Identification of Bacterial Membrane Selectivity of Romo1-Derived Antimicrobial Peptide AMPR-22 via Molecular Dynamics

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.

Structure of the Bacterial Cell Envelope and Interactions with Antimicrobials: Insights from Molecular Dynamics Simulations

“…In a study on AMPR11 and AMPR22 interacting with bacterial inner membranes, it was observed that AMPR22 adopted greater helicity by forming hydrogen bonds with cardiolipin. 185 On account of the heterogeneity in the chemical structure of bacterial outer membrane LPS molecules, the insertion barriers for antimicrobial peptides show variability across different regions of LPS. Free energy landscapes determined by Sharma and Ayappa for the antimicrobial peptide CM15 186 using umbrella sampling simulations indicated spontaneous penetration into the O-antigen region with a large barrier in the core saccharide region.…”

“…Understanding the lipid-mediated changes in peptide conformation is an important aspect in the design of synthetic peptides. In a study on AMPR11 and AMPR22 interacting with bacterial inner membranes, it was observed that AMPR22 adopted greater helicity by forming hydrogen bonds with cardiolipin . On account of the heterogeneity in the chemical structure of bacterial outer membrane LPS molecules, the insertion barriers for antimicrobial peptides show variability across different regions of LPS.…”

Alkylated EDTA potentiates antibacterial photodynamic activity of protoporphyrin

“…Antibiotic resistance is a significant global public health threat, resulting in at least 1.27 million deaths worldwide in 2019 [ 1 ]. The misuse and overuse of antibiotics are the primary factors driving the development of drug-resistant strains [ 2 , 3 ]. Despite the urgent need for new antibiotic therapies, the pace of antibiotic discoveries has noticeably slowed down in recent decades due to scientific challenges and inadequate financial incentives [ 4 ].…”

Cypate‐loaded hollow mesoporous Prussian blue nanoparticle/hydrogel system for efficient photodynamic therapy/photothermal therapy dual‐modal antibacterial therapy

“…Microbial contamination and infections result in over 30% of death worldwide 1,2 . Currently, there are more challenges in the clinical treatment of infectious diseases, due to the abuse or misuse of antibiotics, drug tolerance, and the building of pathogenic biofilm, leading to serious clinical issues and even death 3,4 . The studies by the World Health Organization (WHO) indicated that current antibiotics will fail to control pathogens in the next 20 years 5 .…”

“…1,2 Currently, there are more challenges in the clinical treatment of infectious diseases, due to the abuse or misuse of antibiotics, drug tolerance, and the building of pathogenic biofilm, leading to serious clinical issues and even death. 3,4 The studies by the World Health Organization (WHO) indicated that current antibiotics will fail to control pathogens in the next 20 years. 5 Therefore, developing nextgeneration antimicrobial strategy to overcome these challenges we faced and combat infections is an unmet clinical need.…”