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Abstract
Methicillin-resistant Staphylococcus aureus (MRSA), are the most frequent cause of sepsis, which urgently demanding new drugs for treating infection. Two homologous insect CSαβ peptides-DLP2 and DLP4 from Hermetia illucens were firstly expressed in Pichia pastoris, with the yields of 873.5 and 801.3 mg/l, respectively. DLP2 and DLP4 displayed potent antimicrobial activity against Gram-positive bacteria especially MRSA and had greater potency, faster killing, and a longer postantibiotic effect than vancomycin. A 30-d serial passage of MRSA in the presence of DLP2/DLP4 failed to produce resistant mutants. Macromolecular synthesis showed that DLP2/DLP4 inhibited multi-macromolecular synthesis especially for RNA. Flow cytometry and electron microscopy results showed that the cell cycle was arrested at R-phase; the cytoplasmic membrane and cell wall were broken by DLP2/DLP4; mesosome-like structures were observed in MRSA. At the doses of 3‒7.5 mg/kg DLP2 or DLP4, the survival of mice challenged with MRSA were 80‒100%. DLP2 and DLP4 reduced the bacterial translocation burden over 95% in spleen and kidneys; reduced serum pro-inflammatory cytokines levels; promoted anti-inflammatory cytokines levels; and ameliorated lung and spleen injury. These data suggest that DLP2 and DLP4 may be excellent candidates for novel antimicrobial peptides against staphylococcal infections.
Highlights
In recent years, there has been a rapid emergence of highly antibiotic-resistant bacterial infections in both nosocomial and community settings, which is a major cause of morbidity and mortality worldwide[1, 2]
An amphipathic surface can be observed in DLP2, DLP4, sapecin, and lucifensin (Fig. 1C), indicating that these peptides maybe interact with anionic membranes of bacteria
The results showed that the expression level and antimicrobial activity of DLP2 and DLP4 were increased with induction time, and approximately 175 mg/l of target peptides was obtained from the culture supernatant in the shaking flask after 120 h of induction
Summary
There has been a rapid emergence of highly antibiotic-resistant bacterial infections in both nosocomial and community settings, which is a major cause of morbidity and mortality worldwide[1, 2]. More than 70 insect defensins have been identified in various arthropods, including Sarcophaga, Sapecin, and Aedes[9,10,11] They commonly contain an N-terminal loop, an α-helix, and an antiparallel β-sheet, forming a “cysteine-stabilized alpha beta (CSαβ)” or “loop-helix-sheet” structure[12]. These insect CSαβ defensins are active mainly against Gram-positive bacteria, including S. aureus, Micrococcus luteus, and Aerococcus viridians[7]. The 40-residue DLP4 peptide shares high sequence similarity (60‒67.5%) to other insect defensins, such as sapecin[14], defensin A12, and lucifensin[15]; it exhibited potent antibacterial activity against Gram-positive bacteria including MRSA with the minimal inhibitory concentrations (MICs) of 0.59‒2.34 μM, but not Gram-negative bacteria such as Escherichia coli, Enterobacter aerogenes, and Pseudomonas aeruginosa[13]. The antibacterial and inflammatory properties of DLP2 and DLP4 were examined in a mouse peritonitis model of MRSA infection
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