Expression and characterization of pantothenate energy-coupling factor transporters as an anti-infective drug target.

This study investigates the potential of energy-coupling factor (ECF) transporters as promising anti-infective targets to combat antimicrobial resistance (AMR). ECF transporters, a subclass of ATP-binding cassette (ABC) transporters, facilitate the uptake of B-vitamins across bacterial membranes by utilizing ATP as an energy source. Vitamins are essential cofactors for bacterial metabolism and growth, and they can either be synthesized de novo or absorbed from the environment.

Dual inhibitors of virulence factors LecA and LasB.

Dual inhibitors of two key virulence factors of , the lectin LecA and the protease LasB, open up an opportunity in the current antimicrobial-resistance crisis. A molecular hybridization approach enabled the discovery of potent, selective, and non-toxic thiol-based inhibitors, which simultaneously inhibit these two major extracellular virulence factors and therefore synergistically interfere with virulence. We further demonstrated that the dimerization of these monovalent dual inhibitors under physiological conditions affords divalent inhibitors of LecA with a 200-fold increase in binding affinity.

Novel and Extremely Sensitive NiAlO-NiO Nanostructures on an ITO Sensing Electrode for Enhanced Detection of Ascorbic Acid.

The current study focused on the design of an extremely sensitive electrochemical sensor of ascorbic acid based on a mixture of NiAlO-NiO nanoparticles that, produced in a single step using the sol-gel method, on an ITO electrode. This new sensing platform is useful for the detection of ascorbic acid with a wide range of concentrations extending from the attomolar to the molar. SEM micrographs show the porous structure of the NiAlO-NiO sample, with a high specific surface area, which is beneficial for the catalytic performance of the nanocomposite.

Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor.

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV.

Clean Synthetic Strategies to Biologically Active Molecules from Lignin: A Green Path to Drug Discovery.

Deriving active pharmaceutical agents from renewable resources is crucial to increasing the economic feasibility of modern biorefineries and promises to alleviate critical supply-chain dependencies in pharma manufacturing. Our multidisciplinary approach combines research in lignin-first biorefining, sustainable catalysis, and alternative solvents with bioactivity screening, an in vivo efficacy study, and a structural-similarity search. The resulting sustainable path to novel anti-infective, anti-inflammatory, and anticancer molecules enabled the rapid identification of frontrunners for key therapeutic indications, including an anti-infective against the priority pathogen Streptococcus pneumoniae with efficacy in vivo and promising plasma and metabolic stability.

Revision of the Absolute Configurations of Chelocardin and Amidochelocardin.

Even with the aid of the available methods, the configurational assignment of natural products can be a challenging task that is prone to errors, and it sometimes needs to be corrected after total synthesis or single-crystal X-ray diffraction (XRD) analysis. Herein, the absolute configuration of amidochelocardin is revised using a combination of XRD, NMR spectroscopy, experimental ECD spectra, and time-dependent density-functional theory (TDDFT)-ECD calculations. As amidochelocardin was obtained via biosynthetic engineering of chelocardin, we propose the same absolute configuration for chelocardin based on the similar biosynthetic origins of the two compounds and result of TDDFT-ECD calculations.

NRF2 activators inhibit influenza A virus replication by interfering with nucleo-cytoplasmic export of viral RNPs in an NRF2-independent manner.

In addition to antioxidative and anti-inflammatory properties, activators of the cytoprotective nuclear factor erythroid-2-like-2 (NRF2) signaling pathway have antiviral effects, but the underlying antiviral mechanisms are incompletely understood. We evaluated the ability of the NRF2 activators 4-octyl itaconate (4OI), bardoxolone methyl (BARD), sulforaphane (SFN), and the inhibitor of exportin-1 (XPO1)-mediated nuclear export selinexor (SEL) to interfere with influenza virus A/Puerto Rico/8/1934 (H1N1) infection of human cells. All compounds reduced viral titers in supernatants from A549 cells and vascular endothelial cells in the order of efficacy SEL>4OI>BARD = SFN, which correlated with their ability to prevent nucleo-cytoplasmic export of viral nucleoprotein and the host cell protein p53.

Hit-optimization using target-directed dynamic combinatorial chemistry: development of inhibitors of the anti-infective target 1-deoxy-d-xylulose-5-phosphate synthase.

Target-directed dynamic combinatorial chemistry (tdDCC) enables identification, as well as optimization of ligands for un(der)explored targets such as the anti-infective target 1-deoxy-d-xylulose-5-phosphate synthase (DXPS). We report the use of tdDCC to first identify and subsequently optimize binders/inhibitors of the anti-infective target DXPS. The initial hits were also optimized for their antibacterial activity against and during subsequent tdDCC runs.

A hydrogel-based assay for the fast prediction of antibiotic accumulation in Gram-negative bacteria.

The pipeline of antibiotics has been for decades on an alarmingly low level. Considering the steadily emerging antibiotic resistance, novel tools are needed for early and easy identification of effective anti-infective compounds. In Gram-negative bacteria, the uptake of anti-infectives is especially limited.

Evaluation of Bacterial RNA Polymerase Inhibitors in a -Based Wound Infection Model in SKH1 Mice.

Chronic wounds infected with pathogens such as represent a worldwide health concern, especially in patients with a compromised immune system. As antimicrobial resistance has become an immense global problem, novel antibiotics are urgently needed. One strategy to overcome this threatening situation is the search for drugs targeting novel binding sites on essential and validated enzymes such as the bacterial RNA polymerase (RNAP).

Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial Chemistry.

Protein-protein interactions (PPIs) play an important role in numerous biological processes such as cell-cycle regulation and multiple diseases. The family of 14-3-3 proteins is an attractive target as they serve as binding partner to various proteins and are therefore capable of regulating their biological activities. Discovering small-molecule modulators, in particular stabilizers, of such complexes via traditional screening approaches is a challenging task.

Protein-Templated Hit Identification through an Ugi Four-Component Reaction*.

Kinetic target-guided synthesis represents an efficient hit-identification strategy, in which the protein assembles its own inhibitors from a pool of complementary building blocks via an irreversible reaction. Herein, we pioneered an in situ Ugi reaction for the identification of novel inhibitors of a model enzyme and binders for an important drug target, namely, the aspartic protease endothiapepsin and the bacterial β-sliding clamp DnaN, respectively. Highly sensitive mass-spectrometry methods enabled monitoring of the protein-templated reaction of four complementary reaction partners, which occurred in a background-free manner for endothiapepsin or with a clear amplification of two binders in the presence of DnaN.

Cystobactamid 507: Concise Synthesis, Mode of Action, and Optimization toward More Potent Antibiotics.

Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns of healthcare communities nowadays, and these concerns necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids-a novel natural class of antibiotics with broad-spectrum antibacterial activity. In this work, we describe 1) a concise total synthesis of cystobactamid 507, 2) the identification of the bioactive conformation using noncovalently bonded rigid analogues, and 3) the first structure-activity relationship (SAR) study for cystobactamid 507 leading to new analogues with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD.

Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi's Sarcoma-Associated Herpesvirus.

With the aim to develop novel antiviral agents against Kaposi's Sarcoma Herpesvirus (KSHV), we are targeting the latency-associated nuclear antigen (LANA). This protein plays an important role in viral genome maintenance during latent infection. LANA has the ability to tether the viral genome to the host nucleosomes and, thus, ensures latent persistence of the viral genome in the host cells.

Semisynthesis and biological evaluation of amidochelocardin derivatives as broad-spectrum antibiotics.

To address the global challenge of emerging antimicrobial resistance, the hitherto most successful strategy to new antibiotics has been the optimization of validated natural products; most of these efforts rely on semisynthesis. Herein, we report the semisynthetic modification of amidochelocardin, an atypical tetracycline obtained via genetic engineering of the chelocardin producer strain. We report modifications at C4, C7, C10 and C11 by the application of methylation, acylation, electrophilic substitution, and oxidative C-C coupling reactions.

Synthetic studies of cystobactamids as antibiotics and bacterial imaging carriers lead to compounds with high efficacy.

There is an alarming scarcity of novel chemical matter with bioactivity against multidrug-resistant Gram-negative bacterial pathogens. Cystobactamids, recently discovered natural products from myxobacteria, are an exception to this trend. Their unusual chemical structure, composed of oligomeric -aminobenzoic acid moieties, is associated with a high antibiotic activity through the inhibition of gyrase.

Spray-drying of inhalable, multifunctional formulations for the treatment of biofilms formed in cystic fibrosis.

Cystic fibrosis (CF) is a serious lung disease, commonly susceptible to Pseudomonas aeruginosa colonization. The dense mucus together with biofilm formation limit drug permeability and prevent the drug from reaching the site of action, causing treatment failure of the bacterial infection. Besides the use of antibiotics, the mucolytic agent N-acetylcysteine (NAC) is recommended to be co-administered in the treatment of CF.

Reversible immobilization of a protein to a gold surface through multiple host-guest interactions.

Monolayers were formed by specific interactions between adamantylated proteins (transferrin, lysozyme) and a β-cyclodextrin (β-CD) monolayer on a gold surface. Very high stabilities could be reached by multiple interactions of 3-6 adamantyl moieties linked through triethylene glycol spacers to the protein with β-CD rings attached to the surface. Furthermore, bound proteins could be completely removed from the surface through competitive binding of an excess of free adamantane.

Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors.

We are concerned with the development of novel anti-infectives with dual antibacterial and antiretroviral activities for MRSA/HIV-1 co-infection. To achieve this goal, we exploited for the first time the mechanistic function similarity between the bacterial RNA polymerase (RNAP) "switch region" and the viral non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Starting from our previously discovered RNAP inhibitors, we managed to develop potent RT inhibitors effective against several resistant HIV-1 strains with maintained or enhanced RNAP inhibitory properties following a structure-based design approach.

Surface plasmon resonance--more than a screening technology: insights in the binding mode of σ70:core RNAP inhibitors.

Aim: Antibiotic resistance has become a major health problem. The σ(70):core interface of bacterial RNA polymerase is a promising drug target. Recently, the coiled-coil and lid-rudder-system of the β' subunit has been identified as an inhibition hot spot.