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<p>Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) exemplifies high-level antibiotic resistance in this major human pathogen. Its resistance to chloramphenicol is majorly conferred by enzymatic inactivation via chloramphenicol acetyltransferases (CATs). This modification sterically blocks the antibiotic’s ribosomal binding and thus neutralizes its inhibitory potency. Although CATs have been structurally studied across diverse bacteria species, the structures of <i>S. aureus</i> CATs (saCATs) have remained uncharacterized. To address this gap and elucidate species-specific resistance mechanisms, we determined the first high-resolution crystal structure of saCAT1, the prototypical saCAT enzyme. Structural analysis delineates the active site architecture and reveals the molecular basis for substrate recognition of both chloramphenicol and fusidic acid (FA). Further enzymatic assays demonstrated that the <i>K</i><sub>m</sub> value against chloramphenicol is 16.9 µM, and the <i>K</i><sub>i</sub> value of the inhibitor FA is 83.7 µM, indicating that the inhibitory capacity of FA is relatively limited. These findings provide an essential structural framework for understanding chloramphenicol resistance in <i>S. aureus</i> and facilitate the rational design of novel antimicrobial strategies to combat multidrug-resistant pathogens.</p>

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Structural basis for antibiotic resistance by chloramphenicol acetyltransferase type A in Staphylococcus aureus

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月23日

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  • Kaiyue Wang,
  • Junwei Chen,
  • Wanfang Li,
  • Min Wang,
  • Tingwen Fan,
  • Dongbo Bu,
  • Sheng Ye

摘要

Methicillin-resistant Staphylococcus aureus (MRSA) exemplifies high-level antibiotic resistance in this major human pathogen. Its resistance to chloramphenicol is majorly conferred by enzymatic inactivation via chloramphenicol acetyltransferases (CATs). This modification sterically blocks the antibiotic’s ribosomal binding and thus neutralizes its inhibitory potency. Although CATs have been structurally studied across diverse bacteria species, the structures of S. aureus CATs (saCATs) have remained uncharacterized. To address this gap and elucidate species-specific resistance mechanisms, we determined the first high-resolution crystal structure of saCAT1, the prototypical saCAT enzyme. Structural analysis delineates the active site architecture and reveals the molecular basis for substrate recognition of both chloramphenicol and fusidic acid (FA). Further enzymatic assays demonstrated that the Km value against chloramphenicol is 16.9 µM, and the Ki value of the inhibitor FA is 83.7 µM, indicating that the inhibitory capacity of FA is relatively limited. These findings provide an essential structural framework for understanding chloramphenicol resistance in S. aureus and facilitate the rational design of novel antimicrobial strategies to combat multidrug-resistant pathogens.