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LL-37-derived peptides eradicate multidrug-resistant Staphylococcus aureus from thermally wounded human skin
Elisabeth M Haisma1, Anna de Breij2, Heelam Chan2
1Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands e.m.haisma@lumc.nl.
Abstract:
Burn wound infections are often difficult to treat due to the presence of multidrug-resistant bacterial strains and biofilms. Currently, mupirocin is used to eradicate methicillin-resistant Staphylococcus aureus (MRSA) from colonized persons; however, mupirocin resistance is also emerging. Since we consider antimicrobial peptides to be promising candidates for the development of novel anti-infective agents, we studied the antibacterial activities of a set of synthetic peptides against different strains of S. aureus, including mupirocin-resistant MRSA strains. The peptides were derived from P60.4Ac, a peptide based on the human cathelicidin LL-37. The results showed that peptide 10 (P10) was the only peptide more efficient than P60.4Ac, which is better than LL-37, in killing MRSA strain LUH14616. All three peptides displayed good antibiofilm activities. However, both P10 and P60.4Ac were more efficient than LL-37 in eliminating biofilm-associated bacteria. No toxic effects of these three peptides on human epidermal models were detected, as observed morphologically and by staining for mitochondrial activity. In addition, P60.4Ac and P10, but not LL-37, eradicated MRSA LUH14616 and the mupirocin-resistant MRSA strain LUH15051 from thermally wounded human skin equivalents (HSE). Interestingly, P60.4Ac and P10, but not mupirocin, eradicated LUH15051 from the HSEs. None of the peptides affected the excretion of interleukin 8 (IL-8) by thermally wounded HSEs upon MRSA exposure. In conclusion, the synthetic peptides P60.4Ac and P10 appear to be attractive candidates for the development of novel local therapies to treat patients with burn wounds infected with multidrug-resistant bacteria.
Insights
New synthetic peptides, P60.4Ac and P10, show promise in treating burn wound infections caused by multidrug-resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). These peptides are effective against biofilms and resistant strains, offering a potential alternative to current treatments.
Area of Science:
- Antimicrobial drug discovery
- Wound infection research
- Bacterial resistance mechanisms
Background:
- Burn wound infections pose significant challenges due to multidrug-resistant bacteria and biofilms.
- Emerging mupirocin resistance in methicillin-resistant Staphylococcus aureus (MRSA) necessitates novel therapeutic strategies.
- Antimicrobial peptides (AMPs) are promising candidates for developing new anti-infective agents.
Purpose of the Study:
- To evaluate the antibacterial and antibiofilm activities of synthetic peptides derived from P60.4Ac against various Staphylococcus aureus strains, including mupirocin-resistant MRSA.
- To assess the efficacy of these peptides in eradicating MRSA from human skin models.
- To determine the safety profile of the synthetic peptides on human epidermal models.
Main Methods:
- Synthesis of peptides based on P60.4Ac, a derivative of the human cathelicidin LL-37.
- In vitro testing of antibacterial and antibiofilm activity against MRSA strains.
- Assessment of cytotoxicity on human epidermal models.
- In vivo efficacy studies using thermally wounded human skin equivalents (HSEs) infected with MRSA.
Main Results:
- Peptide 10 (P10) demonstrated superior efficacy in killing MRSA strain LUH14616 compared to P60.4Ac and LL-37.
- Both P10 and P60.4Ac showed significant antibiofilm activity and were more effective than LL-37 in eliminating biofilm-associated bacteria.
- P60.4Ac and P10, but not LL-37 or mupirocin, eradicated MRSA strains from wounded human skin equivalents.
- No toxic effects were observed on human epidermal models.
Conclusions:
- The synthetic peptides P60.4Ac and P10 exhibit potent antibacterial and antibiofilm activities against multidrug-resistant bacteria.
- These peptides demonstrate efficacy in eradicating MRSA from infected human skin equivalents, outperforming mupirocin in some cases.
- P60.4Ac and P10 represent promising candidates for developing novel topical therapies for burn wound infections.