A Gram-negative-selective antibiotic that spares the gut microbiome.

Infections caused by Gram-negative pathogens are increasingly prevalent and are typically treated with broad-spectrum antibiotics, resulting in disruption of the gut microbiome and susceptibility to secondary infections. There is a critical need for antibiotics that are selective both for Gram-negative bacteria over Gram-positive bacteria, as well as for pathogenic bacteria over commensal bacteria. Here we report the design and discovery of lolamicin, a Gram-negative-specific antibiotic targeting the lipoprotein transport system.

Correction to "An Iterative Approach Guides Discovery of the FabI Inhibitor Fabimycin, a Late-Stage Antibiotic Candidate with Efficacy against Drug-Resistant Gram-Negative Infections".

[This corrects the article DOI: 10.1021/acscentsci.2c00598.

An Iterative Approach Guides Discovery of the FabI Inhibitor Fabimycin, a Late-Stage Antibiotic Candidate with Efficacy against Drug-Resistant Gram-Negative Infections.

Genomic studies and experiments with permeability-deficient strains have revealed a variety of biological targets that can be engaged to kill Gram-negative bacteria. However, the formidable outer membrane and promiscuous efflux pumps of these pathogens prevent many candidate antibiotics from reaching these targets. One such promising target is the enzyme FabI, which catalyzes the rate-determining step in bacterial fatty acid biosynthesis.

Synthesis of Fusidic Acid Derivatives Yields a Potent Antibiotic with an Improved Resistance Profile.

Fusidic acid (FA) is a potent steroidal antibiotic that has been used in Europe for more than 60 years to treat a variety of infections caused by Gram-positive pathogens. Despite its clinical success, FA requires significantly elevated dosing (3 g on the first day, 1.2 g on subsequent days) to minimize resistance, as FA displays a high resistance frequency, and a large shift in minimum inhibitory concentration is observed for resistant bacteria.

Gram-Negative Antibiotic Active Through Inhibition of an Essential Riboswitch.

Multidrug-resistant Gram-negative (GN) infections for which there are few available treatment options are increasingly common. The development of new antibiotics for these pathogens is challenging because of the inability of most small molecules to accumulate inside GN bacteria. Using recently developed predictive guidelines for compound accumulation in , we have converted the antibiotic Ribocil C, which targets the flavin mononucleotide (FMN) riboswitch, from a compound lacking whole-cell activity against wild-type GN pathogens into a compound that accumulates to a high level in , is effective against Gram-negative clinical isolates, and has efficacy in mouse models of GN infections.

Implementation of permeation rules leads to a FabI inhibitor with activity against Gram-negative pathogens.

Gram-negative bacterial infections are a significant public health concern, and the lack of new drug classes for these pathogens is linked to the inability of most drug leads to accumulate inside Gram-negative bacteria. Here, we report the development of a web application-eNTRyway-that predicts compound accumulation (in Escherichia coli) from its structure. In conjunction with structure-activity relationships and X-ray data, eNTRyway was utilized to re-design Debio-1452-a Gram-positive-only antibiotic-into versions that accumulate in E.

Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis.

The chemical diversification of natural products provides a robust and general method for the creation of stereochemically rich and structurally diverse small molecules. The resulting compounds have physicochemical traits different from those in most screening collections, and as such are an excellent source for biological discovery. Herein, we subject the diterpene natural product pleuromutilin to reaction sequences focused on creating ring system diversity in few synthetic steps.

Characterization of the Saffron Derivative Crocetin as an Inhibitor of Human Lactate Dehydrogenase 5 in the Antiglycolytic Approach against Cancer.

Inhibition of lactate dehydrogenase (LDH) represents an innovative approach to tackle cancer because this peculiar glycolytic metabolism is characteristic of most invasive tumor cells. An investigation into the biological properties of saffron extracts led to the discover of their LDH-inhibition properties. In particular, the most important saffron components, crocetin, was found to inhibit LDH (IC = 54.

Reactive Oxygen Species Synergize To Potently and Selectively Induce Cancer Cell Death.

A distinctive feature of cancer cells is their elevated levels of reactive oxygen species (ROS), a trait that can cause cancer cells to be more sensitive to ROS-inducing agents than normal cells. ROS take several forms, each with different reactivity and downstream consequence. Here we show that simultaneous generation of superoxide and hydrogen peroxide within cancer cells results in significant synergy, potently and selectively causing cancer cell death.

A Potent Inhibitor of Protein Sequestration by Expanded Triplet (CUG) Repeats that Shows Phenotypic Improvements in a Drosophila Model of Myotonic Dystrophy.

Myotonic dystrophy is the most common form of adult-onset muscular dystrophy, originating in a CTG repeat expansion in the DMPK gene. The expanded CUG transcript sequesters MBNL1, a key regulator of alternative splicing, leading to the misregulation of numerous pre-mRNAs. We report an RNA-targeted agent as a possible lead compound for the treatment of myotonic dystrophy type 1 (DM1) that reveals both the promise and challenges for this type of small-molecule approach.

Salicylketoximes That Target Glucose Transporter 1 Restrict Energy Supply to Lung Cancer Cells.

The glucose transporter GLUT1 is frequently overexpressed in most tumor tissues because rapidly proliferating cancer cells rely primarily on glycolysis, a low-efficiency metabolic pathway that necessitates a very high rate of glucose consumption. Because blocking GLUT1 is a promising anticancer strategy, we developed a novel class of GLUT1 inhibitors based on the 4-aryl-substituted salicylketoxime scaffold. Some of these compounds are efficient inhibitors of glucose uptake in lung cancer cells and have a notable antiproliferative effect.

Dual targeting of the Warburg effect with a glucose-conjugated lactate dehydrogenase inhibitor.

Effective glucose diet: We report the development and activity of glucose-conjugated LDH-A inhibitors designed for dual targeting of the Warburg effect (elevated glucose uptake and glycolysis) in cancer cells. Glycoconjugation could be applied to inhibitors of many enzymes involved in glycolysis or tumor metabolism.

A study on Korean nursing students' educational outcomes.

The purpose of this study was to describe outcome indicators of nursing education including critical thinking, professionalism, leadership, and communication and to evaluate differences among nursing programs and academic years. A descriptive research design was employed. A total of 454 students from four year baccalaureate (BS) nursing programs and two three-year associate degree (AD) programs consented to complete self-administered questionnaires.

Development of fluorescent glucose bioprobes and their application on real-time and quantitative monitoring of glucose uptake in living cells.

We developed a novel fluorescent glucose bioprobe, GB2-Cy3, for the real-time and quantitative monitoring of glucose uptake in living cells. We synthesized a series of fluorescent glucose analogues by adding Cy3 fluorophores to the α-anomeric position of D-glucose through various linkers. Systematic and quantitative analysis of these Cy3-labeled glucose analogues revealed that GB2-Cy3 was the ideal fluorescent glucose bioprobe.

Pharmacophore-based strategy for the development of general and specific scFv biosensors for abused antibiotics.

We developed fluorescent biosensor systems that are either general or selective to fluoroquinolone antibiotics by using a single-chain variable-fragment (scFv) as a recognition element. The selectivity of these biosensors to fluoroquinolone antibiotics was rationally tuned through the structural modification on the pharmacophore of fluoroquinolone antibiotics and the subsequent selection of scFv receptor modules against these antibiotics-based antigens using phage display. The resulting A2 and F9 scFv's bound to their representative antigen with a moderate affinity (K(D) in micromolar range as determined by surface plasmon resonance).

Surface modification for small-molecule microarrays and its application to the discovery of a tyrosinase inhibitor.

Small-molecule microarrays are powerful, high-throughput tools for gathering information about direct binding events between proteins of interest and small molecules. However, nonspecific binding on modified glass slides is the major factor reducing the quality of information obtained in proteomic screening with small-molecule microarrays. To improve the signal-to-noise ratio by suppressing the background signal, we tested several surface modification methods for glass slides.

An international comparison of Korean and Chinese nursing students with nursing curricula and educational outcomes.

Aim: The aim of this study was to compare Korean and Chinese nursing students with respect to their nursing curricula and educational outcomes including critical thinking, professionalism, leadership, communication skills, and nursing practice skills.

Methods: Data were collected from 762 nursing college students (355 in Korea and 407 in China) using the validated self-report questionnaires. The instruments were translated into Chinese for the Chinese students.

Antidiabetic and antiobesity effects of Ampkinone (6f), a novel small molecule activator of AMP-activated protein kinase.

Adenosine 5'-monophosphate (AMP) activated protein kinase (AMPK) has emerged as an attractive target molecule for the treatment of metabolic disorders, including obesity and type 2 diabetes. In this study, we identified a novel small molecule, ampkinone (6f), as an indirect AMPK activator, which was derived from the small molecule library constructed by diversity-oriented synthesis. Ampkinone stimulated the phosphorylation of AMPK via the indirect activation of AMPK in various cell lines.

Small molecule microarray: functional-group specific immobilization of small molecules.

Proteomic screening with small molecule microarrays can be a powerful tool in conjunction with various forward chemical genetics screening and high-throughput phenotype assays. Small molecule microarray screening can provide high quality information from the direct binding interaction between proteins of interest and a collection of small molecules in a high-throughput fashion. To realize this potential of small molecule microarray in the postgenomic era, the immobilization of small molecules on the surface of microscope glass slides has been a critical step, to apply small molecule library in protein screening assays and dissecting the protein network.

Effect of the Auricular Acupressure Therapy on Dysmenorrhea of Puberty Girls.

Purpose: The purpose of this study was to identify the effect of auricular acupressure therapy on dysmenorrhea of puberty girls.

Methods: This study was a pretest-posttest design with a nonequivalent control group. The subjects of this study were 61 girls who were middle and high school students in Seoul and the experiencing dysmenorrhea; 31 for the experimental group and 30 for the control group.

Crystal structure of Tpa1 from Saccharomyces cerevisiae, a component of the messenger ribonucleoprotein complex.

Tpa1 (for termination and polyadenylation) from Saccharomyces cerevisiae is a component of a messenger ribonucleoprotein (mRNP) complex at the 3' untranslated region of mRNAs. It comprises an N-terminal Fe(II)- and 2-oxoglutarate (2OG) dependent dioxygenase domain and a C-terminal domain. The N-terminal dioxygenase domain of a homologous Ofd1 protein from Schizosaccharomyces pombe was proposed to serve as an oxygen sensor that regulates the activity of the C-terminal degradation domain.

[Predictors of facility adaptation in nursing home residents].

Purpose: The purposes of this study were to examine the relationships among activities of daily living, self-efficiency, nursing home care quality and nursing home adaptation, and to identify the influencing factors of nursing home adaptation in nursing home residents.

Methods: The study employed a descriptive correlational design. The data were collected from 148 older adults without dementia by interview from six nursing homes in three cities from February 1, 2008 to February 28, 2008.

Enhanced efficacy of 7-hydroxy-3-methoxycadalene via glycosylation in in vivo xenograft study.

7-Hydroxy-3-methoxycadalene, isolated from Zelkova serrata Makino, was confirmed as a biologically active natural compound. In this study, the efficacy of cadalene as an anticancer agent was tested. In order to address the poor physicochemical properties of cadalene, we designed and synthesized glycosylated cadalene derivatives for improved solubility and efficient drug delivery as a potential prodrug.

A practical procedure for producing silver nanocoated fabric and its antibacterial evaluation for biomedical applications.

A novel and universal procedure has been developed for producing nanosized stable silver particles on cotton fabrics in a simple and cost-effective manner with complete control of the silver loading level on the fabrics; the antibacterial effect of Ag-nanocoated fabrics on various bacteria was evaluated by growth inhibition; for biomedical applications, skin irritation tests on guinea pigs were performed and no side effects were observed.