Inhibitors of Cell Wall Synthesis Flashcards
Name the inhibitors of cell wall synthesis
1) B-Lactams
2) Fosfomycin
3) Cycloserine
4) Bacitracin
5) Vancomycin
6) Dalbavancin
7) Telavancin
8) Oritavancin
What is the antibiotic vancomycin classified as?
A glycopeptide
Which antibiotics are classified as lipoglycopeptides?
Dalbavancin, Telavancin, and Oritavancin
Are all inhibitors of cell wall synthesis bacteriostatic or bactericidal at the clinical dose?
Bactericidal
What is the one stipulation when considering whether or not the inhibitors of cell wall synthesis will be useful to treat an infection?
The bacteria have to be replicating
What antibiotics have a beta-lactam ring in their structure?
Penicillins, cephalosporins, monobactams, and carbapenems
Which antibiotic inhibits the conversion of NAG to NAM?
Fosfomycin
Which enzyme is fosfomycin a structural analog of?
Phosphoenolpyruvate
What enzyme does fosfomycin inhibit?
enolpyruvate transferase
What class of beta-lactamases has better antimicrobial action?
Class 2
Which beta-lactamase inhibitors are class 1?
1) Clavulanic acid
2) Avibactam
3) Tazobactam
4) Sulbactam
What beta-lactamases are class 1 inhibitors best at inhibiting?
Serine B-lactamases
What can happen to carbapenems when attacked by carbapenemases and metallo-B-lactamases?
They can be hydrolyzed which irreversibly inactivates them
Which class 1 inhibitor of beta-lactamases is effective against most extended spectrum B-lactamases and carbapenemases?
Avibactam
What is the relationship between B-lactams and class 1 B-lactamase inhibitors?
Synergistic
What is the relationship between a B-lactam and a carbapenem?
Antagonistic
Why is there an antagonistic relationship between a B-lactam and a class 2 B-lactamase inhibitor?
Because carbapenems cause an increase in the release of B-lactamases which destroy the B-lactam antibiotic
What are the main mechanisms of resistance to B-lactams in gram-negative bacteria?
Active efflux and impaired drug entry
What can a bacterial cell modify in order to prevent B-lactams from being productive?
Penicillin-binding proteins
What are the features of a gram-positive bacteria?
They have a thick peptidoglycan cell wall, but they aren’t highly sophisticated
What are the features of a gram-negative bacteria?
They have a very thin peptidoglycan layer, but they are highly adaptive
What do beta-lactams bind to in order to inhibit cell wall synthesis?
They bind covalently to penicillin-binding proteins
What step do beta-lactams inhibit?
Step 5
How many domains does the penicillin-binding protein have?
2
What are the two domains of the penicillin-binding protein?
The transpeptidase domain and the glycosyltransferase domain
Which domain do beta-lactams inhibit?
Only the transpeptidase domain
What does the transpeptidase domain do?
It cross-links the polypeptide chains to form the rigid peptidoglycan layer
What step does cycloserine inhibit?
2
What steps do vancomycin, dalbavancin, telavancin, and oritavancin inhibit?
4 and 5
What step does fosfomycin inhibit?
1
What step does bacitracin inhibit?
3
How do VERSA strands protect themselves against vancomycin?
They add a D-lactate to the end of the D-Ala so that vancomycin can’t bind
What can vancomycin bind to in order to kill bacterial cells?
They can bind to the terminus of D-Ala-D-Ala and to the pentaglycine bridge
What is the result of vancomycin being able to bind to two different binding sites in the bacterial cell?
It can inhibit the transpeptidation step and the transglycosylation step
How do VISA strands protect themselves against vancomycin?
They thicken the cell wall by adding more D-Ala-D-Ala residues that are false targets for vancomycin
What do dalbavancin, telavancin, and oritavancin share with vancomycin?
a primary mechanism of action
What do dalbavancin, telavancin, and oritavancin have that classify them as lipoglycopeptides?
A long, lipophilic side chain
What does the lipophilic side chain help telavancin do?
Depolarize the cell membrane and compromise its function
What does the lipophilic side chain help oritavancin do?
It dimerizes to strongly anchor itself to the cell membrane improving the ability to bind to targets
Studies show that oritavancin can inhibit what?
RNA synthesis
Why can oritavancin be used in bacterial infections that are resistant to vancomycin?
Because it has a higher affinity for D-Ala-D-Lactate
