Mechanism of Action of Antibiotics Flashcards
What are the central principles of antibiotic use?
- Anti-bacterials target processes that humans do not possess (e.g bactrial cell wall)
- Anti-bacterials target processes that humans possess but the bacterial versions are sufficiently different
- The toxicity of anti-bacterials is greater to bacteria than it is to human
SELECTIVE TOXICITY
What are the 3 main classes of cell wall inhibitors?
- Beta-Lactams (penicillins and cephalosporins)
- Vancomycin
- Bacitracin
What are the bacterial enzymes called that destroy the cell wall peptidoglycan architecture?
Bacterial autolysins
What subsances inhibit the synthesis of glycopeptides?
- Glycopeptides
Vancomycin
Teicoplanin
What substances cause peptidoglycan cross-linking?
Penicillins and cephalosporins
Cabapenems, monobactams
What is the structure and function of carbapenems?
- Broad antibacterial spectrum
- Much broader than other Beta-lactams
- Permenantly acylate PBPs
Name a fluoroquinolone drug
Ciprofloxacin
Describe the mechanism of action of Beta-lactam and cephalosporins
Target penicillin binding proteins and prevent peptidoglycan cross-linking
Describe the mechanism of action of glycopeptides
Prevent transglycolation and transpeptidation by binding to C-terminal D-Ala-D-Ala. They essentially inhibit the synthesis of the peptidoglyca cell wall
What does the penicillin nucleus look like?
Square ring with Nitrogen in one corner
What antibiotics have a greater mechanism of action B-lactams (cephalosporins + penicillins) or carbapenems?
Carbapenems
By what mechanisms can bacterial cells become resistant to B-Lactam antibiotics?
- Destruction by B-lactamase (S.aureus)
- Failure to reach target enzyme - changes to outer membrane porins and polysaccharide components of gram-negative organisms (e.g Pseudomonas spp)
- Failure to bind to the transpeptidase (S. pneumoniae)
What can bacitracin antibiotics be used to treat?
Infections of skin and eye by streptococci and staphylococci
Name 2 bacterial folate agonists
Sulphonamides and trimethoprim
When is trimethoprim commonly used?
In the treatment of community aquired UTIs
What is the combined treatment of sulphonamide and trimethoprim called?
Sulphamethoxazole (SMX) and trimethoprim known as Co-trimoxazole
SMX is combined with pyrimethamine to treat what?
Drug-resistant malaria and toxoplasmosis
When can metronidazole be used?
- Originally an antiprotozoal agent
- Active against anaerobic bacteria such as Bacteriodes, Clostridilia ansd some streptococci
- Anaerobic sepsis secondary to bowel disease
- Effective in the therapy of pseudomembranous colitis, a clostridial infection associated with antibiotic therapy
- Used with other drugs to treat peptic uceration
Name 2 miscellaneous antibacterial agents
- Nitrofurans
- Polymixins
When are nitrofurans indicated?
UTIs due to Enterobacteriaceae
When are polymixins indicated?
Topical use for Pseudomonas infections
When are fluoroquinolones indicated?
- Enterobacteriaceae
- H influenza
- B-lactamase producing gonorrhea (possible 1 dose)
- Camphylobacter (diarrhoea)
- Pseudomonas aeruginosa
- Salmonella (including typhoid but resistance emerging)
Describe the structure of DNA gyrase
A tetrameric enzyme consisting of two GryA and two GyrB subunits
How does DNA gyrase work?
- Forms a transient covalent bond with DNA
- Breaks the DNA
- Passing the DNA through the break
- Repairs the break
What enzyme does sulphonamide inhibit?
Dihydropteroate synthetase (bacterial folate antagonist)
What enzyme does trimethoprim inhibit?
Dihydrofolate reductase
bacterial folate antagonist
What are the 4 classes of B-lactamase inhibitors?
- ACD use serine to hydrolyse
- B uses zinc ions to hydrolyse
How does Bacitracin inhibit the cell wall?
Interferes with the dephosphorylation of the lipid carrier which moves the early cell wall components through the membrane
What is clavulanic acid?
It is a Beta-lactamase inhibitor and boosts the effects of penicillins, it prevents bacteria from destroying penicillin
What are carbapenems active against?
- Gram +ves and -ves and anaerobes
- Poorly active against MRSA
Name 4 cephalosporin antibiotics?
- Cefalexin
- Cefuroxime
- Cefotaxime
- Cefadroxil
How does Vancomycin work?
- Glycopeptide antibiotic
- Binds to peptide chain of peptidoglycan
- Interferes with the elongation of the peptidoglycan backbone
- Very specific interaction with D-Ala-D-Ala which explains the minimal development of resistnace to the antibiotic (resistance can be found in MRSA and some resistant streptococci and enterococci)
What is the difference between bactericidal and bacteriostatic?
- Bacteriostatic reduces the growth of bacteria whereas bactericidal actually kills the bacteria
How does streptomycin work?
Changes the shape of 30S r-RNA and causes m-RNA to be read incorrectly
How does Chloramphenicol work?
Binds to 50S r-RNA and inhibits formation of peptide bond
How does Erythromycin work?
Binds to 50S r-RNA and prevents movement along m-RNA
How does Tetracycline work?
Interferes with the t-RNA anticodon reading of m-RNA codon
What drugs are used primarily as an alternative to penicillins?
Macrolides (e.g erythromycin and clarithromycin)
What are the side-effects of erythromycin?
Mild gut disturbances, hypersensitivity reactions, transient hearing disturbances and rarely cholestatic jaundice
What are the side-effects of clarithromycin?
- QT prolongation
- Mild gut disturbances, hypersensitivity reactions, transient hearing disturbances and rarely cholestatic jaundice
What are the side-effects of clindamycin?
- Mainly GI disturbances but a potentiallt fatal condition PSEUDOMEMBRANEOUS COLITIS, can occur; this is an acute inflammation of the colon due to a necrotising toxin produced by the clindamycin-resistant Clostridium difficle whcih may be a part of the normal gut flora
When are aminoglycosides used?
- Reserved for serious infections
- Enterobacteriaceae and Pseudomonas which give rise to septixaemia and serious UTIs
- Hospital aquired pneumonia, respiratory and intra-abdominal infections due to Pseudomonas
- Rare problematic infections such ad complicated Brucellosis, Yersinia pestis (the plague)
What are the side-effects of aminoglycosides?
- Renal toxicity due to damage of kidney tubules
- Ototoxicity with a progressive damage to nad destruction of the sensory cells in the cochlea and vestibular organ of the ear. This can result in vertigo, ataxia and loss of balance as well as auditory disturbances including deafness
- Neuromuscular block which is usually only seen when the drug is given continually with a neuromuscular blocker and is due to the block of calcium entry into nerves which is necessary for transmitter release
Describe the pharmokinetics of aminoglycosides?
- Polar agent confines to extracellular fluid
- Does not cross BBB
- Excreted by the kidney
- Have to be administered by IV
What are the cautions in the use of aminoglycosides?
- Elderly
- Renal failure
- Interaction with other renal toxic drugs
- Caution in severe sepsis that is causing acute renal failure
- Consider pharmacokinetics carefully
What are tetracyclines (inhibits bacteria ribosome) used against
- First choice for rickettsia, mycoplasma and chlamydia infections, brucellosis, cholera, plague and Lyme disease
- Can be used in COPD
- Important role in the treatment of chronic aacne
What are the side-effects of tetracycline?
- Most common are gut upsets (changing gut flora populations)
- Hepatic and renal dysfunction
- Photosensitivity
- Binding to bone and teeth causing staining; dental hypoplasia and bone deformities
- Vestibular toxicity (dizziness and nausea)
When is chloramphenicol used?
- Broad spectrum
- Low risk of aplastic anaemia means that it is now limited to indications for serious infections when no other drug is suitable (indications include meningitis and brain abscess)
What is the structure of topoisomerase 4?
Tetrameric enzyme consisting of 2 ParC and 2 ParE sub-units
What is the function of topoisomerase 4?
- Involved in chromosomal partitioning
- catalyses ATP dependant relaxation of negatively and positvely supercoiled DNA and unknotting of un-picked duplex DNA
- No action against super-coiling
