10-11-22 – The Mechanism of Action of Antibiotics Flashcards
Learning outcomes
- Describe the main principles of antimicrobial chemotherapy
- List the main classes of antibacterial drugs in use
- Understand and provide examples of the concept of anti-microbial spectrum
- Understand the processes involved in choosing the correct antimicrobial
What 3 things do antibacterials target? What principle are these 3 targets based off of?
- 3 things antibacterials target:
1) Anti-bacterials target processes that humans do not possess (e.g., bacterial cell wall)
2) Anti-bacterials target processes that humans possess but the bacterial versions are sufficiently different
3) Anti-bacterials can target processes that aren’t used much by humans, but are essential for bacteria, leading to toxicity being greater for bacteria than humans (e.g bacteria need to create their own folate/folic acid)
- These 3 targets are based off of the principle of selective toxicity
What are peptidoglycans?
What are these strands made up of?
What gives the bacterial cell wall its strength?
- Bacterial cell walls are made up of various strands of peptidoglycans, which are not present in eukaryotes
- The strands are made up of multiple amino sugars such as N-Acetylglucosamine (NAG) and N-Acetylmuramic Acid (NAMA)
- NAMA has a short peptide side chain, which can cross link to form a lattice work of a strong elastic macromolecule
- This cross-linking gives the cell all its strength
What are 5 different antibiotic classes that work against the cell membrane, including
* Target
* Mechanism
* Example of each drug class?
What are the 3 main classes of bacterial wall inhibitor antibiotics?
How do these drugs affect bacteria?
- 3 main classes of bacterial wall inhibitor antibiotics:
1) b-Lactams (penicillins and cephalosporins)
2) Vancomycin
3) Bacitracin - Inhibiting bacterial cell wall synthesis normally leads to the death of the bacteria.
- It appears that imbalance in the cell wall architecture triggers bacterial autolysins that kill the cell
How do Beta-lactams function?
What does this lead to?
What reaction is this? How do bacteria protect against this?
- Beta-lactams prevent the cross-linking between the short peptide side chains of NAMA, meaning peptide cross-links cannot occur
- This results in the bacterial cells losing all its strength and being killed
- This is known as a bactericidal anti-biotic, as the bacterial cell is killed
- Some bacteria have beta lactamase, which is an enzyme that can break down the beta lactam ring that is central to the core of beta-lactam anti-biotics
What effect does the penicillin nucleus have?
How can we modify it?
- The penicillin nucleus by itself is not active
- By adding things to it, we generate antibiotics such as Penicillin G and Ampicillin
- This is part of the semi-synthetic revolution
What are the 4 different types of penicillin?
What are 2 examples of Naturally occurring penicillin?
What are 5 examples of B-lactamase resistant penicillin?
What are 2 examples of Broad-spectrum penicillins?
What are 4 examples of Extended-spectrum pencillins?
- 4 different types of penicillin:
1) Naturally occurring penicillin
* Penicillin G
* Penicillin V (derived from penicillin G)
2) B-lactamase resistant penicillin
* Dicloxacillin
* Cloxacillin
* Methicillin
* Nafcillin
* Oxacillin
3) Broad-spectrum penicillins
* Ampicillin
* Amoxicillin
4) Extended-spectrum pencillins
* Azlocillin
* Carbenicillin
* Piperacillin
* Ticarcillin
What are the 6 gram-positive and gram-negative Penicillin G and V work on?
Which gram-positive rods do Penicillin G and V work on?
What 2 spirochaetes do Pencillin G and V work on?
- 6 gram-positive and gram-negative Cocci Penicillin G and V work on:
1) Staphylococcus (infections of wounds, boils)
2) Streptococcus haemolytic types (septic infections)
3) Enterococcus (endocarditis)
4) Pneumococcus (pneumonia).
5) Neisseria gonorrhoeae (gonorrhoea)
6) Neisseria menigitidis (meningitis)
- Penicillin G and V work on work on Clostridium (tetanus, gangrene) gram-positive rods
- Spirochaetes Penicillin G and V work on:
1) Treponema (syphilis)
2) Actinomyces (abscesses).
What do B-lactamase resistant penicillins treat?
What 5 additional things can broad spectrum penicillins be used for?
What do extended-spectrum pencillins cover?
How effective are these drugs?
- B-lactamase resistant penicillins have the same spectrum as ordinary pencillins, but are B-lactamase resistant
- Broad spectrum penicillins are used for the same as b-lactamase resistant penicillins, but also B-lactamase free strains of:
1) H. Influenzae
2) N. Gonorrhoeae
3) E. Coli
4) Salmonella
5) Moraxella catarrhalis (sinusitis)
- Extended-spectrum pencillins cover the same as broad-spectrum bacteria plus Pseudomonas Aeruginosa
- Extended spectrum antibiotics are some of the best drugs on the market, till we reach Extended Spectrum B-Lactamase
What are Carbapenems?
What is an example of carbapenem?
What spectrum can they be used for?
What are they resistant to?
What are PBPs?
How can carbapenems bind to these?
What are carbapenems active against?
What do they do poorly against?
What are they not active against?
- Antibiotics = antibacterials
- Carbapenems are a type of B-lactam
- An example of a carbapenem is Meropenem
- Carbapenems are broad spectrum antibiotics, with a much broader spectrum than other β-lactams (cephalosporins & penicillins)
- They are generally resistant to the typical beta-lactamases
- PBPs are penicillin binding proteins, which are proteins on the surface of bacteria that have a high affinity for penicillin
- Carbapenems can bind to multiple types of PBPs, permanently acylating them (a lot of penicillins can only bind to 1 type of PBP, e.g PBP1)
- Carbapenems are active against both Gram positive and Gram-negative bacteria and anaerobes
- They do poorly active against MRSA
- They are not active against bacteria lacking a cell wall
What are 4 mechanisms of bacterial resistance to B-lactam antibiotics?
What are examples of bacteria that use each mechanism?
- 4 mechanisms of bacterial resistance to B-lactam antibiotics:
1) Destruction by b-lactamase e.g, S. aureus (staph aureus)
2) Failure to reach target enzyme- changes to outer membrane porins and polysaccharide components of gram-negative organisms e.g Pseudomonas spp (pseudomonas aeruginosa)
3) Failure to bind to the transpeptidase e.g S. pneumonia (Streptococcus pneumoniae)
4) Inhibition of release of autolysins
What are the 4 classes of Beta-lactamases?
What is used for their hydrolysis?
What is used as a B-lactamase inhibitor for Class A?
What is an alternative to B-lactamase resistant antibiotics?
- The 4 classes of B-lactamases are A, C, D and B
- ACD uses serine to hydrolyse
- B uses zinc ions to hydrolyse
- The B-lactam compounds clavulanic acid and sulbactam act as strong inhibitors of Class A, but not C and D
- Co-administration of B-lactamase inhibitors with a B-lactam antibiotic is an alternative approach to the use of B-lactamase-resistant antibiotics
What are cephalosporins an alternative to?
How are cephalosporins classified?
What 6 conditions can cephalosporins be used to treat?
What are 4 examples of cephalosporins?
What can overuse of cephalosporins result in?
- Cephalosporins are an alternative to penicillins (as they have similar indications).
- There are fewer of them and they are classified by generations, 1st, 2nd, and 3rd
- 6 conditions can cephalosporins be used to treat:
1) Septicaemia
2) Pneumonia
3) Meningitis
4) Biliary tract infections
5) Urinary tract infections
6) Sinusitis
- 4 examples of cephalosporins:
1) Cefalexin
2) Cefuroxime
3) Cefotaxime
4) Cefadroxil
- Overuse of cephalosporins can facilitate the emergence of C. difficile
What is vancomycin?
What does it bind to?
What does it interfere with?
What interaction does vancomycin utilise?
Why is this a positive?
What 3 things that have vancomycin resistance?
- Vancomycin is a glycopeptide antibiotic
- It binds to the peptide chain of peptidoglycan
- Interferes with the elongation of the peptidoglycan backbone
- Vancomycin utilises a very specific interaction with D-Ala-D-Ala
- This is a positive, as it means development of resistance to the antibiotic is very minimal
- What 3 things that have vancomycin resistance:
1) MRSA
2) Some resistant streptococci
3) Some resistant Enterococci
What are 2 examples of bacterial folate antagonists?
How do these antibiotics work?
Why is this a good pathway to target?
- 2 examples of bacterial folate antagonists:
1) Sulphonamides
2) Trimethoprim - These are antibiotics which act through an inhibition of the folate pathway in bacteria
- This is a good pathway to target, as the folate system is important in cell metabolism and bacteria must make their own supply but we don’t as we get it in diet
- This makes bacteria susceptible to drugs which interfere with folate metabolism: thus, we have our ‘selective toxicity’ target
What are 5 types of inhibitors of bacterial ribosomal actions? How do they work (also in picture)?
- 5 types of inhibitors of bacterial ribosomal actions:
1) Macrolides (Erythromycin, Clarithromycin)
* Erythromycin binds to 50S rRNA and prevent movement along mRNA
2) Clindamycin (Lincosamide class antibiotic)
3) Aminoglycosides e.g streptomycin
* Streptomycin changes shape of 30s rRNA and causes mRNA to be read incorrectly
4) Tetracyclines e.g minocycline and tigecycline
* Tetracycline interferes with the tRNA anticodon reading of mRNA codon
5) Chloramphenicol
* Binds to 50S rRNA and inhibits the formation of the peptide bond
- These antibiotics work by either stopping RNA from being read properly, so proteins aren’t produced, or will interfere with the way proteins are produced, so they don’t work properly
What are 3 examples of tetracyclines?
What 7 conditions are tetracyclines the first drug of choice for?
What 3 other things are tetracyclines used to treat?
- 3 examples of tetracyclines:
1) Tetracycline
2) Minocycline
3) Tigecycline - 7 conditions are tetracyclines the first drug of choice for:
1) Rickettsia
* Genus of nonmotile, gram-negative bacteria
2) Mycoplasma
* Mycoplasma is a genus of bacteria that, like the other members of the class Mollicutes, lack a cell wall around their cell membranes
3) Chlamydia infections
4) Brucellosis
* infection you can catch from unpasteurised milk and cheese
5) Cholera
* Cholera is an acute diarrheal illness caused by infection of the intestine with Vibrio cholerae bacteria
6) Plague
* Caused by the bacterium Yersinia pestis
7) Lyme disease
* Lyme disease is a bacterial infection that can be spread to humans by infected ticks
- 3 other things are tetracyclines used to treat:
1) Tigecycline used in management of resistant Gram-negative infection
2) Can be used in COPD
3) Important role in treating chronic acne
Inhibition of protein synthesis by antibiotics diagram
What is DNA Gyrase?
What are the 4 steps in the mechanism of DNA Gyrase?
How do quinolones affect this mechanism?
- DNA Gyrase is A tetrameric enzyme consisting of two GyrA and two GyrB subunits
- It is also a type 2 topoisomerase
- 4 steps in the mechanism of DNA Gyrase:
1) Forms transient covalent bond with DNA
2) Breaks the DNA
3) Passing the DNA through the break
4) Repairs the break
- Quinolones dually target DNA gyrase and topoisomerase IV binding to specific domains and conformations (they inhibit bacterial DNA Gyrase)
- This blocks DNA strand passage catalysis and stabilizes DNA–enzyme complexes that block the DNA replication apparatus
- This generates double breaks in DNA that underlie quinolones’ bactericidal activity.
What is the spectrum and use of:
1) Nalidixic acid
2) Norfloxacin and Ciprofloxacin
3) Moxifloxacin, Gatifloxacin, and Gemifloxacin
Describe the flow chart of choosing an antibiotic
