Insights into the Antimicrobial Activity and Cytotoxicity of Engineered α-Helical Peptide Amphiphiles

Mao, Zhi; Yang, Jing; Han, Jun; Gao, Ling; Liu, Hongxia; Lu, Zhaoxin; Zhao, Haizhen; Bie, Xiaomei

doi:10.1021/acs.jmedchem.6b00922

Cited by 67 publications

(61 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The net charge was +6 and the hydrophobicity was 40%-60%, which is consistent with the statistical information on natural AMPs [2,18]. Hydrophobic amino acids F, I, and L were used to damage microbial cell membranes [19]. Flexible (GG) and rigid (pG) loops were selectively inserted into the middle of two symmetric heptad repeat sequences to enhance cell selectivity [17,20].…”

Section: Introductionsupporting

confidence: 75%

High Cell Selectivity and Bactericidal Mechanism of Symmetric Peptides Centered on d-Pro–Gly Pairs

Jia

Wang

Zhang

et al. 2020

IJMS

View full text Add to dashboard Cite

Antimicrobial peptides (AMPs) have a unique action mechanism that can help to solve global problems in antibiotic resistance. However, their low therapeutic index and poor stability seriously hamper their development as therapeutic agents. In order to overcome these problems, we designed peptides based on the sequence template XXRXXRRzzRRXXRXX-NH 2 , where X represents a hydrophobic amino acid like Phe (F), Ile (I), and Leu (L), while zz represents Gly-Gly (GG) or d-Pro-Gly (pG). Showing effective antimicrobial activity against Gram-negative bacteria and low toxicity, designed peptides had a tendency to form an α-helical structure in membrane-mimetic environments. Among them, peptide LR pG (X: L, zz: pG) showed the highest geometric mean average treatment index (GM TI = 73.1), better salt, temperature and pH stability, and an additive effect with conventional antibiotics. Peptide LR pG played the role of anti-Gram-negative bacteria through destroying the cell membrane. In addition, peptide LR pG also exhibited an anti-inflammatory activity by effectively neutralizing endotoxin. Briefly, peptide LR pG has the potential to serve as a therapeutic agent to reduce antibiotic resistance owing to its high therapeutic index and great stability.

show abstract

Section: Introductionsupporting

confidence: 75%

High Cell Selectivity and Bactericidal Mechanism of Symmetric Peptides Centered on d-Pro–Gly Pairs

Jia

Wang

Zhang

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Interestingly, substituting the aliphatic hydrophobic I6 and L9 with alanine also resulted in a twofold activity reduction, suggesting that aliphatic side chains also played an important role (peptides 14 and 17 ; MICs 12.5 μ m ; Table ). Indeed, the aliphatic leucine side chains in AMPs have been observed to insert into model phospholipid membranes while another study showed that leucine increases the propensity of peptides to form amphiphilic helices in solution, a structural requirement for antibacterial activity . Based on this, we decided to conduct a leucine scan to identify which residue can be replaced with leucine without bioactivity loss.…”

Section: Resultsmentioning

confidence: 99%

Designing an ultra‐short antibacterial peptide with potent activity against Mupirocin‐resistant MRSA

Arfan

Ong

et al. 2018

Chem Biol Drug Des

View full text Add to dashboard Cite

Staphylococcus aureus is the pathogen responsible for the majority of human skin infections. In particular, the methicillin-resistant variety, MRSA, has become a global clinical concern. The extensive use of mupirocin, the first-line topical antibacterial drug of choice, has led to the emergence of mupirocin-resistant MRSA globally, resulting in the urgent need for a replacement. Antimicrobial peptides are deemed plausible candidates. Herein, we describe a structure-activity relationship approach in the design of an ultra-short peptide with potent anti-MRSA activity with a rapid, bactericidal mode of action. Coupled to a low cytotoxic activity, we believe our lead compound can be developed into a topical antibacterial agent to replace mupirocin as the first-line drug for treating MRSA skin infections.

show abstract

“…Generally, the improvement of helical propensity with the increase of chain length is due to the enhancement of hydrogen-bonding interaction along the helical backbone, which stabilizes the helical structure [40][41][42]. Higher α-helical propensity leads to greater affinity between peptides and microbial membranes, resulting in better membrane permeabilization in bacteria [43]. In present study, hybrid peptides, CA-TP and CA-FO, with higher helical contents possessed remarkable antimicrobial activity than their parental peptides ( Table 2).…”

Section: Discussionmentioning

confidence: 99%

Hybridization with Insect Cecropin A (1–8) Improve the Stability and Selectivity of Naturally Occurring Peptides

Yang

Wang

et al. 2020

IJMS

View full text Add to dashboard Cite

Antimicrobial peptides (AMPs) offer great hope and a promising opportunity to overcome the rapid development of drug-resistant pathogenic microbes. However, AMPs often lack the stability required for a successful systemic drug. Hybridizing different AMPs is a simple and effective strategy to obtain novel peptides. N-terminal fragment of cecropin A (CA (1-8)) is often used to hybridize with other AMPs to reduce cytotoxicity. However, hybridizing with CA (1-8) in improving the stability of AMPs is not clear. Therefore, a series of peptides were designed by combining with CA (1–8) and their antibacterial activity and stability in the presence of salts and human serum were evaluated. The resultant α-helical hybrid peptide CA-FO composed of CA (1-8) and the most potent region of Fowlicidin-2 (FO (1–15)) exhibited excellent antibacterial activity (2-8 μM) and cell selectivity toward bacterial over mammalian cells. Moreover, CA-FO still retained vigorous antimicrobial activity in the presence of human serum and salts at physiological concentrations. CA-FO exhibited effective antibacterial activity by increasing membrane permeability and damaging membrane integrity. In conclusion, these results indicated the success of hybridization in designing and optimizing AMPs with improved stability and selectivity and the peptide CA-FO can be further evaluated as peptide-therapy to treat bacterial infections.

show abstract

Insights into the Antimicrobial Activity and Cytotoxicity of Engineered α-Helical Peptide Amphiphiles

Cited by 67 publications

References 54 publications

High Cell Selectivity and Bactericidal Mechanism of Symmetric Peptides Centered on d-Pro–Gly Pairs

High Cell Selectivity and Bactericidal Mechanism of Symmetric Peptides Centered on d-Pro–Gly Pairs

Designing an ultra‐short antibacterial peptide with potent activity against Mupirocin‐resistant MRSA

Hybridization with Insect Cecropin A (1–8) Improve the Stability and Selectivity of Naturally Occurring Peptides

Contact Info

Product

Resources

About