becoming more common
  • possible that the carriage of MRSP can occur for months
  • If a dog has MRSP, they should not be put in contact with any other dogs / cats, because they could transmit it
    • should not put yourself in contact with the dog either
  • can somewhat prevent MRSP from overall happening a little bit by using antibiotics responsibly yourself and for your pet

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  • "Darobactin binds to that [BamA] protein and jams it, so it cannot open anymore. The bacteria cannot build a proper cell envelope, and that causes death." (Lewis, 2019.)
  • identified the nematode as a possible host for an effective antibiotic because of the way these worms feed on insects
    • target their larvae and releasing bacteria, then have to fight pathogens similar to those inside the human body
  • makes Darobactin a promising candidate for human use 
  • even if animal microbiome antibiotics haven't been successful in humans before, Photorhabdus has evolved over 370 million years to fend off gram-negative bacteria

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  • Information from expert - Dr. Till Schäberle , from Institute of Insecticidal Biotechnology
  • Discovered Darobactin on November 21 st , 2019
  • Following chart is information about which bacteria Darobactin has been tested on in his lab
    • Pseudomonas aeruginosa 
    • P. aeruginosa 
    • Shigella sonnei 
    • K. pneumoniae 
    • E. coli 
    • Salmonella Typhimurium
    • Moraxella catarrhalis
    • Acinetobacter baumannii
    • S. aureus
    • Clostridium bifermentans
    • Mycobacterium tuberculosis
    • Symbiotic gut bacteria (MIC)
    • Bifidobacterium longum
    • Bacteroides fragilis
    • And many more…
  • This shows that Darobactin is effective on a large range of gram-negative bacteria, even MRSA, a very close relative of MRSP
  • Antibiotic resistance can be seen as one of the biggest threats to human health
  • Although, currently facing a pandemic
  • Some people say antibiotic resistance can be seen as a 'slow pandemic situation
  • If Darobactin is effective in humans so far there is no harms on using it for dogs in the future

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  • Information from Dr. Kevin MacAulay , from Glamorgan Animal Clinic
  • Gram-negative bacterial infections occur in dogs very often
  • Treated with many different oral, injectable, or topical antibiotics 
  • Any new treatment with promises to help fight infections (including Darobactin) would be in testing for all kinds of species including dogs
  • When dealing with antibiotic resistant diseases in dogs, vets try to use a treatment that uses a different path to kill bacteria than the resistant antibiotic would have used 

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  • Information from Dr. Timsy Bhando
  • Darobactin was tested on Staphylococcus aureus strain 
  • Several novel antimicrobials have recently been developed and are in various stages of clinical trials, including ceftobiprole, omadacycline, dalbavancin, oritavancin, iclaprim and delafloxacin
  • Antivirulence compounds also promising alternatives that may be able to attenuate bacterial virulence and reverse antibiotic resistance
  • recent study identified anti-virulence compound, MAC-545496 that reversed resistance to various β-lactam antibiotics including penicillins, cephalosporin and more in MRSA
  • MRSP has also emerged as a clinically important pathogen and resistance to several classes of antimicrobials, such as the fluoroquinolones, tetracyclines and a few others
  • Few antimicrobials that show activity against MRSP strains include amikacin, rifampicin, vancomycin and linezolid
  • The use of natural products MRSP strains have also been reported 

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  • Information from Dr. Kevin MacAulay, Dr. Till Schäberle , and Dr. Timsy Bhando
  • Anytime researchers find novel pathways for an antibiotic to kill bacteria, then it allows chances to overcome the pathways tried before that bacteria have now become resistant to - more research needed
  • Vets / doctors in clinical practice only learn about a new drug once it has been researched for many years thoroughly, followed by rigorous testing by health agencies which need to approve the use of the drug before it can be mass produced, delivered, and administered to the general population
  • Many years, maybe 10 yrs until Darobactin developed into a medicinal drug
  • Has the potential to enter clinical trials soon
  • Process of discovering and developing new antibiotics is complex, time-consuming, and expensive
  • Moving a potential antibiotic candidate from concept to market may take as long as 15yrs and can cost approx. $ 1billion 
  • After early lab research, molecules do preclinical testing
  • Includes extensive lab and animal experiments to determine safety
  • The antibiotic then undergoes many phases of clinical trials that want to gather evidence for its safety and effectiveness
  • Thus approved by FDA or Health Canada

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Conclusion

My hypothesis was correct because after analyzing all of the data brought to me, I concluded that the antibiotic Darobactin would be suitable for treating MRSP and most infections it causes. Darobactin, from the research I collected, would be able to battle MRSP and also many of the gram-negative infections it can cause. The new antibiotic has already been tested on many bacteria and found to be positive, and most of these bacteria are all similar or related to MRSP and the bacteria it can cause in some way. There are also no limiting factors saying that Darobactin will not be effective in dogs, as most antibiotics today are effective in both humans and our household pets and I have found no evidence suggesting Darobactin will be any different. 

 

Citations

Acknowledgement

Dr. Till Schaberle, PhD

Dr. Kevin MacAulay, DVM, BSc

Dr. Timsy Bhando, PhD

Dr Eric Brown, PhD

 

Mr. Hotzel - teacher :)