Antibiotics and antibiotic resistance Pt. 2 Flashcards
Vancomycin Mechanism of action
Binds to D-ala-D-ala at the end of peptide side chain in peptidoglycan precursors, blocking PBPs from catalzying crosslinking
Effective on many Gram-positives but not on gram-negative because vancomycin is too big to penetrate pores of outer membrane of gram-negative
Vancomycin mechanism of resistance
- Modification of antibiotic target - altered peptidoglycan structure that lacks D-ala-D-ala groups
- Genes encoding resistance found on plasmids or transposons transferred between bacteria
- Vancomycic resistance often associated with enterococcie in hospital settings (VRE)
Cycloserine
Function:
Mechanism of Action
Function: Inhibits peptidoglycan crosslinking
- Structurally similar to D-alanine
- Used as second line anti-tuberculosis therapy
Mechanism of Action: Competitive inhibitor of D-alanine in two sequential reactions
- Alanine racemase (L-ala to D-ala)
- D-alanyl-D-alanine synthetase (D-ala to D-ala-D-ala)
Bacitracin
Use:
Mechanism of Action:
_______ are 10 times more sensitive than other related bacteria
Use: Bacitracin “A disks” are a diagnostic test for Group A Streptococci - too toxic for systemic use
Mechanism of action: Binds to pyrophospate on the lipid carrier for peptidoglycan precursors and blocks its recycling
Group A Streptococci
Daptomycin:
Mechanism of action:
Daptomycin: Lipopetide antibiotic; bactericidal, narrow spectrum (Gram positive)
Mechanism of action: Binds to and disrupts cytopasmic membrane, possibly via loss of membrane potential
Polymyxins:
Mechanism of Action:
Adverse Effects:
Polymyxins: Lipopeptide antibiotics - bactericidal narrow spectrum (Gram negative)
Mechanism of Action: Bind to LPS in outer membrane of gram negative bactera, leading to disruption of both the outer membrane and cytoplasmic membrane
Adverse Effects: due to toxicity, limit use to infections caused by antibiotic resistant bacteria or topical use
Bacterial protein synthesis (translation)
Protein synthesis occurs in 2 phases: intiation and elongation
30S subunit forms “initiation complex” w/ mRNA message, initiation tRNA
The 50S subunit joins, resulting in the functional 70S ribosome that forms peptide bonds to produce the protein
Tetracyclines
Type:
Mechanism of Action:
Type: Bacteriostatic, broad spectrum
Mechanism of Action: Binds to 30S ribosomal subunit and interferes with binding of aminoacyl tRNA to the ribosome
Mechanism of resistance to tetracycline
- Tetracycline efflux pump - most common
- Mutations on the ribosome
*Tetracycline has lost its effectiveness due to overuse and widespread resistance
Aminoglycosides
Type:
Mechanism of Action:
Type: Bactericidal, broad spectrum
Mechanism of Action: Binds irreversibly to 30S ribosomal subunit and causes misreading and premature release of ribosome from mRNA
- Gram negatives > gram positives
Aminoglycosides
Adverse effects:
Mechanism of resistance:
Adverse effects: Ototoxic and nephrotoxic
Mechanism of resistance: Enzymatic modification of the antibiotic to prevent aminoglycoside binding to the ribosome
Macrolides
Type:
Mechanism of Action:
Type: Bacteriostatic, primarily active against Gram-positive bacteria (useful in patients allergic to β-lactams)
Mechanism of Action: Binds 50S ribosomal subunit to block elongation of proteins
Macrolides Mechanism of Resistance (2)
- Enzymatic modification (methylation) of ribosomal RNA - Erythromycin can’t bind methylated ribosome
- Efflux pumps can expel macrolides from cells enabling protein synthesis to occur
Chloramphenicol
Type:
Toxicity:
Type: Bacteriostatic
Toxicity: Potential toxicity limits use to very severe infections
Toxicity probably derives from lack of selectivity - inhibits ribosomes in mitochondria
Chloramphenicol
Mechanism of Action:
Mechanims of resistance:
Mechanism of Action: Binds 50S ribosome subunit to inhibit peptidyl transferase activity - elongation
Mechanims of resistance: Bacterial enzyme catalyzes addition of acetyl group to drug preventing ribosome binding
Clindamycin
Type:
Use:
Type: Bacteriostatic (inactive against gram-negative)
Use: Useful for treatment of community acquired MRSA (Methicillin-resistant Staphylococcus aureus); often used to treat infections by toxin-producing S. aureus
Clindamycin
Mechanism of Action:
Mechanism of Resistance:
Mechanism of Action: Binds 50S ribosomal subunit
Mechanism of Resistance: Enzymatic modification (methlylation) or rRNA
Exhibits cross-resistance with macrolides (bacteria that are resistant to macrolides are also resistant to clindamycin)
Linezolid (Status, Treatment)
New class of antibiotic - inhibitor of protein synthesis - first new antibiotic in > 30 years
Indicated in treatment of complicated skin infections caused by Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae (not effective against most gram-negative)
Linezolid
Mechanism of Action:
Mechanism of resistance:
Mechanism of Action: Binds to unique site on 50S subunit to prevent formation of 70S complex
Mechanism of resistance: Point mutations in ribosomal components that prevent linezolid binding - no cross resistance with other antibiotics
1st generation inhibitor of DNA replication
Mechanism of Action:
Nalidixic acid - synthetic quinolone
Mechanism of Action: binds bacterial DNA gyrase and or topoisomerase to inhibit its catalytic function - disrupts DNA replication and repair - results in DNA damage
2nd generation inhibitors of DNA replication
Fluoroquinolones - Bactericidal, broad spectrum
Same mechanism of action as Nalidixic acid
Inhibitors of DNA replication - Mechanisms of resistance (2)
- Point mutations in bacterial DNA gyrase prevent antibiotic binding and render the enzyme resistant to the action of quinolones
- Efflux pump-mediated resistance also observed
Metronidazole
Use:
Mechanism of Action:
Use: Used to treat anaerobic bacterial infections; common treatment for C. difficile pseudomembranous colitis
Mechanism of Action: in an anaerobic environment a radical is produced, leading to toxic metabolites that damage DNA
Rifampicin:
Mechanism of action:
Mechanism of resistance:
Mechanism of action: Binds β-subunit of bacterial RNA polymerase to inhibit RNA synthesis (rapid selection for resitance)
Mechanism of resitance: Acquisition of mutations in β-subunit of RNA polymerase that prevent antibiotic from binding
