Mechanism and Action of Antibiotics Flashcards
Give the target, mechanism and an example of beta-lactam and cephalopsorin antibiotics
Penicillin Binding Proteins
Preventing peptidoglycan cross-linking
Examples:
- Penicillin G + V
- Flucloxacillin
- Tazobactam
Give the target, mechanism and an example of glycopeptide antibiotics
C-terminal D-Ala-D-Ala
Prevents transglycolation and transpeptidation
Examples:
- Vancomycin
- Teicoplanin
Give the target, mechanism and an example of cyclic peptide antibiotics
C55-isopropyl pyrophosphate
Prevents carriage of building blocks of peptidoglycan bacterial cell wall outside of the inner membrane
Examples:
- Bacitracin
- Polymyxin
Give the target, mechanism and an example of phosphonic acid antibiotics
murA protein
Inhibits the first stage of peptidoglycan synthesis
Example:
- Fosphomycin
Give the target, mechanism and an example of Lipopeptide antibiotics
Cell wall stress stimulon (genetic target that controls a large number of genes through a single stimulus)
Calcium-dependent membrane depolarisation
Example:
- Daptomycin
What are the 3 main classes of bacterial cell wall inhibitiors?
β-Lactams
Vancomycin
Bacitracin
What is the action of bacterial cell wall inhibitors?
inhibiting bacterial cell wall synthesis normally leads ti death of bacteria.
Imbalance in cell wall architecture triggers bacterial autolysins that kill the cell
What is common to the chemical structure of penicillins?
What are the causative gram positive and gram negtaive cocci that can be treated with penicillins?
– Staphyloccus (infections of wounds, boils)
– Streptococcus haemolytic types (septic infections)
– Enterococcus (endocarditis)
– Pneumococcus (pneumonia).
– Neisseria gonorrhoeae (gonorrhoea)
– Neisseria menigitidis (meningitis)
What is the causitive gram positive rod that can be treated with penicillin?
Clostridium (tetanus, gangrene)
What are the causative spirochetes that can be treated with penicillin?
Treponema (syphillis) also Actinomyces (abscesses)
What are the β-lactamase resistant penicillins and what is their benefit?
- Methicillin
- Oxacillin
- Nafcillin
- Cloxacillin
- Dicloxacillin
Not broken down by rhe evolutionary response of bacteria so broadening the spectrum and overcoming resistance
What are the broad spectrum penicillins? And what is their additional function?
Ampicillin and Amoxicillim
Treat β-lactamase free strains of:
- H. Influenzae
- N. Gonorrhoeae
- E. Coli
- Salmonella
- Morasella catarrhalis (sinusitis)
What are the extended-spectrum penicillins? And what additonal bacteria do they cover?
- Carbenicillin
- Ticaracillin
- Azlocillin
- Piperacillin
Pseudomonas Aeruginosa
How does the bacterial spectrum of carbapenems compare with that of β-lactams (cephalosporins and penicillins)
Much broader antibacterial spectrum
generally resistant to typical beta-lactamases
What is the action of carbapenems?
bind penicillin binding protwina permanently acylating them (can bind multiple)
What are carbapenems active against?
both gram positive and gram negative bacteria and anaerobes
What are carbapenems not acitve against?
MRSA and bacteria lacking a cell wall
Give examples of mechanisms of bacteria resistance to β-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 → Pseudomonas spp
- Failure to bind to the transpeptidase → S. pneumoniae
How many classes of β-lactamases are there? And what are they named?
4 classes
A, B, C, D
What classes of β-lactamases use serine to hydrolyse?
A, C, D
What classes of β-lactamases use zinc ions to hydrolyse?
B
What β-lactam compounds act as strong inhibitors of class A but not C and D?
CLAVULANIC ACID & SULBACTAM
What is an alternative apprach to the use of beta-lactamase resistant antibiotics?
co-administration of beta-lactamase inhibitors with a beta-lactam antibiotic
What drugs are used as an alternative to penicillins? And how are these drugs classified?
Cephaloporins
1st, 2nd, 3rd
What are cephalosporins used to treat?
- septicaemia
- pneumonia
- meningitis
- bilary tract infections
- UTIs
- sinusitis
What are the common cephalosporins used in clinical practice?
- Cefalexin
- cefuroxime
- cefotaxime
- cefadroxil
What does over use of cephalosporins result in the mergence of?
C. difficile
What type of antibiotics is Vancomycin and what is its mechanism of action?
Glycopeptide antibiotic
Binds to the peptide chain of peptidoglycan and interfers with the elongation of the peptidoglycan backbone
What explains the minimal resistance to vancomycin?
very specific interactopm with D-Ala-D-Ala
Describe the range of activity of vancomycin?
narrow range of activity
What bacteria have developed some resistance to vancomycin?
MRSA
some streptococci and enterococci
What is bacitracin?
Polypeptide and bactericidal (kills bacteria)
What is the action of bacitracin?
interfers with the dephosphorylation of the lipid carrier which moves the early cell wall components through the membrane
How is bacitracin used?
used as an ointment to treat infectioms of the skin and eye by streptococci and staphylococci (topical use)
What are the main bacterial folate antagonists?
sulphonamides and trimethoprim
What is the action of sulphonamides and trimethoprim? And why is this beneficial?
inhbition of the folate pathway in bacteria
We get folate from our diets where as bacteria have to make their own so this makes folate metabolism a ‘selective toxicity’ target
Draw a diagram showing the mechanim of sulphonamides and trimethoprim
What is trimethoprim most commonly used for?
treatment of UTIs
What is the name of trimethoprim in a combined treatment and what is it combined with?
co-trimoxazole
sulphamethoxasole (SMX)
What is co-trimoxazole used to treat?
combination treatment of toxoplasmosis (parasitic disease)
What other things can can co-trimoxazole be used for in combination without drugs?
treatment of opportunistic infections in patients with AIDS
e.g. pnumoctsis jiroveci (pneumonia)
What can be used to treat drug-resistant makaria and toxoplasmosis?
SMX combined with pyrimethamine
Give some examples of inhibitors of bacterial ribsosomal actions and what actions they inhibit
- chloramphenicol - binds to rRNA and inhibits the formation peptide bonds between adjacent amino acids
- Erythromycin - binds to rRNA and prevents the movement along mRNA
- Tetracycline - interfers with tRNA anticodon reading of mRNA codon
- Streptomycin - changes shape of rRNA and causes mRNA to be read incorrectly
Give the main examples of macrolides
erythromycin and clarithromycin
When are macrolides primarily used?
alternative to penicillins in patinets who are allergic
What are macrolides active against?
- mycoplasma Chamydia
- Legionella
- community acquired lower respiratory tract infections
- H.Influenzae (menigitis)
- Corynebacterium (diptheria)
- Campylobacter (diarrhoea)
- Chlamydia trachomatis
- Toxoplasma gondii in the context of pregnancy
How large is the theraputic window of macrolides?
narrow theraputic windows
What are the common side effects of erythromycin?
- Mild gut disturbance
- hypersensitivity reactions
- transient hearing disturbances
- RARE: cholestatic jaundice
What additional side effect does clarithromycin have in additional to those presented by erythomycin?
QT prolongation
What are the main advserse effects of Clindamycin?
- GI disturbances
- pseudomembranous colitis (potentially fatal)
What is pseudomembranous colitis?
this is an acute inflammation of the colon due to a necrotising toxin produced by the clindamycin-resistant Clostridium difficile which may be a part of the normal gut flora.
What drug is part of the lincosamide class?
Clinamycin?
What is clindamycin active against?
- gram positive cocci - including staphylococci
- wide range of anaerobic species - bacteroides species
What can clindamycin treat when used in combination?
- anaerobic species
- necrotising fascitis - staphylococcal infections of joints and bones
When is clindamycin used in eye drop form?
to treat staphylococcal conjunctivitis
What are the main examples of aminoglycosides
- gentamicin
- amikacin
- tobramycin
- neomycin
- streptomycin
Why should aminoglycosides be reserved for the treatment of serious infections?
relative toxicity and parenteral adminisatration
What can aminoglycosides be used to treat?
- Enterobacteriaceae and Pseudomonas which give rise to septicaemia and serious urinary tract infections
- Hospital acquired pneumonia ,respiratory and intra- abdominal infections due to Pseudomonas
- Rare problematic infections such as complicated Brucellosis, Yersinia pestis (the plague)
What are the major side effects of aminoglycosides?
- Renal toxicity due to damage of the kidney tubules.
- Ototoxicity with a progressive damage to and 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 concomitantly with a neuromuscular blocker and is due to the block of calcium entry into nerves which is necessary for transmitter release.
What are the pharmacokinetics of aminoglycosides?
- polar agent confided to extracellular fluid
- does not cross the BBB
- excreted by the kidney
- have to be administrated intravenously
What are the cautions when using aminoglycosides?
- caution in the elderly
- caution with renal failure
- interaction with other renal toxic drugs
- caution in severe sepsis that is cauing acute renal failure
What are tetracyclines the drug of first choice for?
- rickettsia
- mycoplasma
- Brucellosis
- Cholera
- plague
- can be used in COPD
- Treating chronic acne
What is used in the management of gram negative infection?
Tigecycline
What are the main side effects of tetracyclines?
- gut uosets
- hepatic and renal dysfunction
- photosensitivity
- Binding to bone and teeth causing staining; dental hypoplasia and bone deformities
- vestibular toxicity (dizziness and nausea)
What type of antibioric is chroamphenical and what is it indicated for?
broad spectrum
menigitis and brain abscess when other agents cannot be used
What is topoisomerase IV and how does it work?
- Tetrameric enzyme consisting of two ParC and two ParE sub-units
- Involved in chromosomal partitioning
- Catalyses ATP dependent relaxation of negatively and positively supercoiled DNA and unknotting of un-nicked duplex DNA
- No action against super-coiling
What is DNA gyrase and how does it work?
- A tetrameric enzyme consisting of two GryA and two GyrB subunits
- Transient covalent bond with DNA
- Breaks the DNA
- Passing the DNA through the break
- Repairs the break
Draw stage I of the DNA gyrase pathway?
Draw stage II of the DNA gyrase pathway?
Draw stage III of the DNA gyrase pathway?
Draw stage IV of the DNA gyrase pathway?
Draw the action of quinolone on the DNA gyrase pathway?
What is the most commonly used fluroquinolones and what are they commonly active against?
Ciprofloxacin
- enterobacteriaceae
- H.influenzae
- β-lactamase-producing N.gonorrhea
- Camphylobacter (diarrhoea).
- Pseudomonas aeruginosa.
- Salmonella (including typhoid but resistance is emerging)
What is the spectrum of naladixic acid and its uses?
gram negative bacilli
UTI
What is the spectrum of norfloxacin and ciproflocacin and its uses?
gram negative bacilli, mycoabacteria, chlamydia
systemic infection
What is the spectrum of moxifloxacin, gaitfloaxcin, gemifloxacin and its uses?
gram negative bacilli, gram positive bacteria
UTI, systemic infection, acute lower respiratory tract infection
What are the actions of metronidazole
- Originally an antiprotozoal agent
- Under anaerobic conditions it generates toxic radicals that
- damage bacterial DNA
- Active against anaerobic bacteria such as Bacteriodes,
- Clostridia and some streptococci
- Important in the treatment of anaerobic infections such as
- sepsis secondary to bowel disease
- Effective in the therapy of pseudomembranous colitis, a clostridial infection associated with antibiotic therapy
- Used with other drugs (omeprazole, amoxicillin) to treat Helicobacter pylori infections which give rise to peptic ulceration.
What is nitrofuratonin used to treat?
UTI due to enterobacteriaceae
What are polymixins? And what is their mechanism of action
These are branched chain decapeptides with cationic detergent properties. Their mechanism of action involves interaction with the phospholipids of the cell membrane and disruption of its structure. Eventually the cell membrane is breached and there is loss of intracellular constituents.
Topical use for cutaneous pseudomonas infections
