9 research outputs found
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Rapid Assembly of Infection-Resistant Coatings: Screening and Identification of Antimicrobial Peptides Works in Cooperation with an Antifouling Background.
Bacterial adhesion and the succeeding biofilm formation onto surfaces are responsible for implant- and device-associated infections. Bifunctional coatings integrating both nonfouling components and antimicrobial peptides (AMPs) are a promising approach to develop potent antibiofilm coatings. However, the current approaches and chemistry for such coatings are time-consuming and dependent on substrates and involve a multistep process. Also, the information is limited on the influence of the coating structure or its components on the antibiofilm activity of such AMP-based coatings. Here, we report a new strategy to rapidly assemble a stable, potent, and substrate-independent AMP-based antibiofilm coating in a nonfouling background. The coating structure allowed for the screening of AMPs in a relevant nonfouling background to identify optimal peptide combinations that work in cooperation to generate potent antibiofilm activity. The structure of the coating was changed by altering the organization of the hydrophilic polymer chains within the coatings. The coatings were thoroughly characterized using various surface analytical techniques and correlated with the efficiency to prevent biofilm formation against diverse bacteria. The coating method that allowed the conjugation of AMPs without altering the steric protection ability of hydrophilic polymer structure results in a bifunctional surface coating with excellent antibiofilm activity. In contrast, the conjugation of AMPs directly to the hydrophilic polymer chains resulted in a surface with poor antibiofilm activity and increased adhesion of bacteria. Using this coating approach, we further established a new screening method and identified a set of potent surface-tethered AMPs with high activity. The success of this new peptide screening and coating method is demonstrated using a clinically relevant mouse infection model to prevent catheter-associated urinary tract infection (CAUTI)
Tuning Activity of Antimicrobial Peptides by Lipidation
Antimicrobial peptides (AMPs) are amino acid-based bioactive molecules that specifically target microbes. As such, they are a potent class of antibiotics, especially against bacterial infections. Naturally occurring AMPs are usually too long to be considered for therapeutic applications. To solve this, short sequences that mimic the activity of AMPs are designed. However, such endeavors are often accompanied with a reduction in antibacterial activity. To counter this, lipophilic molecules can be attached that function as a lipid anchor and target the short sequence to the bacterial membrane. For a range of short AMPs, this strategy has proven to lead to more active constructs. Although these lipidated short AMPs often work as complex target specific surfactants, more delicate modes of action that do not deviate too much from the nonlipidated counterparts are also known. This is readily observed by the large differences in activities that are detected when alterations in the lipid chain length and chirality of the amino acids residues are implemented. It is not uncommon to see that inactive or poorly active short AMPs can be turned into potent antibacterial agents. Importantly, selectivity of the short lipidated AMPs (lipoAMPs) for the bacterial membrane can be enhanced by alteration of the amino acid chirality. This strategy has led to lipoAMPs with submicromolar activities; in fact, activities that rival that of vancomycin have been observed for several short AMPs. Future research needs to determine (i) the effect of lipidation on the formation of lipid rafts in the bacterial membrane, (ii) if structural complications like branched lipids or chiral substituents on the lipid chain can be used to further increase the activity and selectivity of the conjugates, and (iii) if additional functionalities other than a membrane-anchoring ability can be bestowed on the lipid chain, e.g., redox activity or scavenger for small molecular components that traverse the lipid membrane. The interplay between degree of lipophilicity and the chirality of the amino acids of the AMP also needs further exploration, especially to see if more potent and selective (lipo)AMPs can be obtained that can be applied systemically. It may also be advisable to measure the most potent lipoAMPs in a centralized facility in order to obtain objective and comparable antibacterial activities
Lipid interactions of LAH4, a peptide with antimicrobial and nucleic acid transfection activities
The cationic amphipathic designer peptide LAH4 exhibits potent antimicrobial, nucleic acid transfection and cell penetration activities. Closely related derivatives have been developed to enhance viral transduction for gene therapeutic assays. LAH4 contains four histidines and, consequently, its overall charge and membrane topology in lipid bilayers are strongly pH dependent. In order to better understand the differential interactions of this amphipathic peptide with negatively-charged membranes its interactions, topologies, and penetration depth were investigated in the presence of lipid bilayers as a function of pH, buffer, phospholipid head group, and fatty acyl chain composition using a combination of oriented synchrotron radiation circular dichroism spectroscopy as well as oriented and non-oriented solid-state NMR spectroscopy. This combination of methods indicates that in the presence of lipids with phosphatidylglycerol head groups, the topological equilibria of LAH4 is shifted towards more in-plane configurations even at neutral pH. In contrast, a transmembrane alignment is promoted when LAH4 interacts with membranes made of dimyristoyl phospholipids rather than palmitoyl-oleoyl-phospholipids. Finally, the addition of citrate buffer favours LAH4 transmembrane alignments, even at low pH, probably by complex formation with the cationic charges of the peptide. In summary, this study has revealed that the membrane topology of this peptide is readily modulated by the environmental conditions
Association between plasma levels of PCSK9 and the presence of coronary artery disease in Japanese
Ciprofloxacin Metalloantibiotic: An Effective Antibiotic with an Influx Route Strongly Dependent on Lipid Interaction?
The Mechanisms of Action of Cationic Antimicrobial Peptides Refined by Novel Concepts from Biophysical Investigations
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Porous Silicon Particles for Cancer Therapy and Bioimaging
Porous silicon (pSi) engineered by electrochemical etching of silicon has been explored as a drug delivery carrier with the aim of overcoming the limitations of traditional therapies and medical treatments. pSi is biodegradable, non-cytotoxic and has optoelectronic properties that make this platform material a unique candidate for developing biomaterials for drug delivery and theranostics therapies. pSi provides new opportunities to improve existing therapies in different areas, paving the way for developing advanced theranostic nanomedicines, incorporating payloads of therapeutics with imaging capabilities. However, despite these outstanding advances, more extensive in-vivo studies are needed to assess the feasibility and reliability of this technology for real clinical practice. In this Chapter, we present an updated overview about the recent therapeutic systems based on pSi, with a critical analysis on the problems and opportunities that this technology faces as well as highlighting the growing potential of pSi technolgy