L18 Antibacterial drugs Flashcards
Bacterial cell wall structure simple desc
3-dimensional lattice comprising peptidoglycan
Glycan (aminosugar)
- chains cross-linked by peptide linker chains
- peptidase activity of penicillin binding proteins
What are the linear strands of two alternating aminosugars in a baceterial cell wall
- N-acetyl-muramic acid (NAMA)
- N-acetyl-glucosamine (NAG)
β-lactams
Interactions between β-lactam drugs and various penicillin binding proteins (PBPs) in bacteria explain differences in antibacterial specificity
β-lactams is a
Cell wall synthesis inhibitors and is essential for antibacterial activity
Lactam is a drug class
Amoxicillin (natural or semisynthetic)
Semisynthetic
Amoxicillin (broad or narrow)
Broad
Amoxicillin - β-lactamase resistant?
no
Clavulanic acid (natural or semisynthetic)
Semisynthetic
Clavulanic acid (broad or narrow)
-
Clavulanic acid- β-lactamase resistant?
β-lactamase inhibitor
Yes
A penicillin-like antibiotics
Amoxicillin
A beta-lactamase inhibitor drug
Clavulanic acid
How does Clavulanic acid work
It works by preventing bacteria from destroying amoxicillin so rendering them effective against beta-lactamase producing bacteria.
Pharmacokinetics of penicillins
- stability in acid varies
- lipid insoluble
- do not enter mammalian cells
- cross the blood–brain barrier only if the meninges are inflamed
- most penicillins are eliminated via the renal route (90% by tubular secretion) rapidly
Penicillin resistance
- Modifications/alterations in (penicillan binding proteins) PBPs → decreased drug binding and subsequent ↓ antibacterial activity
- Prevent β-lactams from accessing and traversing pore channels and reaching PBPs in the cell membrane of gram-negative bacteria
- Produce β-lactamase to inactivate β-lactams
Augmentin is the combination of
Amoxicillin + Clavulanic acid
Penicillin-related adverse drug reaction (opening of ß-ring forms what and what happens)
- opening of b-lactam ring → benzylpenicilloyl (major determinant, 95%) and is responsible for the adverse reaction to penicillin.
- hypersensitivity reactions
- Type I - symptoms appear (~ an hour) in the skin, e.g., itch, urticaria; anaphylaxis in up to 0.04%
of patients - Type IV - T-cell mediated
- superinfection such as candidiasis occurs due to prolonged use
β-lactams (II) - cephalosporins generations and spectrum of action
1 → Gram+
2 → less Gram+ (compared to 1), and some Gram
3 → Gram+, and greater Gram
4 → Gram+, and even greater Gram
5 → Expanded Gram+, including MRSA ; common Gram
MRSA
(methicillin-resistant Staphylococcus aureus)
Cephalosporins Pharmacokinetics
- acid stable
- most are administered parenterally; a few can be administered orally
- distribution - extracellular fluid ; some can cross blood-brain barrier to treat meningitis
- excretion is mostly by renal tubular secretion
Cephalosporin-related adverse drug reaction
- similar to penicillins
- cross-reactivity between penicillins and cephalosporins
- opening of b-lactam ring → cephalosporoyl, but is unrelated to adverse drug reaction
- similarity of side chain between penicillins and cephalosporins (1st and 2nd gen.)
Would not give to someone allergic to amoxicillin
70S bacterial ribosome consists of two subunits
- 50S subunit
- 30S subunit
What is the S in 70S ribosome
[S: the Svedberg unit for sedimentation coefficient]
Bacteria protein synthesis steps
- Initiation (aa at a-site)
- Elongation (aa and met bind at A then move to P-site)
- Termination (E-site)
Bacteria protein synthesis Initaiton
The initiation of protein synthesis in bacteria involves a series of steps, including the formation of the 30S preinitiation complex, recognition of the AUG start codon, binding of the 30S subunit to the tRNA fMet at the P site, and the union of the 50S component with the 30S initiation complex to form the 70S initiation complex.
Bacteria protein synthesis Elongation
Key steps in this phase include the arrival of the next tRNA at the A site, formation of the peptide bond, and the shifting of the mRNA through the ribosome by one codon after the peptide bond has been formed.
Bacteria protein synthesis Termination
Steps involved in the termination phase include the arrival of a stop codon in the mRNA at the A site, recognition of the stop codons by release factors, and the subsequent termination of translation, release of the polypeptide from the tRNA and dissociation of the 70S ribosome into its 30S and 50S subunits.
Aminoglycosides are bacteria -cidal or -static
bactericidal
Tetracyclines, Amphenicols and antibacterial macrolides are bacteria -cidal or -static
Bacteriostatic
What does aminogylcosides affect in protein synthesis and how
initiation
[30S] inhibit codon-anticodon interaction;
cause mRNA misreading
What does tetracyclines affect in protein synthesis and how
tRNA binding
[30S] inhibit aminoacyl-tRNA binding to the A site
What does amphenicols affect in protein synthesis and how
transpeptidation
[50S] inhibit peptide bond formation
What does antibacterial macrolides affect in protein synthesis and how
Elongation and translocation
[50S] prevent transfer of tRNA with the growing peptide from A site to P site
Aminoglycosides inhibit
inhibit codon-anticodon interaction, causing mRNA misreading
Aminoglycosides: Spectrum of action
- Gram- bacteria and some Gram+ bacteria
Aminoglycosides graph
time- and concentration-dependent - AUC:MIC
Pharmacokinetics of Aminoglycosides
- administered intramuscularly or intravenously (not absorbed from the GI tract)
- elimination by glomerular filtration (urine)
Ototoxicity and nephrotoxicity of Aminoglycosides
ototoxicity
* hearing loss and impaired vestibular functions
nephrotoxicity
* accumulation in proximal tubular epithelial cells
Deal: inhibit accumulation by inhibit tranporter of that drug to proximal tube so no accumulation to decrease risk of nephrotoxicity
Tetracyclines inhibit
inhibit aa-tRNA binding to the A site
Tetracyclines: Spectrum of action
- broad spectrum of action - Gram- and Gram+ bacteria
Tetracyclines: Pharmacokinetics administration
Administered generally orally but can also be administered parenterally
Tetracyclines and Gastrointestinal disturbance
Direct irritation and modification of gut flora following prolonged use
Tetracyclines and Calcium chelation
- tetracycline accumulation in teeth and growing bones
- staining and bone deformities - avoid in children and pregnant women (category D)
Tetracyclines cause 2 adverse
Gastrointestinal disturbance
Calcium chelation
Amphenicols inhibit
inhibit peptide bond formation
Amphenicols: spectrum of action
broad spectrum of action - Gram- and Gram+ bacteria
Static
Amphenicols: Pharmacokinetics
- chloramphenicol*
- rapid absorption following oral administration
- hepatically cleared (UGT2B7; 10% excreted unchanged in the urine)
Amphenicols and Bone marrow suppression
idiosyncratic; pancytopenia - ↓ in all blood cell elements
Amphenicols and Grey baby syndrome
- insufficient hepatic glucuronidation and excretion in newborns
Antibacterial macrolides prevent what
prevent transfer of tRNA with the growing peptide from A site to P site
Antibacterial macrolides: spectrum of action
Similar spectrum of action to penicillins - useful alternatives
* concentrated within phagocytes - enhance intracellular killing of bacteria
Antibacterial macrolides: Pharmacokinetics
- oral (common) or IV administration
- substrates for and inhibitors of CYP3A4 - drug-drug interactions
Antibacterial macrolides cause
Gastrointestinal disturbance
Mechanisms of resistance to aminoglycosides
drug modification
Mechanisms of resistance to tetracyclines
active efflux of the drug from the cell
Mechanisms of resistance to chloramphenicol
target modification (ribosomal RNA or proteins)
Mechanisms of resistance to macrolides
target modification (ribosomal RNA or proteins); drug degradation (by esterases)
Inhibit bacterial cell wall synthesis
Penicillin and Cephalosporins
Inhibit protein synthesis
Aminoglycosides
Tetracyclines
Amphenicols
Marcolides
Which bacterial cell wall has less peptidoglycan layers (gram +/-)
Gram-negative
Which bacterial cell wall has more peptidoglycan layers than the other cell wall (gram +/-)
Gram-postive bacteria
How does Augmentin work?
Amoxicillin works by interfering with the synthesis of bacterial cell walls, a process crucial for bacterial survival. Dependent on the intact beta-lactam ring in the amoxicillin molecule. Beta-lactamase enzymes produced by some bacteria can break this ring, rendering amoxicillin ineffective.
Clavulanic acid acts as a beta-lactamase inhibitor. This prevents the enzymes from breaking the beta-lactam ring of amoxicillin.
By inhibiting beta-lactamase enzymes, amoxicillin reaches target sites inhibit cell wall synthesis, and ultimately kill the bacteria or stop their growth.
The combination of amoxicillin and clavulanic acid (Augmentin) thus becomes effective against a wider range of bacteria, including those that produce beta-lactamase enzymes and would otherwise be resistant to amoxicillin alone.
