WEEK 4 - Antibiotic discovery piplines: Then and Now

Question 1

What was used before penicillin discovery

Answer 1

Not many options, relied on acient methods e.g.
- Sweat baths
- Blood letting
- Manuka honey (has antimicrobial properties)
- Mercury (has antimicrobial properties BUT could cause toxicity to patient)
- Salvarsan (arsenic based) - better than mercury
- useful agaisnt syphilis
- had antimicrobial property against bacterium causing syphilis

Question 2

What is the difference between Antimicrobial and Antibiotics

Answer 2

Antimicrobial - Something that will kill a bacterium
- BROAD term, includes things suitable (e.g. antibiotics) and not suitbale (e.g. bleach) for human treatment

Antibitoics - Human safe treatment that kills bacteria
- doesn’t interfere with life of host, i.e. kills patients
- e.g. penicillin, beta-lactam

Question 3

Describe the discovery and design of penicillin

Answer 3

• Accidently discovered in in 1928
• Encourgaed others to try purify enough to test, leading to mass production in 1945

Question 4

Explain The Golden Era (1940’s-60’s)

how new drugs were discovered, what classes of antibitoics were discover

Answer 4

A systemic approach was used to find natural antimicrobial products
- successfule era

• Would take samples from soil and grow
• Would then expose bacteria to natural products grown in soil to see if product had any activity agaisnt the bacterium
• If bacteria was killed, then firther studies would be carried out on the product

Classes of antibitoics discovered:
- Beta-lactams i.e. penicillin
- Tetracyclines
- Macrolides
- Aminoglycosides
- Quinoles
And more

Question 5

What happened after The Golden Era

How were new drugs discovered

Answer 5

1. Discovery of new antibitoic classes declined massively
   - found they were growing / finding the same microorganisms
   -
   SOLUTIONS to new drug discovery:
   
   • Modification of exisiting natural prodcuts = semi-synthetic antimicrobials
     - i.e. adding side chains
   • Manufacturing fully synthetic antimicrobials
   • Develop new beta-lactamase inhibitors
   • Re-use old antibtiotics (which previously were not commonly used)
   • Combine drugs
   • Discover new natural products
     - using iChip (place in soil) , many organsims will not grow on nutrient rich agar plate in a lab due to lack of growth factors, too many nutrients
2. Resistance
   - MRSA, superbug spread and bad infection control began to emerge in 2000s
   - Use of broad-spectrum antimicrobials added to ressitance and had lower success rates but covered all bases to prevent patient death

Question 6

What was the issues with on high throughput screening (HTS) of fully synthetic drugs

A solution to Resistance era (post Golden AGe)

Answer 6

HTS included identifying bacterial targets and designing compounds which targeted these targets

ISSUE:
- Scientisits were unable to get the compound into the bacterial cell
- was unable to pass cell wall (outer membrane)

Question 7

Teixobactin (antibiotic)

Answer 7

A peptidoglycan biosynthesis inhibitor

• Has activity against MRSA, M. tuberculosis and S. pneumoniae
• Has no activity against gram -ive bacteria

Question 8

What factors have caused a decline in clinical development / trials for new drugs

Answer 8

• Developing a novel drug and conducting phase trials are expensive
  
  • investment but massive risk of failure which puts many companies / people off
• Profit isn’t clear
  
  • ## novel treatment may not be used for long, may be last resort = limited sales

Question 9

SUMMARY

Answer 9

Antibiotic pipelines have had to adapt over time, since the end of the golden era of discovery

This was in attempt to keep pace with developing resistance levels

Discovery should only form one arm of the solution, also requiring infection control policy

Repurposing old drugs and beta-lactamase inhibitors are increasingly important
-e.g. colistin