Alternatives to antimicrobials Flashcards
What is antimicrobial resistance?
Occurs when bacteria, viruses, fungi or parasites change over time and no longer respond to previously effective medicines. Increases risk of disease spread, severe illness and death as infections become harder to treat
E.g. excessive use of penicillin which was an effective antibiotic has causes bacteria to develop mechanisms of resistance
What are the causes of antimicrobial resistance?
genetic mutations - can change enzyme activity, inactivate antimicrobial agents or alter the target site of binding for antimicrobial agents
Gene transfer – bacteria with drug-resistant genes may transfer a copy of these genes to other bacteria. Can be horizontal transfer or through agents such as bacteriophage
Misuse of antimicrobials – e.g. taking antibiotics for viral infections, not taking for full course, overuse by inappropriate prescription/inadequate diagnosis
What are some example antibiotics and their sites of action?
Inhibit DNA synthesis – fluoroquinolones
Inhibit RNA polymerase – Rifampin
Inhibit cell wall synthesis – penicillins, cephalosporins, carbapenems, glycopeptides (vancomycin)
Inhibit protein synthesis (bind to ribosomes) - aminoglycosides, tetracyclines, macrolides, clindamycin, chloramphenicol, linezolid
What are some mechanisms of antimicrobial resistance?
Permeability barriers
Efflux pumps
Antibiotic target modification;
- Altered penicillin-binding proteins
- Altered DNA gyrase
Inactivating enzymes;
- Beta-lactamase
- Aminoglycoside-modifying enzymes
What are some naturally occurring alternatives to antimicrobials?
Phage therapy
Antibiotics
Antimicrobial peptides (AMPs)
Probiotics
Bacteriocins
What are antimicrobial peptides (AMPs)?
Small molecules produced as part of innate immunity. Broad range can treat bacteria, fungi, parasites and viruses
Mechanism is either membrane action (forming pores or disrupting membrane to cause efflux of cell contents) or non-membrane action (inhibiting cell wall, enzyme activity, protein folding or lyase release)
Advantages -
Not prone to resistance development
Broad spectrum activity
Disadvantages -
Expensive large-scale production
Susceptible to proteolysis and toxicity
What are bacteriocins?
Only the tail of phage, no head.
Ribosomally synthesised peptides, synthesised by bacteria to kill other bacteria. Prevents competition
Classification -
Gram-negative – colicins, colicin-like, phage-tail-like, microcin. Can inhibit DNA gyrase, RNA. polymerase, or Asp-tRNA synthase
Gram-positive – class I (modified), class II (unmodified). Can form pores or inhibit peptidoglycan synthesis .
Advantages -
Specific to strains of bacteria
Resistant to heat and UV
Disadvantages -
Expensive large-scale production
Susceptible to proteolysis
What is phage modification?
Gene mutation, gene replacement or gene integration of foreign genes to expand host range or enhance effect. Either using mutagenic agents or homologous recombination-based approaches
Phage (lytic?) lifecycle -
Attachment of phage to host cell, injection of phage DNA
Synthesis of viral genome and proteins
Assembly of virions from new phage DNA/proteins
Lysis of cell and release of novel virions
Lysogenic cycle -
Integration of phage DNA with host genome
Lysogenic bacterium reproduces as normal
Prophage can excise from bacterium’s genome and enter lytic cycle
Advantages -
More specific
Safe for humans
Continuous dose supply due to replication
Amenable to genetic engineering
Disadvantages -
Immunogenicity
Pharmacokinetics
Release of bacterial endotoxins, failure to remove endotoxins and pyrogenic substances
Resistance development (less change with phage cocktails)
No phage products for humans yet as regulation is strict
Why can biotechnology sometimes be dangerous?
Outcomes of biotechnology can be slightly unpredictable, potentially cause new infectious microbes due to gene transfer of antimicrobial genes, sometimes phage can integrate with the chromosome of the cell can be dangerous
