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Published on: September 8, 2021
Modular Engineering of Lysostaphin with Significantly Improved Stability and Bioavailability for Treating MRSA
Jingwei Liu1,2, Yumei Li1, Shuang Wang2,3
1Department of Pediatric Intensive Care Unit, Children's Medical Center, The First Hospital of Jilin University, Changchun 130021, China.
Abstract:
Methicillin-resistant Staphylococcus aureus (MRSA) is a refractory pneumonia-causing pathogen due to the antibiotic resistance and the characteristics of persisting inside its host cell. Lysostaphin is a typical bacteriolytic enzyme for degrading bacterial cell walls via hydrolysis of pentaglycine cross-links, showing potential to combat multidrug-resistant bacteria. However, there are still grand challenges for native lysostaphin because of its poor shelf stability and limited bioavailability. To tackle these limitations, a modular assembly strategy is proposed to actively engineer the native lysostaphin, involving nanoassembly preparation via fusing with lysine-rich polypeptide. The engineered lysine component significantly improves the membrane-penetration capability of lysostaphin, greatly increasing its intracellular antibacterial activity by 12-fold compared to wild-type lysostaphin. Notably, the half-life of the nanoassembled lysostaphin is approximately 13 times longer than that of its native counterpart, greatly outperforming other studies. Most importantly, the shelf stability of our engineered lysostaphin is significantly improved, retaining over 99.9% of antibacterial activity after 12 weeks at room temperature. This modular assembly strategy successfully enhances the overall performance of lysostaphin, offering great promise for a platform technique to refine enzymatic material for widespread clinical demands.
Insights
Engineered lysostaphin combats antibiotic-resistant bacteria like MRSA. This nanoassembly strategy improves stability and bioavailability, offering a promising platform for clinical applications against persistent infections.
Area of Science:
- Biochemistry
- Microbiology
- Materials Science
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) causes difficult-to-treat pneumonia due to antibiotic resistance and intracellular persistence.
- Lysostaphin, a bacteriolytic enzyme, degrades bacterial cell walls but suffers from poor stability and bioavailability.
Purpose of the Study:
- To engineer native lysostaphin using a modular assembly strategy to overcome its limitations.
- To enhance the antibacterial activity, bioavailability, and shelf stability of lysostaphin for combating MRSA infections.
Main Methods:
- A modular assembly strategy was employed, fusing native lysostaphin with a lysine-rich polypeptide to create a nanoassembled enzyme.
- The engineered lysostaphin's membrane-penetration capability, intracellular antibacterial activity, half-life, and shelf stability were evaluated.
Main Results:
- The engineered lysostaphin demonstrated a 12-fold increase in intracellular antibacterial activity compared to wild-type lysostaphin.
- The nanoassembled lysostaphin exhibited a 13-fold longer half-life and retained over 99.9% activity after 12 weeks at room temperature.
- The modular assembly strategy significantly improved lysostaphin's overall performance and shelf stability.
Conclusions:
- The modular assembly strategy successfully enhances lysostaphin's efficacy and stability for combating MRSA.
- Engineered lysostaphin shows significant promise as a platform technology for clinical applications against multidrug-resistant bacterial infections.
