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Identification of Bacterial Membrane Selectivity of Romo1-Derived Antimicrobial Peptide AMPR-22 via Molecular
Hana Kim1, Young Do Yoo1, Gi Young Lee2
1Laboratory of Molecular Cell Biology, Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Korea.
Abstract:
The abuse or misuse of antibiotics has caused the emergence of extensively drug-resistant (XDR) bacteria, rendering most antibiotics ineffective and increasing the mortality rate of patients with bacteremia or sepsis. Antimicrobial peptides (AMPs) are proposed to overcome this problem; however, many AMPs have attenuated antimicrobial activities with hemolytic toxicity in blood. Recently, AMPR-11 and its optimized derivative, AMPR-22, were reported to be potential candidates for the treatment of sepsis with a broad spectrum of antimicrobial activity and low hemolytic toxicity. Here, we performed molecular dynamics (MD) simulations to clarify the mechanism of lower hemolytic toxicity and higher efficacy of AMPR-22 at an atomic level. We found four polar residues in AMPR-11 bound to a model mimicking the bacterial inner/outer membranes preferentially over eukaryotic plasma membrane. AMPR-22 whose polar residues were replaced by lysine showed a 2-fold enhanced binding affinity to the bacterial membrane by interacting with bacterial specific lipids (lipid A or cardiolipin) via hydrogen bonds. The MD simulations were confirmed experimentally in models that partially mimic bacteremia conditions in vitro and ex vivo. The present study demonstrates why AMPR-22 showed low hemolytic toxicity and this approach using an MD simulation would be helpful in the development of AMPs.
Insights
Antimicrobial peptides (AMPs) like AMPR-22 offer a solution to drug-resistant bacteria. Molecular dynamics simulations reveal AMPR-22
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- Antibiotic misuse drives extensively drug-resistant (XDR) bacteria, increasing sepsis mortality.
- Antimicrobial peptides (AMPs) show promise but often have toxicity issues.
- AMPR-11 and its derivative AMPR-22 exhibit broad-spectrum activity and low hemolytic toxicity.
Purpose of the Study:
- To elucidate the atomic-level mechanism behind AMPR-22's reduced hemolytic toxicity and enhanced efficacy.
- To understand the molecular interactions governing AMPR-22's preferential binding to bacterial membranes.
Main Methods:
- Molecular dynamics (MD) simulations of AMPR-11 and AMPR-22 interacting with membrane models.
- In vitro and ex vivo experimental validation of simulation findings under bacteremia-mimicking conditions.
Main Results:
- AMPR-11 utilizes polar residues for preferential binding to bacterial membranes over eukaryotic ones.
- AMPR-22, with lysine substitutions, exhibits a 2-fold increase in bacterial membrane binding affinity.
- AMPR-22 specifically interacts with bacterial lipids (lipid A, cardiolipin) via hydrogen bonds, explaining its low toxicity.
Conclusions:
- Molecular dynamics simulations successfully explained the low hemolytic toxicity and high efficacy of AMPR-22.
- The study provides a mechanistic basis for AMPR-22's therapeutic potential against sepsis.
- This MD simulation approach can guide the rational design of novel antimicrobial peptides.
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