Lecture 16: Medical Biotechnology (Alternatives to Antibiotics)

Question 1

What are different types of biotechnology?

Answer 1

Red: medical processes
White: industrial
Green: agricultural
Blue: marine/aquatic

Question 2

what are different multi-resistant strains?

Answer 2

Hospital acquired:
Vancomycin resistant Enterococci
Multi-drug resistant Staph aureus
Cephalosporin resistant gram-negatives

Community acquired:
MD pneumococci
MDR Salmonella
MDR Shigella
Fluoroquinolone gonococci
MDR tuberculosis

Question 3

How could antimicrobial resistance be combatted

Answer 3

1. Increase speed of Antibiotic development
2. Track resistance data nationwide
3. Restrict their use
4. Direct observed dosing
5. Use narrow spectrum antibiotics
6. Antimicrobial cocktails
7. Develop alternative therapies

Question 4

What is the Yersinia pestis plague case study?

Answer 4

Cause of three devastating pandemics

Currently found in more than 200 species of wild rodent. Transmission of plague is by a minimum of 80 flea species

Still remains a serious problem for international public health

Small outbreaks of plague continue to occur throughout the world, with about 2000 annual cases

Question 5

How is the plague treated today?

Answer 5

Local application of antiseptics. E.g., iodine, mercuric chloride, carbonic acid, or quinine.

Incision or even severing bubos

Bacteriophages or animal hyperimmune sera

real success against plague after sulphanilamide and streptomycin availability

Antibiotics are essential (tertracycline, streptomycin etc)

Question 6

What are bacteriophages?

Answer 6

Potential antibiotic alternative

First used as a therapy in 1925 by d’Herelle who used a highly virulent anti-plagye phage isolated in 1920 in indo-china from rat faeces to treat 4 cases of bubonic plague

This never developed further due to lack of understanding of the mechanisms of phage interactions

Question 7

What does the efficacy of phage treatment depend on?

Answer 7

The route: oral, intramuscular, aerosol spray

Frequency of application

Question 8

What are the benefits of phages?

Answer 8

1. Highly specific and targets only bacteria of interest. Prevents
   affecting normal gut flora
2. Mechanism of action is completely different from all available
   antibiotics so is even effective against MDR bacteria
3. Potential last line of defence
4. Pharmacokinetics of bacteriophage therapy is such that the
   initial dose increases exponentially as virus multiplies = no
   need to repeat treatment
5. Evidence that phage can penetrate poorly vascularised tissues
   and can cross blood-brain barrier
6. Extensive clinical experience in former SU and eastern Europe
   has reported v few side effects and allergic reactions
7. Cheap and easy to produce
8. HOWEVER ITS NOT EASY TO DEVELOP

Question 9

What are problems with phages?

Answer 9

1. Narrow host range, should only use those phages strongly lytic
   for bacterial strain
2. May not always remain lytic under physiological conditions,
   bacteria can become resistant
3. Sterilization of phage preparation environments require
   sterilization, but this may harm the phage
4. Can be inactivated by neutrilizing antibody, prompting allergic reactions
5. pharmacokinetics more complicated due to self-replication
6. Might endow bacteria with toxic or antibiotic resistance genes

Question 10

What is the pyrophage?

Answer 10

Commercial name of a cocktail of phages against:
staphlococci
streptococci
P. areuginosa
Proteus spp.
E. coli

Used for:
pre- & post-surgery
burn wounds
osteomyelitis
skin, eye, ear infections
wound dressing product called - ‘PhagoBioDerm’

Question 11

What are target virulence factors of Yersinia?

Answer 11

Adhesins - important for initial contact with eukaryotic cells and for colonisation
1. preferably bind to oligosaccharides in host cells
2. Inhibition: treatment of host cells with TUNICAMYCIN prevents
oligosaccharide synthesis, reducing infection rates by >50%

Yersiniabactin siderophore - required for iron scavenging
1. Can use inhibitors of key enzymes or mimics of substrates
2. Inhibitors of SALICYLATION enzymes required for siderophore
synthesis, therefore limits growth in iron-limiting (host)
conditions

Type 3 secretion system (ysc-yop) - delivers microbial “effector” proteins into host cells
1. Inhibitors include compounds belonging to a class of acylated
hydrazones of different salicylaldehydes, monoanionic squaric
acids, peptidic a-ketocarboxylic acids, sulfonamides

Other targets:
1. biofilms
2. exotoxin neutrilization
3. inhibition of two-component systems
4. other secretion systems

Question 12

What do probiotics do?

Answer 12

1. Competitive exclusion of pathogens
2. Enhance gut mucosal layer
3. Modulation of immune system
4. Production of antibiotic molecules