12 Anti-microbial therapies Flashcards
What is Prontosil?
One of the very first examples of an anti-bacterial drug
Prontosil details
- First sulphonamide
- Bacteriostatic
- Synthetic
- Some host toxicity
What does bacteriostatic mean?
Does not kill bacteria but stops it from growing
Gram positive bacteria
Thick peptidoglycan
Single mebrane
Gram negative bacteria
Inner membrane- phospholipids
Outer membrane - mixture of phospholipids and lipopolysaccharides
Why is it easier to develop drugs against gram +ve bacteria?
Gram negative –> To get something across outer layer - hydrophilic, to get something across inner layer- hydrophobic
Very difficult to find molecules with both of those properties
How do Beta-lactams work?
Interfere with the synthesis of the peptidoglycan component of the bacterial cell wall
- Bind to penicillin binding proteins, binding to active sites and inactivating them
Examples of Beta-lactams
Penicillin
Methicillin
What is an antibiotic?
An antimicrobial agent produced by a microorganism that kills or inhibits other microirganisms
What does antimicrobial mean?
Chemical that selectively kills or inhibits microbes
What does bactericidal mean?
Kills bacteria
What does antiseptic mean?
Chemical that kills or inhibits microbes that is usually used topically to prevent infection
What is the minimal inhibitory concentration (MIC)?
The lowest concentration of antibiotics required to inhibit growth
Three stages of resistance
- Sensitive (killed, inhibited by low concs)
- Intermediate
- Resistant
What is a high concentration of antibiotics?
Any concentration that is above what can be achieved clinically (breakpoint)
Antibiotic resistance comes about by
Natural selection (certain strains resistant before use due to mutations)
What happens when a selection pressure such as an antibiotic is applied?
Susceptible bugs are killed off, resistant bugs are left - high prevalence of AB resistant strains
Vancomycin
Resistance reported much later
Not used very much, very toxic
Diagnostics and bacteriology can take
24-48 hrs to get susceptibility
Examples of aminoglycosides
Gentamicin
Streptomycin
How do aminoglycosides work?
Bactericidal
- Inhibit protein synthesis (30S ribosomal subunit) and RNA proofreading causing damage to the cell mebrane
- Very toxic
How does rifampicin work?
Bacericidal
- Targets RpoB subunit of RNA polymerase
- Makes secretions go orange/red affecting compliance
How does vancomycin work?
Bactericidal
- Targets Lipid II component of cell wall biosynthesis and cross linking
- Toxic (limited use)
How does linezolid work?
Bacteriostatic
- Inhibits initiation of protein synthesis by binding to 50S rRNA subunit
- Gram +ve only
How does daptomycin work?
Bactericidal
- Targets bacterial cell mebrane
- Gram +ve
- Toxic
4 mechanisms of antibiotic resistance
- Altered target site
- Inactivation of antibiotic
- Altered metabolism
- Decreased drug accumulation
How does an altered target site work?
- Gene encoding target modifying enzyme
- e.g. MRSA encodes alternative PBP with ow affinity for beta-lactams
How does inactivation of antibiotic occur?
- Enzymatic degradation/alteration
- Beta-lactamase
- e.g. ESBL, NDM-1
How does altered metabolism work?
- Increased production of enzyme substrate (competitive inhibition)
- Bacteria can switch to other metabolic pathways
How does decreased drug accumulation work?
Reduced penetration of antiobiotic into bacterial cell or increased efflux of AB out of the cell (pumping out)
How do macrolides work?
Target 50S ribosomal subunit preventing amino-acyl transfer (+ve + -ve)
Examples of macrolides
Erythromycin
Azithromycin
How do quinolones work?
Bactericidal
Target DNA gyrase in -ve and topoisomera IV in +ve
How are plasmids sources of resistant genes?
Can be swapped between bacteria, carry multiple AB res genes
How are transposons a source of resistance?
Integrate into chromosomal DNA, transfer genes from plasmid to chromosome
How is naked DNA a source of resistance?
DNA from dead bacteria is released into the environment
What is transformation?
Uptake of extracellular DNA
What is transduction?
Phage-mediated DNA transfer
What is conjugation?
Pilus-mediated DNA transfer
Measurements made in vitro
May not fully reflect the situation in vivo
Why is HAI a big problem?
Hospitals provide strong selective pressure for AB resistance
Large numbers of people re receiving high doses
Examples of HAIs
- MRSA
- Clostridium difficile
- E. coli
- Acineterbacter baumannii
- VISA (vancomycin insensitive S aureus)
Risk factors for HAI
- Immunosupression
- Crowded wards
- Presence of pathogens
- Broken skin (wounds)
- Staff –> vectors
How to slow down resistance
- Reduce use of broad-spectrum
- Combination therapy
- Tighter controls, restrictions
What may be used in the future?
- New antibiotics/vaccines
- Better screening
- Novel approaches (phae lysins, photo active compounds)
