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Evolution of an inducible penicillin-target protein in methicillin-resistant Staphylococcus aureus by gene fusion
Abstract:
A new beta-lactam-inducible penicillin-binding protein (PBP) that has extremely low affinity to penicillin and most other beta-lactam antibiotics has been widely found in highly beta-lactam(methicillin)-resistant Staphylococcus aureus (MRSA). The gene for this protein was sequenced and the nucleotide sequence in its promoter and close upstream area was found to show close similarity with that of staphylococcal penicillinase, while the amino acid sequence over a wide range of the molecule was found to be similar to those of two PBPs of Escherichia coli, the shape-determining protein (PBP 2) and septum-forming one (PBP 3). Probably the MRSA PBP (Mr 76462) evolved by recombination of two genes: an inducible type I penicillinase gene and a PBP gene of a bacterium, causing the formation of a beta-lactam-inducible MRSA PBP.
Insights
A novel penicillin-binding protein (PBP) with low beta-lactam antibiotic affinity is prevalent in methicillin-resistant Staphylococcus aureus (MRSA). This MRSA PBP likely evolved from gene recombination, contributing to antibiotic resistance.
Area of Science:
- Microbiology
- Molecular Biology
- Antibiotic Resistance
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant public health threat due to its resistance to beta-lactam antibiotics.
- Penicillin-binding proteins (PBPs) are crucial targets for beta-lactam antibiotics.
Purpose of the Study:
- To characterize a newly identified beta-lactam-inducible penicillin-binding protein (PBP) found in highly resistant MRSA strains.
- To investigate the genetic origin and evolutionary pathway of this novel MRSA PBP.
Main Methods:
- Gene sequencing of the novel PBP and its upstream regulatory regions.
- Bioinformatic analysis comparing nucleotide and amino acid sequences with known staphylococcal and Escherichia coli genes.
- Affinity assays to determine the interaction of the novel PBP with beta-lactam antibiotics.
Main Results:
- A novel beta-lactam-inducible PBP (Mr 76462) was identified in MRSA, exhibiting extremely low affinity for penicillin and other beta-lactam antibiotics.
- Sequence analysis revealed similarities to staphylococcal penicillinase and Escherichia coli PBPs (PBP 2 and PBP 3).
- The nucleotide sequence in the promoter region showed similarity to staphylococcal penicillinase genes.
Conclusions:
- The identified MRSA PBP likely evolved through recombination between an inducible penicillinase gene and a PBP gene from another bacterium.
- This novel PBP contributes to the high-level beta-lactam resistance observed in certain MRSA strains.
- Understanding the evolution of such resistance mechanisms is critical for developing new therapeutic strategies against MRSA.