Simultaneous Targeting of NQO1 and SOD1 Eradicates Breast Cancer Stem Cells via Mitochondrial Futile Redox Cycling.

Triple-negative breast cancer (TNBC) contains the highest proportion of cancer stem-like cells (CSC), which display intrinsic resistance to currently available cancer therapies. This therapeutic resistance is partially mediated by an antioxidant defense coordinated by the transcription factor NRF2 and its downstream targets that include NAD(P)H quinone oxidoreductase 1 (NQO1). In this study, we identified the antioxidant enzymes NQO1 and superoxide dismutase 1 (SOD1) as therapeutic vulnerabilities of ALDH+ epithelial-like CSCs and CD24-/loCD44+/hi mesenchymal-like CSCs in TNBC.

Establishing Quantifiable Guidelines for Antimicrobial α/β-Peptide Design: A Partial Least-Squares Approach to Improve Antimicrobial Activity and Reduce Mammalian Cell Toxicity.

Antimicrobial peptides (AMPs) are promising candidates to combat pathogens that are resistant to conventional antimicrobial drugs because they operate through mechanisms that involve membrane disruption. However, the use of AMPs in clinical settings has been limited, at least in part, by their susceptibility to proteolytic degradation and their lack of selectivity toward pathogenic microbes vs mammalian cells. We recently reported on the design of α- and β-peptide oligomers structurally templated upon the naturally occurring α-helical AMP aurein 1.

Porin-independent accumulation in Pseudomonas enables antibiotic discovery.

Gram-negative antibiotic development has been hindered by a poor understanding of the types of compounds that can accumulate within these bacteria. The presence of efflux pumps and substrate-specific outer-membrane porins in Pseudomonas aeruginosa renders this pathogen particularly challenging. As a result, there are few antibiotic options for P.

Cationic Homopolymers Inhibit Spore and Vegetative Cell Growth of .

A wide range of synthetic polymers have been explored for antimicrobial activity. These materials usually contain both cationic and hydrophobic subunits because these two characteristics are prominent among host-defense peptides. Here, we describe a series of nylon-3 polymers containing only cationic subunits and their evaluation against the gastrointestinal, spore-forming pathogen .

Compound Uptake into Can Be Facilitated by -Alkyl Guanidiniums and Pyridiniums.

Multidrug-resistant Gram-negative bacterial infections are on the rise, and with no FDA approvals for new classes of broad-spectrum antibiotics in over 50 years, these infections constitute a major threat to human health. A significant challenge is the inability of most compounds to accumulate in Gram-negative bacteria. Recently developed predictive guidelines show that appending a primary amine to an appropriately shaped compound can enhance Gram-negative accumulation.

Small-Molecule Morphogenesis Modulators Enhance the Ability of 14-Helical β-Peptides To Prevent Candida albicans Biofilm Formation.

is an opportunistic fungal pathogen responsible for mucosal candidiasis and systemic candidemia in humans. Often, these infections are associated with the formation of drug-resistant biofilms on the surfaces of tissues or medical devices. Increased incidence of resistance to current antifungals has heightened the need for new strategies to prevent or eliminate biofilm-related fungal infections.

Preventing S. aureus biofilm formation on titanium surfaces by the release of antimicrobial β-peptides from polyelectrolyte multilayers.

Staphylococcus aureus infections represent the major cause of titanium based-orthopaedic implant failure. Current treatments for S. aureus infections involve the systemic delivery of antibiotics and additional surgeries, increasing health-care costs and affecting patient's quality of life.

14-Helical β-Peptides Elicit Toxicity against C. albicans by Forming Pores in the Cell Membrane and Subsequently Disrupting Intracellular Organelles.

Synthetic peptidomimetics of antimicrobial peptides (AMPs) are promising antimicrobial drug candidates because they promote membrane disruption and exhibit greater structural and proteolytic stability than natural AMPs. We previously reported selective antifungal 14-helical β-peptides, but the mechanism of antifungal toxicity of β-peptides remains unknown. To provide insight into the mechanism, we studied antifungal β-peptide binding to artificial membranes and living Candida albicans cells.

Incorporation of β-Amino Acids Enhances the Antifungal Activity and Selectivity of the Helical Antimicrobial Peptide Aurein 1.2.

Antimicrobial peptides (AMPs) are attractive antifungal drug candidates because they kill microbes via membrane disruption and are thus unlikely to provoke development of resistance. Low selectivity for fungal vs human cells and instability in physiological environments have limited the development of AMPs as therapeutics, but peptidomimetic AMPs can overcome these obstacles and also provide useful insight into AMP structure-function relationships. Here, we describe antifungal peptidomimetic α/β-peptides templated on the natural α-peptidic AMP aurein 1.

Antifungal activity of a β-peptide in synthetic urine media: Toward materials-based approaches to reducing catheter-associated urinary tract fungal infections.

Unlabelled: Catheter-associated urinary tract infections (CAUTI) are the most common type of hospital-acquired infection, with more than 30 million catheters placed annually in the US and a 10-30% incidence of infection. Candida albicans forms fungal biofilms on the surfaces of urinary catheters and is the leading cause of fungal urinary tract infections. As a step toward new strategies that could prevent or reduce the occurrence of C.

Correction: Hydrophobicity of Antifungal β-Peptides Is Associated with Their Cytotoxic Effect on In Vitro Human Colon Caco-2 and Liver HepG2 Cells.

[This corrects the article DOI: 10.1371/journal.pone.

Hydrophobicity of Antifungal β-Peptides Is Associated with Their Cytotoxic Effect on In Vitro Human Colon Caco-2 and Liver HepG2 Cells.

The widespread distribution of fungal infections, with their high morbidity and mortality rate, is a global public health problem. The increase in the population of immunocompromised patients combined with the selectivity of currents treatments and the emergence of drug-resistant fungal strains are among the most imperative reasons to develop novel antifungal formulations. Antimicrobial β-peptides are peptidomimetics of natural antimicrobial peptides (AMPs), which have been proposed as developmental platforms to enhance the AMPs selectivity and biostability.

Intraluminal Release of an Antifungal β-Peptide Enhances the Antifungal and Anti-Biofilm Activities of Multilayer-Coated Catheters in a Rat Model of Venous Catheter Infection.

is the most prevalent cause of hospital-acquired fungal infections and forms biofilms on indwelling medical devices that are notoriously difficult to treat or remove. We recently demonstrated that the colonization of on the surfaces of catheter tube segments can be reduced in vitro by coating them with polyelectrolyte multilayers (PEMs) that release a potent antifungal β-peptide. Here, we report on the impact of polymer structure and film composition on both the inherent and β-peptide-mediated ability of PEM-coated catheters to prevent or reduce the formation of biofilms in vitro and in vivo using a rat model of central venous catheter infection.

Antifungal Activity of 14-Helical β-Peptides against Planktonic Cells and Biofilms of Candida Species.

Candida albicans is the most prevalent cause of fungal infections and treatment is further complicated by the formation of drug resistant biofilms, often on the surfaces of implanted medical devices. In recent years, the incidence of fungal infections by other pathogenic Candida species such as C. glabrata, C.

Polymer multilayers loaded with antifungal β-peptides kill planktonic Candida albicans and reduce formation of fungal biofilms on the surfaces of flexible catheter tubes.

Candida albicans is the most common fungal pathogen responsible for hospital-acquired infections. Most C. albicans infections are associated with the implantation of medical devices that act as points of entry for the pathogen and as substrates for the growth of fungal biofilms that are notoriously difficult to eliminate by systemic administration of conventional antifungal agents.

Hydrophobicity and helicity regulate the antifungal activity of 14-helical β-peptides.

Candida albicans is one of the most prevalent fungal pathogens, causing both mucosal candidiasis and invasive candidemia. Antimicrobial peptides (AMPs), part of the human innate immune system, have been shown to exhibit antifungal activity but have not been effective as pharmaceuticals because of low activity and selectivity in physiologically relevant environments. Nevertheless, studies on α-peptide AMPs have revealed key features that can be designed into more stable structures, such as the 14-helix of β-peptide-based oligomers.

Sheet-like assemblies of charged amphiphilic α/β-peptides at the air-water interface.

There is growing interest in the design of molecules that undergo predictable self-assembly. Bioinspired oligomers with well-defined conformational propensities are attractive from this perspective, since they can be constructed from diverse building blocks, and self-assembly can be directed by the identities and sequence of the subunits. Here we describe the structure of monolayers formed at the air-water interface by amphiphilic α/β-peptides with 1:1 alternation of α- and β-amino acid residues along the backbone.

Carbohydrate microarrays for enzymatic reactions and quantification of binding affinities for glycan-protein interactions.

Glycans are involved in a variety of physiological and pathological processes through interactions with proteins. Thus, the molecular basis of glycan-protein interactions provides valuable information on understanding biological phenomena and exploiting more effective carbohydrate-based therapeutic agents and diagnostic tools. Carbohydrate microarray technology has become a powerful tool for evaluating glycan-mediated biological events in a high-throughput manner.

Chemical microarrays constructed by selective attachment of hydrazide-conjugated substances to epoxide surfaces and their applications.

Microarray technology has received considerable attention for rapid analysis of biomolecular interactions and high-throughput screening to identify binding partners. An efficient and selective immobilization technique of substances on the surface is essential for successful construction of microarrays. Although a variety of immobilization methods have been exploited to prepare microarrays over the past decade, a superior technique needs to be developed for diverse applications.

Nylon-3 copolymers that generate cell-adhesive surfaces identified by library screening.

Polymers in the nylon-3 family contain subunits derived from beta-amino acids, which are linked to one another via amide bonds. Thus, the nylon-3 backbone is homologous to the alpha-amino acid-based backbone of proteins. This molecular-level homology suggests that nylon-3 materials might be intrinsically protein-mimetic.

Construction of carbohydrate microarrays by using one-step, direct immobilizations of diverse unmodified glycans on solid surfaces.

Carbohydrate microarrays have received great attention as high-throughput analytic tools in studies of carbohydrate-mediated biological processes. Most of the methods employed to fabricate glycan microarrays rely on the immobilization of modified glycans on the properly derivatized surfaces. This immobilization strategy requires the availability of modified glycans whose syntheses in many cases are time-consuming and difficult.

Synthesis of beta-lactams bearing functionalized side chains from a readily available precursor.

The reaction of chlorosulfonyl isocyanate (CSI) with alkenes provides beta-lactams in quantity, and the products have frequently been used for ring-opening polymerization to generate nylon-3 materials. Prior uses of this approach have focused almost entirely on beta-lactams with purely hydrocarbon substitutents. We show how a variety of beta-lactams bearing protected polar substituents can be generated from CSI-derived building blocks.