Antibiotic discovery

Question 1

What is the definition of an antibiotic?

Answer 1

A chemical (of natural or synthetic origin) which (usually at low concentrations) inhibits microorganisms of some type within a host organism, while not unacceptably interfering with the life of that organism

• Antimicrobial is an UMBRELLA term: an agent that is antagonistic towards a bacterium (broad term)
  e. g. bleach is an antimicrobial that is not an antibiotic (effective, but if injected into a human it would most likely kill or make severely unwell )

Question 2

What antibiotics are created semi-synthetically?

Answer 2

Beta lactams

Question 3

What is the current strategy for developing antibiotics?

Answer 3

1. There is a focus on developing new inhibitors of beta-lactamases
2. Re-purpose old antibiotics
   Fidaxomycin (discovered 1975); FDA Approval (2011) for treatment of CDAD
   Daptomycin discarded (1980s); FDA approved in 2003 for MSSA/MRSA bacteraemia
3. Combine drugs
   Trimethoprim and Sulfamethoxazole
   Beta-lactams and clavulanic acid (co-amoxiclav)
4. Discover new natural products
   A very thin pipeline

Question 4

What is Teixobactin?

Answer 4

• Activity against:
  S. pneumoniae
  MRSA
  M. tuberculosis
• NO activity against gram negatives (cannot penetrate cell wall)
• Novel peptidoglycan biosynthesis inhibitor (targets lipid 2 and 3)
• ## No appreciable resistance yet to be observed

Question 5

What are the problems getting candidates to market place?

Answer 5

1. Risk and time
   Risk of promising lead failing at phase trials is significant
2. Profit not clear
   New antibiotics may be used for last resort, limiting sales
   Many antibiotics dropped for drugs to treat chronic conditions

Question 6

What is Mcr-1?

Answer 6

• new form of resistance to Colistin
• Mcr-1 present in both humans and meat animals
• Carried on a plasmid: plasmid can move between different bacteria – able to infer resistance

Question 7

Why do we care about colistin resistance?

Answer 7

• Discovered 1949 from a Bacillus sp.
• Also called polymyxin E
• Potential nephrotoxicity is more favourable than death due to infection – therefore colistin is one of the very last line treatments
• Colistin is also used in cystic fibrosis patients (gram negative)

Question 8

What is driving resistance? (3)

Answer 8

1. Inappropriate use in agriculture (2/3 fed to livestock). Faecal contamination of water sources
2. Inappropriate use in humans (public pressure, online purchasing without prescription)
3. Waste from manufacturers (environmental exposure to antibiotics)

Question 9

How do we minimise AMR impact?

Answer 9

Improve public awareness
Improve hygiene and sanitation 
Reduce unnecessary use in agriculture
Reduce unnecessary use in humans  
Improve global resistance surveillance
Promote, new rapid diagnostics and AMR research
Promote development and use of vaccines