Reference no: EM132668246
CHT353 Drug Targets - Cardiff University
Beta-lactam antibiotics and beta-lactamases
Question 1. Meropenem is one of the new broad spectrum beta-lactam antibiotics that prevents bacterial cell wall synthesis. Although it is active against gram-positive bacteria, it exhibits better activity against gram-negative bacteria.
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meropenem
Write a curly-arrow mechanism showing how meropenem inhibits its target enzyme, and explain (using a clear diagram) the molecular basis of the unusually high reactivity of the carbonyl group in the beta-lactam ring.
Question 2. Bacteria that express class B beta-lactamases, which contain a Zn(II) ion at the active site, are generally resistance to treatment with meropenem. Write down the reaction product that is formed when the hydrolysis of this antibiotic is catalysed by a class B beta-lactamase.
Question 3. Steady-state kinetic studies showed that kcat/KM = 0.9 μM-1s-1 for meropenem hydrolysis that is catalysed by the class B beta-lactamase expressed in Pseudomonas aeruginosa. State whether meropenem is a good substrate for this enzyme and briefly justify your answer.
Question 4. When treating bacterial infections caused by Pseudomonas aeruginosa, meropenem is usually co-administered in a pill that also contains vaborbactam (shown below).
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vaborbactam
Why is vaborbactam is included in the pill ? Write a curly-arrow mechanism for the interaction of vaborbactam with its drug target.
Other bacterial drug targets
Question 5. Cycloserine is a potent inhibitor of alanine racemase, which is a PLP-dependent enzyme. Using clear diagrams, briefly explain why inhibiting alanine racemase prevents cell wall biosynthesis.
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cycloserine
Question 6. Incubating alanine racemase with cycloserine yields an adduct with the following structure.
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adduct
Given that the amino group of cycloserine mimics that of L-alanine in the active site of alanine racemase, write a curly-arrow mechanism that explains the formation of this adduct and propose a reason to explain why it is unusually stable.
Question 7. Linezolid is a relatively new class of antibiotic, which binds to the 50S subunit of bacterial ribosomes. Draw a cartoon showing the intermolecular interactions between linezolid and its binding site in the 50S subunit, and propose a reason why linezolid does not bind tightly to human ribosomes.
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linezolid
Question 8. Does the fluorine substituent that is present in linezolid have a function? If so, then briefly explain why fluorination might be important for the properties of the drug.