L2 Antibacterial drugs II Flashcards
What antibiotics target cell walls? What antibiotics target the cell membrane?
cell wall/peptidoglycan:
beta-lactams (penicillin)
glycopeptides (vancomycin)
Bacitracin (extracellular)
Fosfomycin (intracellular)
cell membrane:
colistin
daptomycin
What antibiotics target protein synthesis?
tetracyclines and aminoglycosides
Which type of bacteria has 2 membranes and a thin peptidoglycan layer?
gram-negative
Describe gram-positive bacteria
1 membrane and 1 thick peptidoglycan layer
Summarize peptidoglycan synthesis
UDP-GlyNAc is transformed into UDP-MurNAc; amino acids are then added with a 2 D-Ala cap at the end); the phosphate group of the UDP binds to the Lipid in the membrane; from here, UDP-GlyNAc can bind to form a two sugar complex; flippase moves these sugars to from the cytoplasm to the periplasm; PBP acts on the sugars to make the peptidoglycan chains (GTase) and crosslink them (TPase); Lipid is recycled for another round
What are examples of beta-lactams
penicillins, monobactams, cephalosporina, carbapenems
How doe beta-lactams work?
They covalently bind to the TPase domain (via the serine residue) of the PBP thereby inhibiting its normal function in the bacterial cell (which is crosslinking the peptidoglycan chains)
This is because beta-lactams have a beta-lactam ring which is similar in structure to the 2 D-Ala structure
TF: beta-lactams are bacteriostatic
F, they are bactericidal
Why can beta-lactams be life-threatening?
hypersensitivity which includes anaphylaxis can occur through the IgE antibody reaction
What are beta-lactamases
They are enzymes that cleave the beta-lactam rings, rendering beta-lactam antibiotics ineffective. They were developed by bacteria as a resistance mechanism
What are beta-lactams often paired with for treatment of bacterial infection?
beta-lactamase inhibitors
What is NDM-1?
NDM-1 is a subtype of metallo-beta-lactamase which is highly transmissible and confers resistance to beta-lactams
TF: there is a strain of gonorrhea that is resistant to all known antibiotics
True, gonorrhea utilizes all known mechanisms of resistance and is resistant even to the last antibiotic option Ceftriaxone
What are glycopeptides
it is a class of antibiotics that inhibits the cell wall (thus most effective on gram-positive bacteria)
vancomycin is a glycopeptide
How does vancomycin work?
It binds to the 2 D-Ala portion of the peptidoglycan precursor, thus blocking PBP function in both domains (this is because recognition of the D-Ala terminus is required for proper binding)
What antibiotic is used to treat severe C.difficil infections
vancomycin
What is a common resistance mutation in response to vancomycin?
Divergent biosynthesis of Lipid II where the 2 D-Ala terminus is changed to a D-Ala-D-Lac terminus (dubbed VanA/VanB/VanD Lipid II)
Thus the strong interactions between vancomycin and the 2 D-Ala are reduced (less affinity)
How does Bacitracin work?
It inhibits cell wall synthesis by binding to the undecaprenyl pyrophosphate thus preventing the recycling of the Lipid
Which antibiotic(s) is/are nephrotoxic?
Bacitricin and Colistin
*Colistin is also neurotoxic
How do lipopeptide antibiotics work? What are examples of lipopeptides?
Colistin and Daptomycin
Colistin works by binding to lipopolysaccharides on the outer membrane (gram-negative bacteria) using its many positively charged amino groups (at neutral pH); this causes the membrane permeability to increase, leading to cell leakage and death
>gram-negative bacteria
Daptomycin works by interacting with the Ca2+ in the cell membrane and forms pores, resulting in cell leakage and death
>gram-positive bacteria
Which antibiotic(s) is/are used to treat MRSA and VRE?
MRSA = Methicillin-resistant Staphylococcus aureus
Daptomycin
Tetracyclines
Which antibiotic is an intracellular inhibitor from the following: vancomycin, penicillin, fosfomycin, colistin, daptomycin
fosfomycin
How does fosfomycin work?
It inhibits the first step of the peptidoglycan synthesis pathway (which is in the cytoplasm) by irreversibly binding to the enzyme required for the the formation of UDP-GlcNAc
How do aminoglycosides and tetracyclines work?
They bind to the 30s ribosomal subunit and inhibit protein synthesis. Both diffuse through the porin channels in the outer membrane followed by active transport across the cell membrane
What is a postantibiotic effect and give an example
it means the antibiotic still has effects such as suppressing bacterial growth even when under the MIC
Why are aminoglycosides reserved for serious infections?
They demonstrate renal, cochlear and vestibular system toxicity
What are some mechanisms that can cause aminoglycoside resistance
-decrease influx, increase efflux
-mutations in the 30S ribosomal subunit
-inactivation of the aminoglycosides via modifications of its amino group
How are tetracyclines different from aminoglycosides?
They are bacteriostatic and have a broader spectrum
