WBR0642

Author	[[PageAuthor::Serge Korjian M.D. (Reviewed by Serge Korjian)]]
Exam Type	USMLE Step 1
Main Category	Microbiology, Pharmacology
Sub Category	Infectious Disease
Prompt	A pharmaceutical company is manufacturing a novel antibiotic to overcome increasing resistance to macrolides. Its rationale is to create an agent that would be co-administered with azithromycin to counteract the mechanism by which bacteria become resistant to this antibiotic. Which of the following agents would be appropriate to investigate for this purpose?
Answer A	RNA methylation inhibitors
Answer A Explanation	Inhibition of RNA methylation can, in theory, help decrease resistance to macrolides since it targets the main resistance mechanism.
Answer B	Drug acetylation inhibitors
Answer B Explanation	Inhibition of acetylation targets the main mechanism of aminoglycoside resistance rather than that of macrolides.
Answer C	Beta-lactamase inhibitors
Answer C Explanation	Beta-lactamase inhibitors like tazobactam, clavulanic acid, and sulbactam are used with penicillin antibiotics to inhibit destruction of the beta-lactam ring by beta-lactamase producing bacteria.
Answer D	Drug efflux pump blockers
Answer D Explanation	Although drug efflux can be seen as a mechanism of resistance to macrolides, it is minor compared to rRNA methylation.
Answer E	Drug adenylation inhibitors
Answer E Explanation	Drug adenylation is also a form of enzymatic modification seen in resistance to aminoglycosides not in macrolides.
Right Answer	A
Explanation	[[Explanation:: Macrolides are a class of antibiotic agents that act by inhibiting protein synthesis specifically inhibiting translocation. They bind to the 23S rRNA binding site of the 50S subunit. They are commonly used to treat atypical pneumonias, extra-pulmonary chlamydial infections, and non-tuberculous mycobacteria among other infections. The mechanism of resistance to macrolides is by methylation of the 23S rRNA binding site. A suggested mechanism to inhibit resistance it to administer an agent to inhibit bacterial methylation enzymes. Educational Objective: Resistance to macrolides is by methylation of the bacterial 23S rRNA binding site. References: Wright GD. Resisting resistance: new chemical strategies for battling superbugs. Chem Biol. 2000;7(6):R127-32. Walsh C. Molecular mechanisms that confer antibacterial drug resistance. Nature. 2000;406(6797):775-81.]]
Approved	Yes
Keyword	Antibiotic resistance, Macrolides, Methylation
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