MB3057 Antimicrobial drug resistance a global threat 1 - Oggioni

Title: MB3057 Antimicrobial drug resistance: a global threat
Presenter: Marco R. Oggioni, Department of Genetics and Genome Biology, University of Leicester

Drug Target Characteristics:
- Selective for bacterial cells.
- Essential for bacterial replication and survival.
- Mechanisms common to most bacterial cells (broad spectrum).
Resistance Factors:
- Drug resistance reduces the activity spectrum (narrow spectrum).
- Antimicrobial drug use selects for drug resistance.
Types of Antimicrobial Agents:
- Antibiotics (e.g., penicillin): high selectivity, systemic use.
- Antiseptics (e.g., chlorhexidine): reasonable selectivity, topical use.
- Disinfectants (e.g., sodium hypochlorite): low selectivity, environmental use.
Key Points:
- Most agents target bacteria; fewer target fungi, viruses, protozoa, and helminths.
- Clinical antimicrobial agents do not affect bacterial spores, fungi spores, or latent viruses.
- Major Groups:
  - β-lactam compounds (e.g., penicillins, cephalosporins): semisynthetic derivatives with varied properties.
  - Other antibacterial agents: aminoglycosides, tetracyclines, macrolides, glycopeptides, quinolones.

Domains of Life:
- Bacteria, Archaea, Eucarya.
Classification Examples:
- Examples of specific organisms across the spectrum of life, such as:
  - Green nonsulfur bacteria
  - Methanosarcina (Archaea)
  - Eucarya examples like animals and plants.

Macromolecular Structures:
- Targets include ribosomes (30S and 50S), RNA polymerase, or DNA gyrase.
Antibacterial Agents:
- Examples with specific targets:
  - Tetracycline (30S)
  - Penicillin (cell wall)
  - Rifampicin (RNA polymerase)
  - Ciprofloxacin (DNA gyrase).

Agents and Their Clinical Activity Against Bacteria:
- Detailed activity against various bacterial strains:
  - Penicillins: Cell wall agents effective against multiple bacteria.
  - Cephalosporins: Effective against similar bacteria to penicillins.
  - Tetracyclines: Ribosome-targeting agents effective against a variety.
- Other specific agents listed with their spectrum of activity.

Mechanism of Action:
- Glycopeptides such as vancomycin are effective against Gram-positive organisms with multiple resistances.

Examples:
- Various penicillins like ampicillin and cephalosporins like cefuroxime.
- Characteristics and resistance abilities of some agents highlighted.

Allergy Overview:
- Significant proportion of anaphylaxis deaths related to penicillin.
- Testing and cross-reactivity information.

Overview of various inhibitors affecting ribosomal activity including:
- Tetracyclines: Broad-spectrum agents.
- Chloramphenicol: Broad antibacterial spectrum but with serious side effects.
- Aminoglycosides: Risk of toxicity highlighted.
- Macrolides: Effective against specific bacterial infections.

Classes of Inhibitors:
- Sulphonamides & Diaminopyrimidines: Block folic acid biosynthesis.
- Quinolones: Target DNA gyrase, often used for urinary tract infections.

Mechanisms:
- Polymyxins: Disrupt bacterial cell membranes; often used as last resort agents.
- Daptomycin: Effective against resistant Gram-positive organisms.

Key Concepts:
- Antimicrobial drugs demonstrate selective bacterial activity.
- Drug discovery pipeline is concerningly empty; big pharma has shifted focus.

Natural Product-Derived Antibiotics:
- Examples include penicillins, cephalosporins, macrolides, etc.

Comparison of folic acid biosynthesis pathways in humans vs. Neisseria.
- Significance of pathway differences for drug targeting.

Focus on Darobactin:
- Innovations and discoveries related to targeting Gram-negative bacteria.

Use of AI to discover new antibacterial compounds.
Highlights successful identification of effective molecules through deep learning.

Reinforces the successes and future possibilities of AI in discovering novel antibacterial agents.

Recap of essential points regarding AMR and its implications for therapeutic choices.
The alarming rise of AMR statistics and projections for the future.