Investigating the Mechanism of Antimycobacterial and Antiproliferative Activity of (E)-N'-Benzylidenepyrazine-2-Carbohydrazides and their Derivatives.

A series of 33 (E)-N'-benzylidenepyrazine-2-carbohydrazides and their derivatives were synthesized and tested for biological activity. Benzylidene derivatives with 2-OH substitution on the phenyl ring (18: R = 2-OH, 21: R = 2,3-diOH, and 22: R = 2,4-diOH) exhibit various biological activities. Compounds 18 and 21 demonstrate antimycobacterial activity against Mycobacterium tuberculosis H37Ra, M.

Repurposing of FDA-Approved Drugs to Disrupt Iron Uptake in Mycobacterium abscessus: Targeting Salicylate Synthase as a Novel Approach.

Non-tuberculous mycobacteria (NTM) are opportunistic pathogens that lead to severe, persistent infections, particularly in immunocompromised or vulnerable individuals. Infection rates are rising worldwide, highlighting NTM as an increasing threat to public health. There are currently no specific drugs, and the recommended regimens are usually ineffective.

Nature-Inspired Compounds Targeting Escherichia coli WrbA as Biofilm-Modulating Agents: Computational Design, Synthesis, and Biological Evaluation.

Biofilms pose significant challenges in multiple settings due to their resistance to conventional treatments. In this study, we designed and synthesized a novel class of nature-inspired 5,7-dihydroxy-2,2-dimethylchroman-4-one derivatives as binders of WrbA, a potential target for biofilm modulation. Using a structure-based computational approach, a small library of analogs with varied amide moieties was developed and synthesized.

Targeting Ubiquitin-Specific Protease 7 with Novel 5-Amino-Pyrazole Inhibitors: Design, Synthesis, and Biological Evaluation.

To further extend the structure-activity relationships (SARs) of the previously published ubiquitin-specific protease 7 (USP-7) inhibitor STIRUR-41, a small library of 5-aminopyrazoles 1a-d and 2a-d is designed and synthesized. The chemical identity of the desired structure is confirmed by nuclear magnetic resonance and single crystal X-ray diffraction analyses. All novel derivatives are tested as potential USP-7 inhibitors and compounds 1a-d block enzyme activity in a dose-dependent manner and with lower IC values compared to the lead compound STIRUR-41.

Spatiotemporal development of expanding bacterial colonies driven by emergent mechanical constraints and nutrient gradients.

Bacterial colonies growing on solid surfaces can exhibit robust expansion kinetics, with constant radial growth and saturating vertical expansion, suggesting a common developmental program. Here, we study this process for Escherichia coli cells using a combination of modeling and experiments. We show that linear radial colony expansion is set by the verticalization of interior cells due to mechanical constraints rather than radial nutrient gradients as commonly assumed.

Enhancing the activity of γ-hydroxy lactone derivatives as innovative peroxisome proliferator-activated receptor γ non-agonists inhibiting cyclin-dependent kinase 5-mediated phosphorylation.

Insulin resistance (IR) is a pathological condition in which tissues exhibit a reduced response to normal or elevated levels of insulin. Type 2 diabetes mellitus (T2DM) and Metabolic Syndrome are the most prevalent disorders associated with IR. Most of the glitazones, traditional anti-diabetic drugs acting as Peroxisome Proliferator-Activated Receptor γ (PPARγ) agonists, have been withdrawn from the market.

Distantly related bacteria share a rigid proteome allocation strategy with flexible enzyme kinetics.

Bacteria are known to allocate their proteomes according to how fast they grow, and the allocation strategies employed strongly affect bacterial adaptation to different environments. Much of what is currently known about proteome allocation is based on extensive studies of the model organism . It is not clear how much of 's proteome allocation strategy is applicable to other species, particularly since different species can grow at vastly different rates even in the same growth condition.

Novel Quinazolinones Active against Multidrug-Resistant Mycobacterium Tuberculosis: Synthesis, Antimicrobial Evaluation, and in Silico Exploration of Penicillin-Binding Protein 1A as a Potential Target.

Quinazolinone derivatives have emerged as promising scaffolds in antimicrobial drug discovery. This work focuses on the design, synthesis, and evaluation of novel quinazolinone-based compounds and predicts their potential to interact with mycobacterial penicillin-binding proteins (PBPs). Relying on established structure-activity relationships of antibacterial quinazolinones, a total of 53 compounds belonging to three different structural types are synthesized and biologically evaluated for antimycobacterial, antibacterial, and antifungal activities.

Nanoenabling MbtI Inhibitors for Next-Generation Tuberculosis Therapy.

The urgent need for safer and innovative antitubercular agents remains a priority for the scientific community. In pursuit of this goal, we designed and evaluated novel 5-phenylfuran-2-carboxylic acid derivatives targeting () salicylate synthase (MbtI), a key enzyme, absent in humans, that plays a crucial role in virulence. Several potent MbtI inhibitors demonstrating significant antitubercular activity and a favorable safety profile were identified.

Author Correction: From coarse to fine: the absolute Escherichia coli proteome under diverse growth conditions.

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Proteome partitioning constraints in long-term laboratory evolution.

Adaptive laboratory evolution experiments provide a controlled context in which the dynamics of selection and adaptation can be followed in real-time at the single-nucleotide level. And yet this precision introduces hundreds of degrees-of-freedom as genetic changes accrue in parallel lineages over generations. On short timescales, physiological constraints have been leveraged to provide a coarse-grained view of bacterial gene expression characterized by a small set of phenomenological parameters.

A hit expansion of 3-benzamidopyrazine-2-carboxamide: Toward inhibitors of prolyl-tRNA synthetase with antimycobacterial activity.

This study presents an exploration of the chemical space around derivatives of 3-benzamidopyrazine-2-carboxamides, previously identified as potent antimycobacterial compounds with predicted binding to mycobacterial prolyl-transfer RNA synthetase. New urea derivatives (Series-1) were generally inactive, probably due to their preference for cis-trans conformation (confirmed by density functional theory calculations and experimentally by nuclear overhauser effect spectroscopy NMR). Series-2 (3-benzamidopyrazine-2-carboxamides with disubstituted benzene ring) demonstrated that substituents larger than fluorine are not tolerated in the ortho position of the benzene ring.

Eco-Friendly Bio-Based Solvents for the Acetylation of the Amino Group of Amino Acids.

Nature-derived products, like juices and peel extracts of fruits and vegetables, have emerged in recent years as interesting and sustainable alternatives to traditional solvents in several synthetic applications. Herein, we present a green and fast method for the N-acetylation of amino acids, using several bio-based solvents (vinegar, tomato/kiwi/apple peel extracts, lemon juice, etc.).

Structural basis for specific inhibition of salicylate synthase from Mycobacterium abscessus.

Blocking iron uptake and metabolism has been emerging as a promising therapeutic strategy for the development of novel antimicrobial compounds. Like all mycobacteria, M. abscessus (Mab) has evolved several countermeasures to scavenge iron from host carrier proteins, including the production of siderophores, which play a crucial role in these processes.

Synthesis and Characterization of New Triazole-Bispidinone Scaffolds and Their Metal Complexes for Catalytic Applications.

Bispidines are a family of ligands that plays a pivotal role in various areas of coordination chemistry, with applications in medicinal chemistry, molecular catalysis, coordination polymers synthesis, and molecular magnetism. In the present work, triazole moieties were introduced using the CuAAC click-reaction, with the aim of expanding the number of coordination sites on the bispidine core. The 1,2,3-triazole rings were thus synthesized on propargyl-derived bispidines after reaction with different alkyl azides.

Unlocking the Antibiofilm Potential of Natural Compounds by Targeting the NADH:quinone Oxidoreductase WrbA.

Biofilm-dwelling cells endure adverse conditions, including oxidative imbalances. The NADH:quinone oxidoreductase enzyme WrbA has a crucial role in the mechanism of action of antibiofilm molecules such as ellagic and salicylic acids. This study aimed to exploit the potential of the WrbA scaffold as a valuable target for identifying antibiofilm compounds at non-lethal concentrations.

Functional decomposition of metabolism allows a system-level quantification of fluxes and protein allocation towards specific metabolic functions.

Quantifying the contribution of individual molecular components to complex cellular processes is a grand challenge in systems biology. Here we establish a general theoretical framework (Functional Decomposition of Metabolism, FDM) to quantify the contribution of every metabolic reaction to metabolic functions, e.g.

Mechanistic Insights into the Antibiofilm Mode of Action of Ellagic Acid.

Bacterial biofilm is a major contributor to the persistence of infection and the limited efficacy of antibiotics. Antibiofilm molecules that interfere with the biofilm lifestyle offer a valuable tool in fighting bacterial pathogens. Ellagic acid (EA) is a natural polyphenol that has shown attractive antibiofilm properties.

Biological Screening and Crystallographic Studies of Hydroxy γ-Lactone Derivatives to Investigate PPARγ Phosphorylation Inhibition.

PPARγ represents a key target for the treatment of type 2 diabetes and metabolic syndrome. To avoid serious adverse effects related to the PPARγ agonism profile of traditional antidiabetic drugs, a new opportunity is represented by the development of molecules acting as inhibitors of PPARγ phosphorylation by the cyclin-dependent kinase 5 (CDK5). Their mechanism of action is mediated by the stabilization of the PPARγ β-sheet containing Ser273 (Ser245 in PPARγ isoform 1 nomenclature).

Iron Acquisition and Metabolism as a Promising Target for Antimicrobials (Bottlenecks and Opportunities): Where Do We Stand?

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections is one of the most crucial challenges currently faced by the scientific community. Developments in the fundamental understanding of their underlying mechanisms may open new perspectives in drug discovery. In this review, we conducted a systematic literature search in PubMed, Web of Science, and Scopus, to collect information on innovative strategies to hinder iron acquisition in bacteria.

Targeting Siderophore-Mediated Iron Uptake in : A New Strategy to Limit the Virulence of Non-Tuberculous Mycobacteria.

Targeting pathogenic mechanisms, rather than essential processes, represents a very attractive approach for the development of new antimycobacterial drugs. In this context, iron acquisition routes have recently emerged as potentially druggable pathways. However, the importance of siderophore biosynthesis in the virulence and pathogenicity of () is still poorly understood.

Enzyme expression kinetics by Escherichia coli during transition from rich to minimal media depends on proteome reserves.

Bacterial fitness depends on adaptability to changing environments. In rich growth medium, which is replete with amino acids, Escherichia coli primarily expresses protein synthesis machineries, which comprise ~40% of cellular proteins and are required for rapid growth. Upon transition to minimal medium, which lacks amino acids, biosynthetic enzymes are synthesized, eventually reaching ~15% of cellular proteins when growth fully resumes.

Principles of gene regulation quantitatively connect DNA to RNA and proteins in bacteria.

Protein concentrations are set by a complex interplay between gene-specific regulatory processes and systemic factors, including cell volume and shared gene expression machineries. Elucidating this interplay is crucial for discerning and designing gene regulatory systems. We quantitatively characterized gene-specific and systemic factors that affect transcription and translation genome-wide for across many conditions.

Synthesis and Conformational Analysis of Hydantoin-Based Universal Peptidomimetics.

The synthesis of a collection of enantiomerically pure, systematically substituted hydantoins as structural privileged universal mimetic scaffolds is presented. It relies on a chemoselective condensation/cyclization domino process between isocyanates of quaternary or unsubstituted α-amino esters and -alkyl aspartic acid diesters followed by standard hydrolysis/coupling reactions with amines, using liquid-liquid acid/base extraction protocols for the purification of the intermediates. Besides the nature of the α carbon on the isocyanate moiety, either a quaternary carbon or a more flexible methylene group, conformational studies (molecular modeling), in solution (NMR, circular dichroism (CD), Fourier transform infrared (FTIR)), and in solid state (X-ray) showed that the presented hydantoin-based peptidomimetics are able to project their substituents in positions superimposable to the side chains of common protein secondary structures such as α-helix and β-turn, being the open α-helix conformation slightly favorable according to molecular modeling, while the closed β-turn conformation preferred in solution and in solid state.