Synthetic cationic antimicrobial peptides bind with their hydrophobic parts to drug site II of human serum albumin

BACKGROUND: Many biologically active compounds bind to plasma transport proteins, and this binding can be either advantageous or disadvantageous from a drug design perspective. Human serum albumin (HSA) is one of the most important transport proteins in the cardiovascular system due to its great binding capacity and high physiological concentration. HSA has a preference for accommodating neutral lipophilic and acidic drug-like ligands, but is also surprisingly able to bind positively charged peptides. Understanding of how short cationic antimicrobial peptides interact with human serum albumin is of importance for developing such compounds into the clinics. RESULTS: The binding of a selection of short synthetic cationic antimicrobial peptides (CAPs) to human albumin with binding affinities in the μM range is described. Competitive isothermal titration calorimetry (ITC) and NMR WaterLOGSY experiments mapped the binding site of the CAPs to the well-known drug site II within subdomain IIIA of HSA. Thermodynamic and structural analysis revealed that the binding is exclusively driven by interactions with the hydrophobic moieties of the peptides, and is independent of the cationic residues that are vital for antimicrobial activity. Both of the hydrophobic moieties comprising the peptides were detected to interact with drug site II by NMR saturation transfer difference (STD) group epitope mapping (GEM) and INPHARMA experiments. Molecular models of the complexes between the peptides and albumin were constructed using docking experiments, and support the binding hypothesis and confirm the overall binding affinities of the CAPs. CONCLUSIONS: The biophysical and structural characterizations of albumin-peptide complexes reported here provide detailed insight into how albumin can bind short cationic peptides. The hydrophobic elements of the peptides studied here are responsible for the main interaction with HSA. We suggest that albumin binding should be taken into careful consideration in antimicrobial peptide studies, as the systemic distribution can be significantly affected by HSA interactions

The bromotyrosine derivative Ianthelline isolated from the Arctic marine sponge Stryphnus fortis inhibits marine micro- and macrobiofouling

International audienceThe inhibition of marine biofouling by the bromotyrosine derivative ianthelline, isolated from the Arctic marine sponge Stryphnus fortis, is described. All major stages of the fouling process are investigated. The effect of ianthelline on adhesion and growth of marine bacteria and microalgae is tested to investigate its influence on the initial microfouling process comparing with the known marine antifoulant barettin as a reference. Macrofouling is studied via barnacle (Balanus improvisus) settlement assays and blue mussel (Mytilus edulis) phenoloxidase inhibition. Ianthelline is shown to inhibit both marine micro-and macrofoulers with a pronounced effect on marine bacteria (minimum inhibitory concentration (MIC) values 0.1-10 mu g/mL) and barnacle larval settlement (IC50= 3.0 mu g/mL). Moderate effects are recorded on M. edulis (IC50= 45.2 mu g/mL) and microalgae, where growth is more affected than surface adhesion. The effect of ianthelline is also investigated against human pathogenic bacteria. Ianthelline displayed low micromolar MIC values against several bacterial strains, both Gram positive and Gram negative, down to 2.5 mu g/mL. In summary, the effect of ianthelline on 20 different representative marine antifouling organisms and seven human pathogenic bacterial strains is presented

Heterocyclic cellular lipid peroxidation inhibitors inspired by the marine antioxidant barettin

Accepted manuscript version. Published version available at https://doi.org/10.1016/j.bioorg.2018.11.024. Licensed CC BY-NC-ND 4.0.The marine environment remains a rich source for the discovery and development of novel bioactive compounds. The present paper describes the design, synthesis and biological evaluation of a library of small molecule heterocyclic mimetics of the marine 2,5-diketopiperazine barettin which is a powerful natural antioxidant. By mainly focusing on the influence from the brominated indole and heterocyclic core of barettin, a library of 19 compounds was prepared. The compounds comprised a heterocyclic core, either a 2,5 diketopiperazine, an imidazolidinedione or a thioxothiazolidinone, which were mainly monosubstituted with ranging bulky substituents. The prepared compounds were screened for activity in a cellular lipid peroxidation assay using HepG2 cells. Several of the synthetic compounds showed antioxidant properties superior to the positive control barettin. Two of the prepared compounds displayed inhibitory activity similar to commercial antioxidants with significant inhibition at low µg/mL concentrations. The toxicity of the compounds was also investigated against MRC-5 lung fibroblasts and none of the included compounds displayed any toxicity at 50 µg/mL

Anti-Colonization Effect of Au Surfaces with Self-Assembled Molecular Monolayers Functionalized with Antimicrobial Peptides on S. epidermidis

Medical devices with an effective anti-colonization surface are important tools for combatting healthcare-associated infections. Here, we investigated the anti-colonization efficacy of antimicrobial peptides covalently attached to a gold model surface. The gold surface was modified by a self-assembled polyethylene glycol monolayer with an acetylene terminus. The peptides were covalently connected to the surface through a copper-catalyzed [3 + 2] azide-acetylene coupling (CuAAC). The anti-colonization efficacy of the surfaces varied as a function of the antimicrobial activity of the peptides, and very effective surfaces could be prepared with a 6 log unit reduction in bacterial colonization

Design and Biological Evaluation of Antifouling Dihydrostilbene Oxime Hybrids

Source at https://doi.org/10.1007/s10126-018-9802-z. By combining the recently reported repelling natural dihydrostilbene scaffold with an oxime moiety found in many marine antifoulants, a library of nine antifouling hybrid compounds was developed and biologically evaluated. The prepared compounds were shown to display a low antifouling effect against marine bacteria but a high potency against the attachment and growth of microalgae down to MIC values of 0.01 μg/mL for the most potent hybrid. The mode of action can be characterized as repelling via a reversible non-toxic biostatic mechanism. Barnacle cyprid larval settlement was also inhibited at low μg/mL concentrations with low levels or no toxicity observed. Several of the prepared compounds performed better than many reported antifouling marine natural products. While several of the prepared compounds are highly active as antifoulants, no apparent synergy is observed by incorporating the oxime functionality into the dihydrostilbene scaffold. This observation is discussed in light of recently reported literature data on related marine natural antifoulants and antifouling hybrids as a potentially general strategy for generation of improved antifoulants

Benefits and risks of including the bromoform containing seaweed Asparagopsis in feed for the reduction of methane production from ruminants

The agricultural production of ruminants is responsible for 24% of global methane emissions, contributing 39% of emissions of this greenhouse gas from the agricultural sector. Strategies to mitigate ruminant methanogenesis include the use of methanogen inhibitors. For example, the seaweeds Asparagopsis taxiformis and Asparagopsis armata included at low levels in the feed of cattle and sheep inhibit methanogenesis by up to 98%, with evidence of improvements in feed utilisation efficiency. This has resulted in an increasing interest in and demand for these seaweeds globally. In response, research is progressing rapidly to facilitate Asparagopsis cultivation at large scale, and to develop aquaculture production systems to enable a high quality and consistent supply chain. In addition to developing robust strategies for sustainable production, it is important to consider and evaluate the benefits and risks associated with its production and subsequent use as an antimethanogenic feed ingredient for ruminant livestock. This review focuses on the relevant ruminal biochemical pathways, degradation, and toxicological risks associated with bromoform (CHBr3), the major active ingredient for inhibition of methanogenesis in Asparagopsis, and the effects that production of Asparagopsis and its use as a ruminant feed ingredient might have on atmospheric chemistry

General practitioners' reasoning when considering the diagnosis heart failure: a think-aloud study

BACKGROUND: Diagnosing chronic heart failure is difficult, especially in mild cases or early in the course of the disease, and guidelines are not easily implemented in everyday practice. The aim of this study was to investigate general practitioners' diagnostic reasoning about patients with suspected chronic heart failure in comparison with recommendations in European guidelines. METHODS: Think-aloud technique was used. Fifteen general practitioners reasoned about six case vignettes, representing authentic patients with suspected chronic heart failure. Information about each case was added successively in five steps. The general practitioners said their thoughts aloud while reasoning about the probability of the patient having chronic heart failure, and tried to decide about the diagnosis. Arguments for and against chronic heart failure were analysed and compared to recommendations in guidelines. RESULTS: Information about ejection fraction was the most frequent diagnostic argument, followed by information about cardiac enlargement or pulmonary congestion on chest X-ray. However, in a third of the judgement situations, no information about echocardiography was utilized in the general practitioners' diagnostic reasoning. Only three of the 15 doctors used information about a normal electrocardiography as an argument against chronic heart failure. Information about other cardio-vascular diseases was frequently used as a diagnostic argument. CONCLUSIONS: The clinical information was not utilized to the extent recommended in guidelines. Some implications of our study are that 1) general practitioners need more information about how to utilize echocardiography when diagnosing chronic heart failure, 2) guidelines ought to give more importance to information about other cardio-vascular diseases in the diagnostic reasoning, and 3) guidelines ought to treat the topic of diastolic heart failure in a clearer way