Mutation-Based Antibiotic Resistance Mechanism in Methicillin-Resistant <i>Staphylococcus aureus</i> Clinical Isolates

• Main Authors: Tanveer Ali (Author), Abdul Basit (Author), Asad Mustafa Karim (Author), Jung-Hun Lee (Author), Jeong-Ho Jeon (Author), Shafiq ur Rehman (Author), Sang-Hee Lee (Author)
• Format: Book
• Published: MDPI AG, 2021-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

β-Lactam antibiotics target penicillin-binding proteins and inhibit the synthesis of peptidoglycan, a crucial step in cell wall biosynthesis. <i>Staphylococcus aureus</i> acquires resistance against β-lactam antibiotics by producing a penicillin-binding protein 2a (PBP2a), encoded by the <i>mecA</i> gene. PBP2a participates in peptidoglycan biosynthesis and exhibits a poor affinity towards β-lactam antibiotics. The current study was performed to determine the diversity and the role of missense mutations of PBP2a in the antibiotic resistance mechanism. The methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) isolates from clinical samples were identified using phenotypic and genotypic techniques. The highest frequency (60%, 18 out of 30) of MRSA was observed in wound specimens. Sequence variation analysis of the <i>mecA</i> gene showed four amino acid substitutions (i.e., E239K, E239R, G246E, and E447K). The E239R mutation was found to be novel. The protein-ligand docking results showed that the E239R mutation in the allosteric site of PBP2a induces conformational changes in the active site and, thus, hinders its interaction with cefoxitin. Therefore, the present report indicates that mutation in the allosteric site of PBP2a provides a more closed active site conformation than wide-type PBP2a and then causes the high-level resistance to cefoxitin.

Item Description

10.3390/ph14050420
1424-8247