Development of teixobactin analogues containing hydrophobic, non-proteogenic amino acids that are highly potent against multidrug-resistant bacteria and biofilms.

Teixobactin is a cyclic undecadepsipeptide that has shown excellent potency against multidrug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). In this article, we present the design, synthesis, and antibacterial evaluations of 16 different teixobactin analogues. These simplified analogues contain commercially available hydrophobic, non-proteogenic amino acid residues instead of synthetically challenging expensive L-allo-enduracididine amino acid residue at position 10 together with different combinations of arginines at positions 3, 4 and 9.

Propranolol Ameliorates the Antifungal Activity of Azoles in Invasive Candidiasis.

The effectiveness of current antifungal therapies is hampered by the emergence of drug resistance strains, highlighting an urgent need for new alternatives such as adjuvant antifungal treatments. This study aims to examine the synergism between propranolol and antifungal drugs, based on the premise that propranolol is known to inhibit fungal hyphae. In vitro studies demonstrate that propranolol potentiates the antifungal activity of azoles and that the effect is more pronounced for propranolol-itraconazole combination.

Evaluation of Host Defense Peptide (CaD23)-Antibiotic Interaction and Mechanism of Action: Insights From Experimental and Molecular Dynamics Simulations Studies.

Host defense peptides (HDPs) have the potential to provide a novel solution to antimicrobial resistance (AMR) in view of their unique and broad-spectrum antimicrobial activities. We had recently developed a novel hybrid HDP based on LL-37 and human beta-defensin-2, named CaD23, which was shown to exhibit good antimicrobial efficacy against in a bacterial keratitis murine model. This study aimed to examine the potential CaD23-antibiotic synergism and the secondary structure and underlying mechanism of action of CaD23.

Hybrid derivative of cathelicidin and human beta defensin-2 against Gram-positive bacteria: A novel approach for the treatment of bacterial keratitis.

Bacterial keratitis (BK) is a major cause of corneal blindness globally. This study aimed to develop a novel class of antimicrobial therapy, based on human-derived hybrid host defense peptides (HyHDPs), for treating BK. HyHDPs were rationally designed through combination of functional amino acids in parent HDPs, including LL-37 and human beta-defensin (HBD)-1 to -3.

Mussel-Inspired Durable Antimicrobial Contact Lenses: The Role of Covalent and Noncovalent Attachment of Antimicrobials.

Contact lens is a major risk factor for microbial keratitis among contact lens wearers. Chemical strategies that can prevent microbial adhesion and biofilm formation are required to improve a wearer's hygiene and safety. Taking advantage of the material-independent properties of a polydopamine (pDA) coating, we investigated the role of covalent/noncovalent interactions of the antimicrobials and pDA in conferring long-term antimicrobial activities.

SLAP reagents for the photocatalytic synthesis of C3/C5-substituted, N-unprotected selenomorpholines and 1,4-selenazepanes.

Herein, we disclose the first set of unique selenium-containing SLAP (SiLicon Amine Protocol) reagents for the direct synthesis of C3/C5-substituted selenomorpholines and 1,4-selenazepanes from diverse (hetero)aldehydes under mild photocatalytic conditions. Enantiomerically pure 1,2-amino alcohol/α-amino acid versions of these heterocycles were also synthesized. Further, we have shown the late-stage modification of certain biologically active agents using the developed seleno-SLAP reagents.

Multifunctional Antimicrobial Nanofiber Dressings Containing ε-Polylysine for the Eradication of Bacterial Bioburden and Promotion of Wound Healing in Critically Colonized Wounds.

Bacterial colonization of acute and chronic wounds is often associated with delayed wound healing and prolonged hospitalization. The rise of multi-drug resistant bacteria and the poor biocompatibility of topical antimicrobials warrant safe and effective antimicrobials. Antimicrobial agents that target microbial membranes without interfering with the mammalian cell proliferation and migration hold great promise in the treatment of traumatic wounds.

Protective Action of Linear Polyethylenimine against Colonization and Exaggerated Inflammation and .

Increased evolution of multidrug resistant pathogens necessitates the development of multifunctional antimicrobials. There is a perceived need for developing new antimicrobials that can interfere with acute inflammation after bacterial infections. Here, we investigated the therapeutic potential of linear polyethylenimine (LPEI) and .

Antimicrobial Activity and Cell Selectivity of Synthetic and Biosynthetic Cationic Polymers.

The mammalian and microbial cell selectivity of synthetic and biosynthetic cationic polymers has been investigated. Among the polymers with peptide backbones, polymers containing amino side chains display greater antimicrobial activity than those with guanidine side chains, whereas ethylenimines display superior activity over allylamines. The biosynthetic polymer ε-polylysine (εPL) is noncytotoxic to primary human dermal fibroblasts at concentrations of up to 2,000 μg/ml, suggesting that the presence of an isopeptide backbone has greater cell selectivity than the presence of α-peptide backbones.

Latent Oxidative Polymerization of Catecholamines as Potential Cross-linkers for Biocompatible and Multifunctional Biopolymer Scaffolds.

Electrospinning of naturally occurring biopolymers for biological applications requires postspinning cross-linking for endurance in protease-rich microenvironments and prevention of rapid dissolution. The most commonly used cross-linkers often generate cytotoxic byproducts, which necessitate high concentrations or time-consuming procedures. Herein, we report the addition of "safe" catecholamine cross-linkers to collagen or gelatin dope solutions followed by electrospinning yielded junction-containing nanofibrous mats.

Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design.

Protein flexibility poses a major challenge in binding site identification. Several computational pocket detection methods that utilize small-molecule probes in molecular dynamics (MD) simulations have been developed to address this issue. Although they have proven hugely successful at reproducing experimental structural data, their ability to predict new binding sites that are yet to be identified and characterized has not been demonstrated.

Branched Peptide, B2088, Disrupts the Supramolecular Organization of Lipopolysaccharides and Sensitizes the Gram-negative Bacteria.

Dissecting the complexities of branched peptide-lipopolysaccharides (LPS) interactions provide rationale for the development of non-cytotoxic antibiotic adjuvants. Using various biophysical methods, we show that the branched peptide, B2088, binds to lipid A and disrupts the supramolecular organization of LPS. The disruption of outer membrane in an intact bacterium was demonstrated by fluorescence spectroscopy and checkerboard assays, the latter confirming strong to moderate synergism between B2088 and various classes of antibiotics.

Insight into membrane selectivity of linear and branched polyethylenimines and their potential as biocides for advanced wound dressings.

Unlabelled: We report here structure-property relationship between linear and branched polyethylene imines by examining their antimicrobial activities against wide range of pathogens. Both the polymers target the cytoplasmic membrane of bacteria and yeasts, eliciting rapid microbicidal properties. Using multiscale molecular dynamic simulations, we showed that, in both fully or partially protonated forms LPEI discriminates between mammalian and bacterial model membranes whereas BPEI lacks selectivity for both the model membranes.