Abstract
Methicillin resistant Staphylococcus aureus (MRSA) may be found on the skin, nose, and throats of long-term hospitalized patients. While MRSA infections are usually minor, serious infections and death may occur in immunocompromised or diabetic patients, or after exposure of MRSA to blood. This report demonstrates that the antimicrobial peptide (AMP) epinecidin-1 (Epi-1) efficiently protects against MRSA infection in a pyemia pig model. We first found that Epi-1 exhibits bactericidal activity against MRSA. Next, pharmacokinetic analysis revealed that Epi-1 was stable in serum for 4 h after injection, followed by a gradual decrease. This pharmacokinetic profile suggested Epi-1 may bind serum albumin, which was confirmed in vitro. Harmful effects were not observed for doses up to 100 mg/kg body weight in pigs. When Epi-1 was supplied as a curative agent 30 min post-infection, MRSA-induced abnormalities in blood uric acid (UA), blood urea nitrogen (BUN), creatine (CRE), GOT, and GPT levels were restored to normal levels. We further showed that the bactericidal activity of Epi-1 was higher than that of the antibiotic drug vancomycin. Epi-1 significantly decreased MRSA counts in the blood, liver, kidney, heart, and lungs of infected pigs. Elevated levels of serum C reactive protein (CRP), proinflammatory cytokine IL6, IL1β, and TNFα were also attenuated by Epi-1 treatment. Moreover, the MRSA genes, enterotoxin (et)-A, et-B, intrinsic methicillin resistance A (mecA), and methicillin resistance factor A (femA), were significantly reduced or abolished in MRSA-infected pigs after treatment with Epi-1. Hematoxylin and eosin staining of heart, liver, lung, and kidney sections indicated that Epi-1 attenuated MRSA toxicity in infected pigs. A survival study showed that the pyemia pigs infected with MRSA alone died within a week, whereas the pigs post-treated with 2.5 mg/kg Epi-1 were completely protected against death. The present investigation, thus, demonstrates that Epi-1 effectively protects pyemia pigs against pathogenic MRSA without major toxic side effects.
Highlights
Infection by the human pathogen Staphylococcus aureus leads to abscesses in tissue, and in certain instances, it may cause mortality [1]
We investigated the efficacy of Epi-1 in a pyemia pig model, which is physiologically similar to Methicillin-resistant Staphylococcus aureus (MRSA) infection in human beings
Given that cationic antimicrobial peptide (AMP) have broad-ranging antibacterial functions, these molecules have been suggested as alternatives to combat the increasingly common problem of MRSA infection
Summary
Infection by the human pathogen Staphylococcus aureus leads to abscesses in tissue, and in certain instances, it may cause mortality [1]. Vancomycin is widely in use to treat MRSA infections [3], but antimicrobial peptides (AMPs)—which are comprised of short amino acid sequences and serve as a first line of defense agent against invading pathogens in many species—have been suggested as potential highly efficacious alternatives for treating MRSA [4,5,6]. A shorter 21-aa sequence from the C-terminal domain of epinecidin-1 propeptide (amino acids number 22–42) accounts for most of the antimicrobial and anti-tumor activity; for most studies, this propeptide is synthesized in sufficient amounts for experimentation [8,9,10]. Sepsis is a major cause of morbidity and mortality in humans, and the rate of sepsis-related death has increased year by year [11]
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