Lecture 9 - Antibiotics Flashcards
1
Q
What are antibiotics
A
- Antibiotics are used in the treatment and prevention of bacterial growth
- Kill or stop bacterial growth
- Not effective against viral infections
- Classified based on mechanism of action, chemical structure and spectrum of activity
- Narrow spectrum antibiotics target specific bacteria e.g. gram positive or gram negative
- Broad spectrum antibiotics treat many different types of bacteria
2
Q
What is technique for identifying if a bacteria is gram positive or negative
A
- Violet dye applied
- Decolourising agent
- Red dye
- Gram-positive retain violet dye
- Gram-negative lose violet dye and appear red
3
Q
What are beta-lactam anitbiotics
A
- Broad-spectrum antibiotics
4
Q
Describe how penicillin works
A
- Acts by inhibiting the synthesis of peptidoglycan layer of bacterial cell walls by targeting transpeptidase which catalyses the final cross-linking step in peptidoglycan synthesis
- The beta-lactam moiety of penicillin irreversibly binds to serine residue in the transpeptidase active site
5
Q
Describe discovery and development of penicillin
A
- Penicillin G was isolated from penicillium by Flemming 1928
- Natural penicillin derivatives are produced in mould fermentation
- Isolation of 6-aminopenicillin (6-APA) allowed for preparation of semi-synthetic penicillin with improvements in bioavailability, spectrum, stability and tolerance
6
Q
Describe biosynthesis of penicillin G
A
- 3 different amino acids are coupled to give a tripeptide
- Then isopenicillin N synthase converts to convert to isopenicillin N
- This can then produce cephalosporins or can undergo N-acyltransferase to produce penicillin G
7
Q
Where do derivatives of penicillin come from
A
- Adding new side chains to 6-aminopenicillanic acid generated new and effective antibiotics
- Mode of action stays similar
8
Q
What are Cephalosporins
A
- Class of beta-lactam anitbiotics derived from fungus Acremonium
- Cephalosporins disrupt synthesis of peptidoglycan layer forming in the bacterial cell wall
- Antibiotics are isolated and refined from culture or derived from 7-amionocephalosporic acid (7-ACA)
9
Q
How do you make a variety of Cephalosporins
A
- Make cephalosporin C
- Hydrolyse to produce 7-ACA
10
Q
What is antibiotic resistance
A
- Resistance often reflects evolutionary processes which take place during the therapy
- Antibiotic treatment may select for bacterial strains with a physiologically or genetically enhanced capacity to survive high doses of antibiotics
- This results in the preferential growth of resistance bacteria
- Many antibiotics which used to have high efficacy against many bacterial species have become less effective due to increased resistance
11
Q
Describe beta-lactam antibiotic resistance
A
- All beta-lactam anitbiotics have a beta-lactam ring in their structure
- Beta-lactamase enzymes are enzymes capable of hydrolysing the beta-lactam ring and deactivating the molecules antibacterial properties- e.g. penicillinase
- Since penicillin has been used, Penicillinase production spread to bacteria that previously did not previously produce it or only produced in small quantities
- Genes encoding these enzymes may be acquired via plasmid-mediated resistance
12
Q
Are beta-lactam antibiotics useless
A
- Not all bacteria are resistant to beta-lactam antibiotics
- In some instances beta-lactam antibiotics can be co-administered with a beta-lactamase inhibitor
- Current lactamase inhibitors are competitive inhibitors which can be hydrolysed by the lactamase enzyme- block the enzyme which hydrolyse anitbiotics
13
Q
What are 2 beta-lactamase inhibitors
A
- Amoxicillin
- Clavulanic acid
- Both contain beta-lactam rings
14
Q
What is another method of resistance
A
- Penicillin-binding proteins
15
Q
How do penicillin-binding proteins work
A
- Some bacteria have developed novel PCP where beta-lactam antibiotics cannot bind effectively and as a result do not disrupt cell-wall synthesis
16
Q
What are examples of bacteria which use PCP mode of resistance
A
- Methicillin-resistant Staphylococcus aureus (MRSA)
- Penicillin-resistant Streptococcus pneumoniae
17
Q
What is ceftaroline fosamil
A
- A prodrug of the active metabolite ceftaroline - hydrolysed in situ
- Can add functionality which may be cleared at active site- gives beneficial properties
- Ceftaroline has potent in vitro activity against Gram-positive bacteria including methicillin-resistant staphylococcus aureus and streptococcus pneumoniae
18
Q
Describe structure of ceftaroline fosamil
A
- Phosphono- group increases solubility of prodrug so can be hydrolysed in situ
- 1,2,4-thiadiazole ring: Gram negative penetration and affinity for transpeptidase
- Oxime confers Beta-lactam resistance
- Lactam inhibits transpeptidase activity
- 1,3-thiazole ring- anti MRSA activity
19
Q
What are macrolides
A
- Natural products from polyketide
- Large macrocyclic lactone ring attached to one or more deoxy sugar
- Used to treat gram +ve bacteria infections- protein synthesis inhibitors
- Broad spectrum antibiotics, substitute for patients with a penicillin allergy
20
Q
What are examples of macrolides
A
- Erythromycin
- Roxithromycin
- Clarithromycin
21
Q
How is Roxithromycin formed
A
- Semi-synthetic macrolide anitbiotic derived from erythromycin
- Add NH2OH.HCl, Et3N, MeOH to change ketone to N-OH
- Add ether chloride with acetone - attacks N and adds ether
22
Q
What are ketolides
A
- Structurally related to macrolides but are effective against macrolide-resistant bacteria
- Ketolides have 2 ribosomal binding units and a modified sidechain which makes them poor substrate for efflux-pump mediated resistance
23
Q
What are tetracyclines
A
- Protein synthesis inhibitors
- Comprise a linear fuest tetracyclic nucleus
- The simplest tetracycline to display antibacterial activity is tetracycline (6-deoxy-6-demethyltetracycline)- Minimum pharmacophore
24
Q
What is resistance to tetrayclines
A
- Efflux pumps which eject tetracycline from the cell
- Ribosomal protection proteins- dislodge tetracycline from the ribosome
25
Q
How can you produce tetracylcine from chlorotetracycline
A
- Reduce with H2, Pd/C
- Removes Cl
26
Q
Which bits of tetracyclines can be modified
A
- R groups at top can be substituted for selected bacterial species
- 4-(R)-amino group is essential for antibacterial activity
- Substitution of amide by aldehyde or nitriles reduces activity
- Ion chelation increases anti metallo proteinase activity
- Non modifiable region- contact side with ribosome- =O/-OH bit
27
Q
What is chloramphenicol
A
- Isolated from streptomyces venezuelae
- First antibiotic to be synthesised rather than isolated
- Protein synthesis inhibitor
28
Q
What is resistance to chloramphenicol
A
- Reduced membrane permeability to low levels of chloramphenicol
- Acquisition of the cat-gene which encodes chloramphenicol acetyltransferase
29
Q
How does antibiotic resistance occur
A
- High number of bacteria, where a few are resistant to antibiotics
- Antibiotics kill bacteria causing the illness, as well as good bacteria protecting the body from infection
- The resistant bacteria now have preferred conditions to grow and take over
- Bacteria can even transfer their drug-resistance to other bacteria through plasma transfer
30
Q
What are the different categories that WHO uses to tackle antibiotic resistance
A
- Access
- Watch
- Reserve
31
Q
What is access category
A
- Those listed as first and second choice for empiric treatment of the most common infection syndromes
- Antibiotics that should be consistently globally widely available
32
Q
What is Watch category
A
- Generally have higher toxicity concerns and resistance potential
- E.g. penicillins with beta-lactamase inhibitor, macrolides, cephalosporins older
33
Q
What is Reserve category
A
- Includes new antibiotics and ‘last-resort’ treatment options
- Should be protected and prioritised as key targets of high-intensity nation and international stewardship programs to preserve effectiveness
- E.g. cephalosporins newer
