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aa Biomolecules > Lecture 9 - Antibiotics > Flashcards

Lecture 9 - Antibiotics Flashcards

1
Q

What are antibiotics

A
  1. Antibiotics are used in the treatment and prevention of bacterial growth
  2. Kill or stop bacterial growth
  3. Not effective against viral infections
  4. Classified based on mechanism of action, chemical structure and spectrum of activity
  5. Narrow spectrum antibiotics target specific bacteria e.g. gram positive or gram negative
  6. Broad spectrum antibiotics treat many different types of bacteria
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2
Q

What is technique for identifying if a bacteria is gram positive or negative

A
  1. Violet dye applied
  2. Decolourising agent
  3. Red dye
  4. Gram-positive retain violet dye
  5. Gram-negative lose violet dye and appear red
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3
Q

What are beta-lactam anitbiotics

A
  1. Broad-spectrum antibiotics
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4
Q

Describe how penicillin works

A
  1. 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
  2. The beta-lactam moiety of penicillin irreversibly binds to serine residue in the transpeptidase active site
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5
Q

Describe discovery and development of penicillin

A
  1. Penicillin G was isolated from penicillium by Flemming 1928
  2. Natural penicillin derivatives are produced in mould fermentation
  3. Isolation of 6-aminopenicillin (6-APA) allowed for preparation of semi-synthetic penicillin with improvements in bioavailability, spectrum, stability and tolerance
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6
Q

Describe biosynthesis of penicillin G

A
  1. 3 different amino acids are coupled to give a tripeptide
  2. Then isopenicillin N synthase converts to convert to isopenicillin N
  3. This can then produce cephalosporins or can undergo N-acyltransferase to produce penicillin G
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7
Q

Where do derivatives of penicillin come from

A
  1. Adding new side chains to 6-aminopenicillanic acid generated new and effective antibiotics
  2. Mode of action stays similar
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8
Q

What are Cephalosporins

A
  1. Class of beta-lactam anitbiotics derived from fungus Acremonium
  2. Cephalosporins disrupt synthesis of peptidoglycan layer forming in the bacterial cell wall
  3. Antibiotics are isolated and refined from culture or derived from 7-amionocephalosporic acid (7-ACA)
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9
Q

How do you make a variety of Cephalosporins

A
  1. Make cephalosporin C
  2. Hydrolyse to produce 7-ACA
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10
Q

What is antibiotic resistance

A
  1. Resistance often reflects evolutionary processes which take place during the therapy
  2. Antibiotic treatment may select for bacterial strains with a physiologically or genetically enhanced capacity to survive high doses of antibiotics
  3. This results in the preferential growth of resistance bacteria
  4. Many antibiotics which used to have high efficacy against many bacterial species have become less effective due to increased resistance
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11
Q

Describe beta-lactam antibiotic resistance

A
  1. All beta-lactam anitbiotics have a beta-lactam ring in their structure
  2. Beta-lactamase enzymes are enzymes capable of hydrolysing the beta-lactam ring and deactivating the molecules antibacterial properties- e.g. penicillinase
  3. Since penicillin has been used, Penicillinase production spread to bacteria that previously did not previously produce it or only produced in small quantities
  4. Genes encoding these enzymes may be acquired via plasmid-mediated resistance
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12
Q

Are beta-lactam antibiotics useless

A
  1. Not all bacteria are resistant to beta-lactam antibiotics
  2. In some instances beta-lactam antibiotics can be co-administered with a beta-lactamase inhibitor
  3. Current lactamase inhibitors are competitive inhibitors which can be hydrolysed by the lactamase enzyme- block the enzyme which hydrolyse anitbiotics
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13
Q

What are 2 beta-lactamase inhibitors

A
  1. Amoxicillin
  2. Clavulanic acid
  3. Both contain beta-lactam rings
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14
Q

What is another method of resistance

A
  1. Penicillin-binding proteins
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15
Q

How do penicillin-binding proteins work

A
  1. Some bacteria have developed novel PCP where beta-lactam antibiotics cannot bind effectively and as a result do not disrupt cell-wall synthesis
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16
Q

What are examples of bacteria which use PCP mode of resistance

A
  1. Methicillin-resistant Staphylococcus aureus (MRSA)
  2. Penicillin-resistant Streptococcus pneumoniae
17
Q

What is ceftaroline fosamil

A
  1. A prodrug of the active metabolite ceftaroline - hydrolysed in situ
  2. Can add functionality which may be cleared at active site- gives beneficial properties
  3. 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
  1. Phosphono- group increases solubility of prodrug so can be hydrolysed in situ
  2. 1,2,4-thiadiazole ring: Gram negative penetration and affinity for transpeptidase
  3. Oxime confers Beta-lactam resistance
  4. Lactam inhibits transpeptidase activity
  5. 1,3-thiazole ring- anti MRSA activity
19
Q

What are macrolides

A
  1. Natural products from polyketide
  2. Large macrocyclic lactone ring attached to one or more deoxy sugar
  3. Used to treat gram +ve bacteria infections- protein synthesis inhibitors
  4. Broad spectrum antibiotics, substitute for patients with a penicillin allergy
20
Q

What are examples of macrolides

A
  1. Erythromycin
  2. Roxithromycin
  3. Clarithromycin
21
Q

How is Roxithromycin formed

A
  1. Semi-synthetic macrolide anitbiotic derived from erythromycin
  2. Add NH2OH.HCl, Et3N, MeOH to change ketone to N-OH
  3. Add ether chloride with acetone - attacks N and adds ether
22
Q

What are ketolides

A
  1. Structurally related to macrolides but are effective against macrolide-resistant bacteria
  2. 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
  1. Protein synthesis inhibitors
  2. Comprise a linear fuest tetracyclic nucleus
  3. The simplest tetracycline to display antibacterial activity is tetracycline (6-deoxy-6-demethyltetracycline)- Minimum pharmacophore
24
Q

What is resistance to tetrayclines

A
  1. Efflux pumps which eject tetracycline from the cell
  2. Ribosomal protection proteins- dislodge tetracycline from the ribosome
25
Q

How can you produce tetracylcine from chlorotetracycline

A
  1. Reduce with H2, Pd/C
  2. Removes Cl
26
Q

Which bits of tetracyclines can be modified

A
  1. R groups at top can be substituted for selected bacterial species
  2. 4-(R)-amino group is essential for antibacterial activity
  3. Substitution of amide by aldehyde or nitriles reduces activity
  4. Ion chelation increases anti metallo proteinase activity
  5. Non modifiable region- contact side with ribosome- =O/-OH bit
27
Q

What is chloramphenicol

A
  1. Isolated from streptomyces venezuelae
  2. First antibiotic to be synthesised rather than isolated
  3. Protein synthesis inhibitor
28
Q

What is resistance to chloramphenicol

A
  1. Reduced membrane permeability to low levels of chloramphenicol
  2. Acquisition of the cat-gene which encodes chloramphenicol acetyltransferase
29
Q

How does antibiotic resistance occur

A
  1. High number of bacteria, where a few are resistant to antibiotics
  2. Antibiotics kill bacteria causing the illness, as well as good bacteria protecting the body from infection
  3. The resistant bacteria now have preferred conditions to grow and take over
  4. 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
  1. Access
  2. Watch
  3. Reserve
31
Q

What is access category

A
  1. Those listed as first and second choice for empiric treatment of the most common infection syndromes
  2. Antibiotics that should be consistently globally widely available
32
Q

What is Watch category

A
  1. Generally have higher toxicity concerns and resistance potential
  2. E.g. penicillins with beta-lactamase inhibitor, macrolides, cephalosporins older
33
Q

What is Reserve category

A
  1. Includes new antibiotics and ‘last-resort’ treatment options
  2. Should be protected and prioritised as key targets of high-intensity nation and international stewardship programs to preserve effectiveness
  3. E.g. cephalosporins newer

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