Antimicrobial peptides are important candidates for developing new classes of antibiotics because of their potency against antibiotic-resistant pathogens. Current research focuses on topical applications and it is unclear how to design peptides with systemic efficacy. To address this problem, we designed two potent peptides by combining database-guided discovery with structure-based design. When bound to membranes, these two short peptides with an identical amino acid composition can adopt two distinct amphipathic structures: A classic horizontal helix (horine) and a novel vertical spiral structure (verine). Their horizontal and vertical orientations on membranes were determined by solid-state 15N NMR data. While horine was potent primarily against gram-positive pathogens, verine showed broad-spectrum antimicrobial activity. Both peptides protected greater than 80% mice from infection-caused deaths. Moreover, horine and verine also displayed significant systemic efficacy in different murine models comparable to conventional antibiotics. In addition, they could eliminate resistant pathogens and preformed biofilms. Significantly, the peptides showed no nephrotoxicity to mice after intraperitoneal or intravenous administration for 1 wk. Our study underscores the significance of horine and verine in fighting drug-resistant pathogens.
Implant-associated infection is one of the biggest problems in orthopedic surgery. Antimicrobial peptides (AMPs) are well-known components of the innate immunity and less susceptible to the development of pathogen resistance compared to conventional antibiotics. Magnesium alloys as potential biodegradable bone implants have been received much attention in biomaterials field. This study investigated the deposition of calcium phosphate (CaP) coatings and loading of AMPs on the magnesium alloy surface by a biomimetic method. Scanning electron microscope (SEM) results presented that a microporous and plate-like CaP coating was processed on the magnesium alloy surface. X-ray diffractometry (XRD) and Fourier transform infrared spectroscopy (FTIR) analysis showed the main component of coating was hydroxyapatite (HA). Degradation assay in vitro showed that the HA coating deposited onto the magnesium alloy was corroded more slowly than the bare one. The amount of AMP loaded in the HA coating was 11.16±1.99 μg/cm2. The AMP loaded onto HA coatings had slow release for 7 days. The AMP-loaded coating showed antimicrobial activity against Staphylococcus aureus. Its bacterial inhibition rate exceeded 50% after 4 days and the antibacterial effect was sustained for 7 days. The coated magnesium alloys loaded with AMP could improve rat bone marrow mesenchymal stem cells (rBMMSCs) proliferation. Furthermore, it could also promote alkaline phosphatase (ALP) activity of rBMMSCs. Both radiographic evaluation and histopathology analysis demonstrated that implantation of the coated magnesium alloy into the rabbit femoral condyle had promoted bone repair and showed anti-inflammatory effect. The results showed that the AMP loaded onto HA coatings on the magnesium alloy surface could be considered an ideal orthopedic implant against S. aureus infection.
The house fly, Musca domestica L. (Diptera: Muscidae), is involved in phoretic movement of pathogenic agents, but it has a very efficient defense mechanism against infection. It is believed that antimicrobial peptides play a significant role in the defense system of the house fly. Here, we isolated a peptide from the immunized house fly pupae, measured its molecular mass (3987.6 Da) by matrix-assisted laser desorption ionization/time of flight-mass spectrometry, and determined its amino acid sequence by using the Procise Protein Sequencing System (Applied Biosystems, Foster City, CA). The peptide was confirmed as a member of the insect defensin family. It displayed high activity against gram-positive bacteria but lower activity against gram-negative bacteria and fungi. Reverse transcription-polymerase chain reaction showed that the house fly defensin gene was constitutively expressed in naive pupae and strongly up-regulated after immunization. House fly defensin is an amphiphilic peptide with a structure similar to that of the CSalphabeta scaffold of insect defensin A from the flesh fly, Phormia terraenovae Robineau-Desvoidy. To our knowledge, this is the first isolated and characterized house fly antimicrobial peptide, and our work may provide useful information for developing pharmacologically active antimicrobial agents.
Staphylococcus aureus is notoriously known for its rapid development of resistance to conventional antibiotics. S. aureus can alter its membrane composition to reduce the killing effect of antibiotics and antimicrobial peptides (AMPs). To obtain a more complete picture, this study identified the resistance genes of S. aureus in response to human cathelicidin LL-37 peptides by screening the Nebraska Transposon Mutant Library. In total, 24 resistant genes were identified. Among them, six mutants, including the one with the known membrane-modifying gene (mprF) disabled, became more membrane permeable to the LL-37 engineered peptide 17BIPHE2 than the wild type. Mass spectrometry analysis detected minimal lysyl-phosphatidylglycerol (lysylPG) from the mprF mutant of S. aureus JE2, confirming loss-of-function of this gene. Moreover, multiple mutants showed reduced surface adhesion and biofilm formation. In addition, four S. aureus mutants were unable to infect wax moth Galleria mellonella. There appears to be a connection between the ability of bacterial attachment/biofilm formation and infection. These results underscore the multiple functional roles of the identified peptide-response genes in bacterial growth, infection, and biofilm formation. Therefore, S. aureus utilizes a set of resistant genes to weave a complex molecular network to handle the danger posed by cationic LL-37. It appears that different genes are involved depending on the nature of antimicrobials. These resistant genes may offer a novel avenue to designing more potent antibiotics that target the Achilles heels of S. aureus USA300, a community-associated pathogen of great threat.
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