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The screening of 166 extracts from tropical marine organisms (invertebrates, macroalgae) and 3 cyclolipopeptides from microorganisms against yeast prions highlighted the potential of Verongiida sponges to prevent the propagation of prions. We isolated the known compounds purealidin Q (1), aplysamine-2 (2), pseudoceratinine A (3), aerophobin-2 (4), aplysamine-1 (5), and pseudoceratinine B (6) for the first time from the Wallisian sponge Suberea laboutei. We then tested compounds 1–6 and sixteen other bromotyrosine and bromophenol derivatives previously isolated from Verongiida sponges against yeast prions, demonstrating the potential of 1–3, 5, 6, aplyzanzine C (7), purealidin A (10), psammaplysenes D (11) and F (12), anomoian F (14), and N,N-dimethyldibromotyramine (15). Following biological tests on mammalian cells, we report here the identification of the hitherto unknown ability of the six bromotyrosine derivatives 1, 2, 5, 7, 11, and 14 of marine origin to reduce the spread of the PrPSc prion and the ability of compounds 1 and 2 to reduce endoplasmic reticulum stress. These two biological activities of these bromotyrosine derivatives are, to our knowledge, described here for the first time, offering a new therapeutic perspective for patients suffering from prion diseases that are presently untreatable and consequently fatal. [ABSTRACT FROM AUTHOR]

Inflammatory and antimicrobial diseases constitute a major burden for society, and fighting them is a WHO strategic priority. Most of the treatments available to fight inflammatory diseases are anti-inflammatory drugs, such as corticosteroids or immunomodulators that lack cellular specificity and lead to numerous side effects. In addition to suppressing undesired inflammation and reducing disease progression, these drugs lessen the immune system protective functions. Furthermore, treating infectious diseases is more and more challenging due to the rise of microbial resistance to antimicrobial drugs. Thus, controlling the inflammatory process locally without compromising the ability to combat infections is an essential feature in the treatment of inflammatory diseases. We isolated three forms (DRS-DA2N, DRS-DA2NE, and DRS-DA2NEQ) of the same peptide, DRS-DA2, which belongs to the dermaseptin family, from the Mexican tree frog Pachymedusa dacnicolor. Interestingly, DRS-DA2N and DRS-DA2NEQ exhibit a dual activity by inducing the death of leukocytes as well as that of Gram-negative and Gram-positive bacteria, including multiresistant strains, without affecting other cells such as epithelial cells or erythrocytes. We showed that the death of both immune cells and bacteria is induced rapidly by DRS-DA2 and that the membrane is permeabilized, leading to the loss of membrane integrity. We also validated the capacity of DRS-DA2 to regulate the pool of inflammatory cells in vivo in a mouse model of noninfectious peritonitis. After the induction of peritonitis, a local injection of DRS-DA2N could decrease the number of inflammatory cells locally in the peritoneal cavity without inducing a systemic effect, as no changes in the number of inflammatory cells could be detected in blood or in the bone marrow. Collectively, these data suggest that this peptide could be a promising tool in the treatment of inflammatory diseases, such as inflammatory skin diseases, as it could reduce the number of inflammatory cells locally without suppressing the ability to combat infections. [ABSTRACT FROM AUTHOR]

Abstract: Potent and selective antimicrobial cyclic pseudopeptides (ACPPs) mixing α‐ and aza‐β3‐amino acids were developed. Cyclopseudopeptide sequences were designed to investigate the impact of some intrinsic molecular parameters on their biological activities. Fine changes in the nature of the side chains strongly modulated the selectivity of the ACPPs with regard to hemolysis versus antimicrobial activity. The conformational preference of such compounds in various media was extensively studied, and the typical structure of cyclic α/aza‐β3‐pseudopeptides is described for the first time. Interestingly, such scaffolds are stabilized by successive inverse γ‐ and N‐N turns (hydrazino turns), a unique feature due to the aza‐β3 residues. The α‐amino acid side chains form a cluster on one face of the ring, while the aza‐β3‐amino acid side chains are projected around the ring in the equatorial orientation. Such structural data are particularly valuable to fine‐tune the bioactivity of these ACPPs by a structure‐based approach. [ABSTRACT FROM AUTHOR]

Haemolymph-associated microbiota of marine bivalves was explored for antibacterial activity against important aquaculture pathogens. A collection of 843 strains were cultured from the haemolymph of four bivalve species ( Crassostrea gigas, Mytilus edulis, Pecten maximus and Tapes rhomboides) collected by deep-sea diving in the Glenan Archipelago ( France). Cell-free culture supernatants were investigated for antibacterial activity using the well-diffusion assay. About 3% of haemolymph-associated cultivable bacteria displayed antibacterial activity toward Gram-negative pathogens. Among the active bacteria, Pseudoalteromonas strains exhibited the highest antibacterial activity. The cell-free culture supernatant of one of them, named h C g-51, was able to inhibit the growth of bacterial pathogens even after drastic dilution (1 : 1024). Hemocyte survival was not significantly altered in the presence of the haemolymph-associated strains assayed. Moreover, a dose-dependent beneficial effect on hemocyte survival rates was observed with the h C g-51 strain. These results suggest that haemolymph microbiota may participate in bivalve protection and therefore confer a health benefit on the host. As a result, the results highlight bivalve haemolymph microbiota as a promising novel source for aquaculture probiotics. This work also gives a first insight into the contribution of the haemolymph-associated microbiota as part of the bivalve 'hologenome'. [ABSTRACT FROM AUTHOR]

The aim was to identify and study the antibiofilm protein secreted by the marine bacterium Pseudoalteromonas sp. 3J6. The latter is active against marine and terrestrial bacteria, including Pseudomonas aeruginosa clinical strains forming different biofilm types. Several amino acid sequences were obtained from the partially purified antibiofilm protein, named alterocin. The Pseudoalteromonas sp. 3J6 genome was sequenced and a candidate alt gene was identified by comparing the genome-encoded proteins to the sequences from purified alterocin. Expressing the alt gene in another non-active Pseudoalteromonas sp. strain, 3J3, demonstrated that it is responsible for the antibiofilm activity. Alterocin is a 139-residue protein including a predicted 20-residue signal sequence, which would be cleaved off upon export by the general secretion system. No sequence homology was found between alterocin and proteins of known functions. The alt gene is not part of an operon and adjacent genes do not seem related to alterocin production, immunity or regulation, suggesting that these functions are not fulfilled by devoted proteins. During liquid growth, the alt mRNA level peaked during the stationary phase. A single promoter was experimentally identified and several inverted repeats could be binding sites for regulators. alt genes were found in about 30% of the Pseudoalteromonas genomes, and in only few instances of other marine bacteria of the Hahella and Paraglaciecola genera. Comparative genomics yielded the hypotheses that alt gene losses occurred within the Pseudoalteromonas genus. Overall, alterocin is a novel kind of antibiofilm protein of ecological and biotechnological interest. [ABSTRACT FROM AUTHOR]

The occurrence of nosocomial infections has been on the rise for the past twenty years. Notably, infections caused by the Gram-positive bacteria Staphylococcus aureus represent a major clinical problem, as an increase in antibiotic multi-resistant strains has accompanied this rise. There is thus a crucial need to find and characterize new antibiotics against Gram-positive bacteria, and against antibiotic-resistant strains in general. We identified a new dermaseptin, DMS-DA6, produced by the skin of the Mexican frog Pachymedusa dacnicolor, with specific antibacterial activity against Gram-positive bacteria. This peptide is particularly effective against two multiple drug-resistant strains Enterococcus faecium BM4147 and Staphylococcus aureus DAR5829, and has no hemolytic activity. DMS-DA6 is naturally produced with the C-terminal carboxyl group in either the free or amide forms. By using Gram-positive model membranes and different experimental approaches, we showed that both forms of the peptide adopt an α-helical fold and have the same ability to insert into, and to disorganize a membrane composed of anionic lipids. However, the bactericidal capacity of DMS-DA6-NH2 was consistently more potent than that of DMS-DA6-OH. Remarkably, rather than resulting from the interaction with the negatively charged lipids of the membrane, or from a more stable conformation towards proteolysis, the increased capacity to permeabilize the membrane of Gram-positive bacteria of the carboxyamidated form of DMS-DA6 was found to result from its enhanced ability to interact with peptidoglycan., Competing Interests: The authors have declared that no competing interests exist.

Potent and selective antimicrobial cyclic pseudopeptides (ACPPs) mixing α- and aza-β 3 -amino acids were developed. Cyclopseudopeptide sequences were designed to investigate the impact of some intrinsic molecular parameters on their biological activities. Fine changes in the nature of the side chains strongly modulated the selectivity of the ACPPs with regard to hemolysis versus antimicrobial activity. The conformational preference of such compounds in various media was extensively studied, and the typical structure of cyclic α/aza-β 3 -pseudopeptides is described for the first time. Interestingly, such scaffolds are stabilized by successive inverse γ- and N-N turns (hydrazino turns), a unique feature due to the aza-β 3 residues. The α-amino acid side chains form a cluster on one face of the ring, while the aza-β 3 -amino acid side chains are projected around the ring in the equatorial orientation. Such structural data are particularly valuable to fine-tune the bioactivity of these ACPPs by a structure-based approach., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)