Synthesis and structure-activity study of the antimicrobial lipopeptide brevibacillin.

The antimicrobial lipopeptide brevibacillin is a non-ribosomally synthesized peptide produced by with inhibitory activity against several clinically relevant Gram-positive pathogenic bacteria such as , , and . In this study, we report the total synthesis of brevibacillin and analogues thereof as well as structure-activity relationship and cytotoxicity studies. Several novel synthetic analogues exhibited high inhibitory activities with minimal inhibitory concentration values in the low micromolar range against several bacteria including Gram-positive , , , and as well as Gram-negative and .

Synthesis, antimicrobial activity, and mechanistic studies of enterocin DD14, a leaderless two-peptide bacteriocin.

Bacteriocins are promising alternatives to antibiotics in the food, veterinary and medical sectors, but their study and use is often hampered by the low yields and high costs associated with their purification from naturally occurring bacteria. Chemical synthesis has emerged as a means to overcome this limitation and design more active variants. In this study, microwave-assisted solid-phase peptide synthesis was used to produce the leaderless two-peptide bacteriocin enterocin DD14 (EntDD14), composed of EntDD14A (44 amino acids) and EntDD14B (43 amino acids).

Antimicrobial Activity of Synthetic Enterocins A, B, P, SEK4, and L50, Alone and in Combinations, against .

Multidrug-resistant infections are a major threat to the poultry industry. Effective alternatives to antibiotics are urgently needed to prevent these infections and limit the spread of multidrug-resistant bacteria. The aim of the study was to produce by chemical synthesis a set of enterocins of different subgroups of class II bacteriocins and to compare their spectrum of inhibitory activity, either alone or in combination, against a panel of twenty isolates.

Convenient route to Fmoc-homotyrosine metallaphotoredox catalysis and its use in the total synthesis of anabaenopeptin cyclic peptides.

Herein, we report the first solid-phase total synthesis of the natural cyclic peptide anabaenopeptin F and the use of metallaphotoredox catalysis to overcome the key challenges associated with the preparation of the non-proteinogenic amino acid homotyrosine contained in these peptides. Starting from L-homoserine, enantiopure Fmoc-protected homotyrosine was prepared in a straightforward manner by metallaphotoredox catalysis with -Fmoc-()-2-amino-4-bromobutanoic acid and 4--butoxybromobenzene partners. The prepared protected amino acid was used in solid-phase peptide synthesis to achieve the total synthesis of anabaenopeptin F and establish the stereochemistry of the isoleucine residue.

Insights in the Development and Uses of Alternatives to Antibiotic Growth Promoters in Poultry and Swine Production.

The overuse and misuse of antibiotics has contributed to the rise and spread of multidrug-resistant bacteria. To address this global public health threat, many countries have restricted the use of antibiotics as growth promoters and promoted the development of alternatives to antibiotics in human and veterinary medicine and animal farming. In food-animal production, acidifiers, bacteriophages, enzymes, phytochemicals, probiotics, prebiotics, and antimicrobial peptides have shown hallmarks as alternatives to antibiotics.

In vitro assessment of skin sensitization, irritability and toxicity of bacteriocins and reuterin for possible topical applications.

Bacteriocins and reuterin are promising antimicrobials for application in food, veterinary, and medical sectors. In the light of their high potential for application in hand sanitizer, we investigated the skin toxicity of reuterin, microcin J25, pediocin PA-1, bactofencin A, and nisin Z in vitro using neutral red and LDH release assays on NHEK cells. We determined their skin sensitization potential using the human cell line activation test (h-CLAT).

Bacteriocin-Based Synergetic Consortia: a Promising Strategy to Enhance Antimicrobial Activity and Broaden the Spectrum of Inhibition.

Bacteria-derived natural antimicrobial compounds such as bacteriocins, reruterin, and organic acids have recently received substantial attention as food preservatives or therapeutic alternatives in human or animal sectors. This study aimed to evaluate the antimicrobial activity of different bacteria-derived antimicrobials, alone or in combination, against a large panel of Gram-negative and Gram-positive bacteria. Bacteriocins, including microcin J25, pediocin PA-1, nisin Z, and reuterin, were investigated alone or in combination with lactic acid and citric acid, using a checkerboard assay.

Gastrointestinal Stability and Cytotoxicity of Bacteriocins From Gram-Positive and Gram-Negative Bacteria: A Comparative Study.

Bacteriocins are receiving increased attention as potent candidates in food preservation and medicine. Although the inhibitory activity of bacteriocins has been studied widely, little is known about their gastrointestinal stability and toxicity toward normal human cell lines. The aim of this study was to evaluate the gastrointestinal stability and activity of microcin J25, pediocin PA-1, bactofencin A and nisin using models.

Synthesis and biological evaluation of novel 1,4-benzodiazepin-3-one derivatives as potential antitumor agents against prostate cancer.

A novel tumor suppressing agent was discovered against PC-3 prostate cancer cells from the screening of a 1,4-benzodiazepin-3-one library. In this study, 96 highly diversified 2,4,5-trisubstituted 1,4-benzodiazepin-3-one derivatives were prepared by a two-step approach using sequential Ugi multicomponent reaction and simultaneous deprotection and cyclization to afford pure compounds bearing a wide variety of substituents. The most promising compound showed a potent and selective antiproliferative activity against prostate cancer cell line PC-3 (GI = 10.

investigation of gastrointestinal stability and toxicity of 3-hyrdoxypropionaldehyde (reuterin) produced by .

Reuterin (3-hyrdoxypropionaldehyde (3-HPA)) is a highly potent metabolite of , which has applications in food, health, and veterinary sectors. Similar to other natural antimicrobial compounds, the approval of reuterin as a bio-preservative or therapeutic agent by regulatory agencies relies on sufficient data on its cytotoxicity and behavior in the gastrointestinal environment. Although the antimicrobial activity of reuterin has been broadly studied, its safety and toxicity are yet to be explored in detail.

Bacteriocins as a new generation of antimicrobials: toxicity aspects and regulations.

In recent decades, bacteriocins have received substantial attention as antimicrobial compounds. Although bacteriocins have been predominantly exploited as food preservatives, they are now receiving increased attention as potential clinical antimicrobials and as possible immune-modulating agents. Infections caused by antibiotic-resistant bacteria have been declared as a global threat to public health.

Cross-Reactivity to Cephalosporins and Carbapenems in Penicillin-Allergic Patients: Two Systematic Reviews and Meta-Analyses.

Background: There is no recent systematic review on the risk of cross-reactivity to cephalosporins and carbapenems in penicillin-allergic patients despite many new studies on the subject. All past reviews have several limitations such as not including any patient with a T-cell-mediated penicillin allergy.

Objectives: To determine the risk of cross-reactivity to cephalosporins and carbapenems in patients with a proven IgE- or T-cell-mediated penicillin allergy.

The gliotransmitter ACBP controls feeding and energy homeostasis via the melanocortin system.

Glial cells have emerged as key players in the central control of energy balance and etiology of obesity. Astrocytes play a central role in neural communication via the release of gliotransmitters. Acyl-CoA binding protein (ACBP)-derived endozepines are secreted peptides that modulate the GABAA receptor.

Structure-Activity Relationships of the Bacteriocin Bactofencin A and Its Interaction with the Bacterial Membrane.

The antimicrobial peptide bactofencin A is an unmodified non-pediocin-like bacteriocin that inhibits several clinically relevant pathogens, including Listeria monocytogenes and Staphylococcus aureus. Here we report the synthesis and structure-activity relationship studies of bactofencin A and novel analogues thereof. Synthetic bactofencin A was a potent inhibitor of L.

Synthesis, antimicrobial activity and conformational analysis of the class IIa bacteriocin pediocin PA-1 and analogs thereof.

The antimicrobial peptide pediocin PA-1 is a class IIa bacteriocin that inhibits several clinically relevant pathogens including Listeria spp. Here we report the synthesis and characterization of whole pediocin PA-1 and novel analogs thereof using a combination of solid- and solution-phase strategies to overcome difficulties due to instability and undesired reactions. Pediocin PA-1 thus synthesized was a potent inhibitor of Listeria monocytogenes (MIC = 6.

Recent Progress in the Chemical Synthesis of Class II and S-Glycosylated Bacteriocins.

A wide variety of antimicrobial peptides produced by lactic acid bacteria (LAB) have been identified and studied in the last decades. Known as bacteriocins, these ribosomally synthesized peptides inhibit the growth of a wide range of bacterial species through numerous mechanisms and show a great variety of spectrum of activity. With their great potential as antimicrobial additives and alternatives to traditional antibiotics in food preservation and handling, animal production and in veterinary and medical medicine, the demand for bacteriocins is rapidly increasing.

Toward solid-phase peptide fragment ligation by a traceless-Ugi multicomponent reaction approach.

A new methodology to couple peptide fragments on solid support using a traceless isocyanide-based multicomponent reaction is described. The approach uses a microwave-assisted on-resin Ugi four-component reaction to attach a carboxyl free peptide to a supported peptide bearing a free N-terminal amine via the formation of an N-protected amide bond at the ligation site. Afterward, the generated backbone amide protecting group can be efficiently removed by microwave-assisted acidolysis with trifluoroacetic acid to afford a fully deprotected peptide.

Collagencin, an antibacterial peptide from fish collagen: Activity, structure and interaction dynamics with membrane.

In this study, we first report characterization of collagencin, an antimicrobial peptide identified from fish collagen hydrolysate. The peptide completely inhibited the growth of Staphylococcus aureus at 1.88 mM.

One-Pot Photochemical Ring-Opening/Cleavage Approach for the Synthesis and Decoding of Cyclic Peptide Libraries.

A novel dual ring-opening/cleavage strategy to determine the sequence of cyclic peptides from one bead, one compound libraries is described. The approach uses a photolabile residue within the macrocycle and as a linker to allow a simultaneous ring opening and cleavage from the beads upon UV irradiation and provide linearized molecules. Cyclic peptides of five to nine residues were synthesized and the generated linear peptides successfully sequenced by tandem mass spectrometry.

Preparation of N-Substituted N-Arylsulfonylglycines and Their Use in Peptoid Synthesis.

To increase the chemical diversity accessible with peptoids and peptide-peptoid hybrids, N-alkylated arylsulfonamides were used to prepare side chain protected N-substituted glycines compatible with solid-phase synthesis. The described procedures give access to peptoid monomers bearing a wide variety of functional groups from commercially available amines in four straightforward steps. The prepared N-substituted N-arylsulfonylglycines were used as monomers in solid-phase synthesis to introduce relevant functionalized side chains into peptoid oligomers and peptide-peptoid hybrids.

Recent progress in the development of protein-protein interaction inhibitors targeting androgen receptor-coactivator binding in prostate cancer.

The androgen receptor (AR) is a key regulator for the growth, differentiation and survival of prostate cancer cells. Identified as a primary target for the treatment of prostate cancer, many therapeutic strategies have been developed to attenuate AR signaling in prostate cancer cells. While frontline androgen-deprivation therapies targeting either the production or action of androgens usually yield favorable responses in prostate cancer patients, a significant number acquire treatment resistance.

Machine learning assisted design of highly active peptides for drug discovery.

The discovery of peptides possessing high biological activity is very challenging due to the enormous diversity for which only a minority have the desired properties. To lower cost and reduce the time to obtain promising peptides, machine learning approaches can greatly assist in the process and even partly replace expensive laboratory experiments by learning a predictor with existing data or with a smaller amount of data generation. Unfortunately, once the model is learned, selecting peptides having the greatest predicted bioactivity often requires a prohibitive amount of computational time.

Lasso-inspired peptides with distinct antibacterial mechanisms.

Microcin J25 (MccJ25) is an antibacterial peptide with a peculiar molecular structure consisting of 21 amino acids and a unique lasso topology that makes it highly stable. We synthesized various MccJ25-derived peptides that retained some of the inhibitory activity of the native molecule against Salmonella enterica and Escherichia coli. Of the tested peptides, C1, 7-21C and WK_7-21 were the most inhibitory peptides (MIC = 1-250 µM), but all three were less potent than MccJ25.

Practical ring-opening strategy for the sequence determination of cyclic peptides from one-bead-one-compound libraries.

The use of cyclic peptides in one-bead-one-compound libraries is limited by difficulties in sequencing hit compounds. Lacking a free N-terminal amine, such peptides cannot be sequenced by the Edman degradation approach, and complex fragmentation patterns are obtained by tandem mass spectrometry. To overcome this problem, we designed an alternative approach introducing a methionine residue within the macrocycle and as a linker to allow simultaneous ring-opening and release from the resin upon treatment with cyanogen bromide.