A5022476769- Estrogen and related hormone effects
- Hormonal Regulation and Hypertension
- Antimicrobial Peptides and Activities
- Growth Hormone and Insulin-like Growth Factors
- Antibiotic Resistance in Bacteria
- Bacterial biofilms and quorum sensing
- Chemical Reactions and Isotopes
- Pharmacogenetics and Drug Metabolism
- Adrenal Hormones and Disorders
- Biochemical and Structural Characterization
- Sexual Differentiation and Disorders
- Pituitary Gland Disorders and Treatments
- Cancer therapeutics and mechanisms
- Cystic Fibrosis Research Advances
- Pneumonia and Respiratory Infections
- Microbial Natural Products and Biosynthesis
- Bioactive Compounds and Antitumor Agents
- Inhalation and Respiratory Drug Delivery
Abstract Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) – a crucial transcriptional regulator serving major functions in PA virulence enhance antibiotic efficacy eventually prevent AMR. An integrated drug discovery campaign including design, medicinal chemistry‐driven hit‐to‐lead optimization in‐depth biological profiling new QSI...
In the context of cystic fibrosis, Pseudomonas aeruginosa biofilms often develop in vicinity airway mucus, which acts as a protective physical barrier to inhaled matter. However, mucus can also adsorb small drug molecules administered aerosols, including antibiotics, thereby reducing their bioavailability. The efficacy antibiotics is typically assessed by determining MIC using vitro assays. This widespread technique, however, does not consider either bacterial biofilm formation or influence...
Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns healthcare communities nowadays, these necessitate search for novel antibacterial agents. Recently, we discovered cystobactamids-a natural class with broad-spectrum activity. In this work, describe 1) a concise total synthesis cystobactamid 507, 2) identification bioactive conformation using noncovalently bonded rigid analogues, 3) first structure-activity relationship (SAR) study 507 leading to...
Cushing's disease, characterized by elevated plasma cortisol levels, can be controlled inhibition of 11β-hydroxylase (CYP11B1). The previously identified selective and potent CYP11B1 inhibitor 5-((5-methylpyridin-3-yl)methyl)-2-phenylpyridine Ref 7 (IC50= 2 nM) exhibited promutagenic potential as well very low oral bioavailability in rats (F = 2%) was therefore modified to overcome these drawbacks. Successful lead optimization resulted similarly...
Osteoporosis is predominantly treated with drugs that inhibit further bone resorption due to estrogen deficiency. Yet, osteoporosis not only but also stimulate formation, such as potentially inhibitors of 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2), may be more efficacious in the treatment osteoporosis. Blockade 17β-HSD2 thought increase intracellular estradiol and testosterone bone, thereby inhibiting by osteoclasts stimulating formation osteoblasts, respectively. We here describe...
Current therapies of steroid hormone-dependent diseases predominantly alter hormone concentrations (or their actions) in plasma, target and nontarget tissues alike, rather than organs only. Targeted therapy through the inhibition steroidogenic enzymes may pose an attractive alternative with much less side effects. Here, we describe design a nanomolar potent 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitor (compound 15) successful targeted intracrine mouse bone fracture model....
Optimization of the natural antibiotic cystobactamid 507 targeting DNA gyrase and topoisomerase IV was attained by structure– conformation—activity relationship studies. The bioactive conformation recognized as syn using conformationally locked analogues via intramolecular hydrogen bonds. new compounds displayed improved target inhibition, antibacterial activity, stability to metabolism resistance factor AlbD. Mode action study revealed that cystobactamids bind part gyrase–DNA complex at...
In article number 2004369, Martin Empting and colleagues describe a new generation of dual-loaded nanoparticles enabling efficient eradication Pseudomonas aeruginosa biofilms. The squalene-based nanocarrier facilitates co-delivery novel pathogenspecific Quorum Sensing Inhibitor (QSI) together with the standard-of-care antibiotic tobramycin. QSI itself shows high anti-virulence efficacy, favorable DMPK no overt safety pharmacology. When applied as nanoparticle formulation potentiates biofilm...