A 76-year-old hospitalized woman is evaluated for persistent fevers. Four days ago, she was admitted to the hospital for sepsis, for which she has received broad-spectrum empiric intravenous antibiotic therapy. Her temperature is 38.9 C (102 F), blood pressure is 110/80 mm Hg, pulse is 98/min, and respirations are 18/min. Cardiac examination reveals a new diastolic murmur. Multiple blood cultures drawn at different times grow Enterococcus. Echocardiogram reveals mitral valve vegetation suggestive of endocarditis. An intravenous antibiotic is added to the patient's treatment regimen for synergy. Several days later, she develops tinnitus and hearing loss attributed to this antibiotic. The additional antibiotic most directly affects which of the following processes?

Question

A 76-year-old hospitalized woman is evaluated for persistent fevers.  Four days ago, she was admitted to the hospital for sepsis, for which she has received broad-spectrum empiric intravenous antibiotic therapy.  Her temperature is 38.9 C (102 F), blood pressure is 110/80 mm Hg, pulse is 98/min, and respirations are 18/min.  Cardiac examination reveals a new diastolic murmur.  Multiple blood cultures drawn at different times grow Enterococcus.  Echocardiogram reveals mitral valve vegetation suggestive of endocarditis.  An intravenous antibiotic is added to the patient's treatment regimen for synergy.  Several days later, she develops tinnitus and hearing loss attributed to this antibiotic.  The additional antibiotic most directly affects which of the following processes?

Quizplus · Accepted Answer

11ec160b_3bef_df2f_9249_ff43265e8f4b_MD0001_00 This patient with enterococcal endocarditis likely received an aminoglycoside (AG) such as gentamicin, a ribosome-targeting antibiotic. AGs are associated with ototoxicity (hearing loss, tinnitus) and nephrotoxicity. mRNA is translated into amino acids (AAs) and proteins on ribosomes. In prokaryotes, a unique mRNA sequence (Shine-Dalgarno) is located upstream from initiation codon AUG, which recognizes an N-formylmethionine-tRNA. This sequence allows 30S binding to mRNA and this N-formylmethionine-tRNA (forming the prokaryotic 30S initiation complex). The energy for this reaction (GTP hydrolysis) brings the 50S subunit into the initiation complex, resulting in a 70S ribosomal unit. AGs irreversibly bind to bacterial 30S but not eukaryotic 40S; this causes genetic code misreading and bacterial protein synthesis inhibition. AGs also appear to impact translocation, whereby an aminoacyl-tRNA is shifted from the ribosomal A site (after initial binding) to the P site (after AA incorporation into the peptide chain during elongation) to the E site (after AA cleaving from its tRNA). The initial N-formylmethionine-tRNA notably binds at the P site. (Choice A) AGs need to diffuse inside the cell to reach the ribosome. As a result, they are often prescribed synergistically in combination with antibiotics affecting cell wall synthesis. These include penicillins, which impact cell wall cross-linking, or vancomycin. Vancomycin is also associated with ototoxicity, but it is a glycopeptide antibiotic that acts by directly inhibiting peptidoglycan synthesis, not cell wall cross-linking (which occurs at a later stage of cell wall synthesis). Although Enterococcus is generally resistant to AGs, these drugs are routinely used as synergistic agents in combination with penicillins or vancomycin in patients with enterococcal endocarditis; such combinations lead to improved bacterial killing and are the standard of care for this condition. (Choices B and C) Fluoroquinolones act on DNA gyrase to prevent DNA unwinding. Trimethoprim-sulfamethoxazole affects folic acid synthesis. These antibiotics are not classically associated with ototoxicity and are not used synergistically for enterococcal endocarditis. (Choice D) Daptomycin disrupts the bacterial membrane by creating transmembrane channels that cause intracellular ion leakage and cellular membrane depolarization. Its main side effects are myopathy and rhabdomyolysis. (Choice F) tRNA charging refers to initial covalent bonding between tRNA and the corresponding AA, facilitated by aminoacyl-tRNA synthetase; inhibitors of this enzyme are potential antibiotics. Educational objective: Aminoglycosides inhibit genetic code reading and protein synthesis by binding to the prokaryotic 30S ribosomal subunit.

A 76-Year-Old Hospitalized Woman Is Evaluated for Persistent Fevers