Targeting Methicillin-Resistant Staphylococcus aureus with Short Salt-Resistant Synthetic Peptides

Abstract

bThe seriousness of microbial resistance combined with the lack of new antimicrobials has increased interest in the development of antimicrobial peptides (AMPs) as novel therapeutics. In this study, we evaluated the antimicrobial activities of two short synthetic peptides, namely, RRIKA and RR. These peptides exhibited potent antimicrobial activity against Staphylococcus aureus, and their antimicrobial effects were significantly enhanced by addition of three amino acids in the C terminus, which consequently increased the amphipathicity, hydrophobicity, and net charge. Moreover, RRIKA and RR demonstrated a significant and rapid bactericidal effect against clinical and drug-resistant Staphylococcus isolates, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA), linezolid-resistant S. aureus, and methicillin-resistant Staphylococcus epidermidis. In contrast to many natural AMPs, RRIKA and RR retained their activity in the presence of physiological concentrations of NaCl and MgCl 2 . Both RRIKA and RR enhanced the killing of lysostaphin more than 1,000-fold and eradicated MRSA and VRSA isolates within 20 min. Furthermore, the peptides presented were superior in reducing adherent biofilms of S. aureus and S. epidermidis compared to results with conventional antibiotics. Our findings indicate that the staphylocidal effects of our peptides were through permeabilization of the bacterial membrane, leading to leakage of cytoplasmic contents and cell death. Furthermore, peptides were not toxic to HeLa cells at 4-to 8-fold their antimicrobial concentrations. The potent and salt-insensitive antimicrobial activities of these peptides present an attractive therapeutic candidate for treatment of multidrug-resistant S. aureus infections.

Antimicrobial endotoxin‐neutralizing peptides promote keratinocyte migration via P2X7 receptor activation and accelerate wound healing in vivo

“…Notably, the inflammatory response after bacterial infection contributes to the clinical severity of S . aureus skin infection rather than the bacterial burden (Mohamed et al ., ). We could previously demonstrate a strong anti‐inflammatory effect of Pep19‐2.5 against pathogenicity factors of Gram‐positive and Gram‐negative bacteria in skin cells (Pfalzgraff et al ., ).…”

“…Additionally, skin infections caused by S. aureus or P. aeruginosa frequently lead to invasive infections that might result in sepsis (Thangamani et al, 2015;Guillamet and Kollef, 2016). Notably, the inflammatory response after bacterial infection contributes to the clinical severity of S. aureus skin infection rather than the bacterial burden (Mohamed et al, 2014). We could previously demonstrate a strong anti-inflammatory effect of Pep19-2.5 against pathogenicity factors of Gram-positive and Gramnegative bacteria in skin cells .…”

Anti-biofilm activity and synergism of novel thiazole compounds with glycopeptide antibiotics against multidrug-resistant Staphylococci

“…The microtiter dish biofilm formation assay 24 was utilized to assess the ability of the thiazole compounds to disrupt an adherent staphylococcal biofilm, similar to what has been described elsewhere 25 . S. epidermidis ATCC 35984 was transferred to tryptic soy broth and incubated at 37°C for 24 h before being diluted 1:200 in tryptic soy broth + 1% glucose.…”

Activity of tick antimicrobial peptide from Ixodes persulcatus (persulcatusin) against cell membranes of drug-resistant Staphylococcus aureus

“…In the present study, the MIC 90 of IP ranged from 1 to 8 μg ml − 1 in methicillin-susceptible S. aureus, MRSA, VISA and VRSA strains, and were as well or better than those of the synthetic antimicrobial peptide RRIKA (2-4 μg ml − 1 ) and the peptidomimetics LTX-109 (2-4 μg ml − 1 ), previously reported as a new class of drugs with activity against VISA and VRSA strains. 19,20 Also, IP exhibited the most potent anti-S. aureus activity among the tick antimicrobial peptides evaluated in the present study. Although VISA strain Mu50 appeared to be resistant to the action of IP on cell membrane, the MIC 90 of IP was lower than that of Nisin.…”

“…The activity was as good or better than those of vancomycin and other published antimicrobial peptides. [14][15][16][17]19,20 Although, host cytotoxicity and instability in vivo are major limitations of antimicrobial peptides in their application as antimicrobial drugs, we have reported recently that IP lacked toxicity to mammalian and human cells such as fibroblasts, colon epithelial cells and erythrocytes, and built a stable structure unlike other antimicrobial peptides. 12 Thus, IP combines the most important three advantages for clinical setting, which are potent bactericidal activity, low toxicity and structural stability.…”