Intestinal biofilms: pathophysiological relevance, host defense, and therapeutic opportunities.

SUMMARYThe human intestinal tract harbors a profound variety of microorganisms that live in symbiosis with the host and each other. It is a complex and highly dynamic environment whose homeostasis directly relates to human health. Dysbiosis of the gut microbiota and polymicrobial biofilms have been associated with gastrointestinal diseases, including irritable bowel syndrome, inflammatory bowel diseases, and colorectal cancers. This review covers the molecular composition and organization of intestinal biofilms, mechanistic aspects of biofilm signaling networks for bacterial communication and behavior, and synergistic effects in polymicrobial biofilms. It further describes the clinical relevance and diseases associated with gut biofilms, the role of biofilms in antimicrobial resistance, and the intestinal host defense system and therapeutic strategies counteracting biofilms. Taken together, this review summarizes the latest knowledge and research on intestinal biofilms and their role in gut disorders and provides directions toward the development of biofilm-specific treatments.

Gastrointestinal Biofilms: Endoscopic Detection, Disease Relevance, and Therapeutic Strategies.

Gastrointestinal biofilms are highly heterogenic and spatially organized polymicrobial communities that can expand and cover large areas in the gastrointestinal tract. Gut microbiota dysbiosis, mucus disruption, and epithelial invasion are associated with pathogenic biofilms that have been linked to gastrointestinal disorders such as irritable bowel syndrome, inflammatory bowel diseases, gastric cancer, and colon cancer. Intestinal biofilms are highly prevalent in ulcerative colitis and irritable bowel syndrome patients, and most endoscopists will have observed such biofilms during colonoscopy, maybe without appreciating their biological and clinical importance. Gut biofilms have a protective extracellular matrix that renders them challenging to treat, and effective therapies are yet to be developed. This review covers gastrointestinal biofilm formation, growth, appearance and detection, biofilm architecture and signalling, human host defence mechanisms, disease and clinical relevance of biofilms, therapeutic approaches, and future perspectives. Critical knowledge gaps and open research questions regarding the biofilm's exact pathophysiological relevance and key hurdles in translating therapeutic advances into the clinic are discussed. Taken together, this review summarizes the status quo in gut biofilm research and provides perspectives and guidance for future research and therapeutic strategies.

Antibacterial Potential of Extracts and Phytoconstituents Isolated from Syncarpia hillii Leaves In Vitro.

(1) Background: Rapidly increasing antibiotic resistance is one of the greatest threats to global health, affecting individuals regardless of age. Medicinal plants are widely used in traditional medicine to prevent and attenuate infectious conditions with minimal adverse effects. However, only a few have been phytochemically investigated for their medicinal properties and subsequent biological activities. Syncarpia hillii, a plant traditionally used by Indigenous Australians to treat sores, wounds, and skin infections, is no exception. (2) Methods: Primary extracts obtained from mature S. hillii leaves were evaluated for their antibacterial potential against 19 bacterial strains. The methanol extract was subjected to compound isolation and identification due to its preliminary bactericidal efficacy. (3) Results: Staphylococcal species were the most susceptible bacterial strain with a MIC value of 0.63 mg/mL to the S. hillii methanol extract. Quercetin-3-O-ß-D-glucuronide and shikimic acid isolated from S. hillii methanol leaf extracts exhibited enhanced antibacterial effects against the tested bacteria with quercetin-3-O-ß-D-glucuronide eliciting a MIC value of 0.78 µg/mL against E. faecalis. (4) Conclusions: S. hillii leaves are comprised of bioactive compounds that are bactericidal against several Gram-positive and Gram-negative bacteria.

Discovery of a Novel Antimicrobial Agent by the Virtual Screening of a Library of Small Molecules.

A virtual screening approach based upon a combination of docking and pharmacophore methods was utilized on a library of 1.4 million molecules to identify novel antimicrobial agents, which may potentially act via inhibition of the caseinolytic protease. Using this method, compound 6 was found to be bactericidal against three staphylococcal species (minimum inhibitory concentration (MIC)=4-16 µg/mL). Further, subsequent structural optimization of 6 led to the identification of compound 24, which was shown to be the most potent analog within the series (MIC=4 µg/mL) and outperforming the antibiotic controls for two of the staphylococcal species. The newly discovered antimicrobial agent (24) demonstrated excellent in silico ADME properties and was non-toxic when tested on two human skin cell lines. As such, compound 24 has the potential for use as a lead molecule in the development of a novel class of antimicrobial agents.

Structure-Based Scaffold Repurposing toward the Discovery of Novel Cholinesterase Inhibitors.

Cholinesterases (ChE) are well-known drug targets for the treatment of Alzheimer's disease (AD). In continuation of work to develop novel cholinesterase inhibitors, we utilized a structure-based scaffold repurposing approach and discovered six novel ChE inhibitors from our recently developed DNA gyrase inhibitor library. Among the identified hits, two compounds (denoted 3 and 18) were found to be the most potent inhibitor of acetylcholinesterase (AChE, IC50 = 6.10 ± 1.01 µM) and butyrylcholinesterase (BuChE, IC50 = 5.50 ± 0.007 µM), respectively. Compound 3 was responsible for the formation of H-bond and π-π stacking interactions within the active site of AChE. In contrast, compound 18 was well fitted in the choline-binding pocket and catalytic site of BuChE. Results obtained from in vitro cytotoxicity assays and in silico derived physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties indicate that repurposed scaffold 3 and 18 could be potential drug candidates for further development as novel ChE inhibitors.

Recent advances in DNA gyrase-targeted antimicrobial agents.

Antimicrobial resistance is one of the greatest challenges facing the world today. In the United States alone, it is responsible for the death of more than 20,000 people each year. DNA gyrase, a well-validated drug target, is involved in bacterial DNA replication, repair and decatenation. Currently, the fluoroquinolone class of antibacterials act via inhibition of the DNA gyrase enzyme. However, their efficacy is hindered by the increasing incidence of antimicrobial resistance. Therefore, in this review, we provide an account regarding the structure of DNA gyrase and quinoline and non-quinolone inhibitors published within the last five years (2015-2019). Further, we also discuss molecular interactions and structure-activity relationship studies of the published inhibitors.

A randomized, double-blind placebo-controlled study of intranasal standardized cinnamon bark extract for seasonal allergic rhinitis.

OBJECTIVES: The aim of the study was to assess the safety and efficacy of a nasal spray containing a polyphenol-rich standardized extract of cinnamon bark (Cinnamomum zeylanicum) (IND02) for the treatment of seasonal allergic rhinitis (SAR). METHODS: This study was a randomized, double-blind, placebo-controlled study conducted in otherwise healthy men and women, aged between 18 and 75 years old, who were experiencing acute SAR symptoms. Participants were randomized in a 1:1 ratio to a nasal spray containing either IND02 (100 µg/100 µL) or matching placebo in each nostril, twice a day, for seven days. RESULTS: The outcome measures were the rhinoconjunctivitis quality of life questionnaire (RQLQ), the total daily symptom score comprising of day-time nasal, day-time eye, and night-time nasal symptom scores, the Work Productivity and Activities Impairment (WPAI:SHP), the Pittsburgh Sleep Quality Index (PSQI), the Perceived Stress Scale (PSS) and laboratory clinical parameters. RESULTS: The IND02 group showed a statistically and clinically significant reduction in total RQLQ and the sub-domains; activity limitation, sleep problems, nose symptoms, eye symptoms, non-nose/eye symptoms, practical problems and emotional function. There was a significant reduction in the total daily symptom score and sub-domains of total day-time nasal, total day-time eye and total night-time nasal symptoms scores, and total work impairment and regular activity impairment in the IND02 group compared with the placebo group after treatment. The laboratory clinical parameters remained within healthy normal reference range. CONCLUSION: The use of a nasal spray of a standardized extract of cinnamon bark (IND02) over seven days reduced symptom severity and improved quality of life, work productivity and regular daily activities in participants experiencing SAR.

Recent update on anti-dengue drug discovery.

Dengue is the most important arthropod-borne viral disease of humans, with more than half of the global population living in at-risk areas. Despite the negative impact on public health, there are no antiviral therapies available, and the only licensed vaccine, Dengvaxia®, has been contraindicated in children below nine years of age. In an effort to combat dengue, several small molecules have entered into human clinical trials. Here, we review anti-DENV molecules and their drug targets that have been published within the past five years (2014-2018). Further, we discuss their probable mechanisms of action and describe a role for classes of clinically approved drugs and also an unclassified class of anti-DENV agents. This review aims to enhance our understanding of novel agents and their cognate targets in furthering innovations in the use of small molecules for dengue drug therapies.

Multifunctional Analogs of Kynurenic Acid for the Treatment of Alzheimer's Disease: Synthesis, Pharmacology, and Molecular Modeling Studies.

We report the synthesis and pharmacological investigation of analogs of the endogenous molecule kynurenic acid (KYNA) as multifunctional agents for the treatment of Alzheimer's disease (AD). Synthesized KYNA analogs were tested for their N-methyl-d-aspartate (NMDA) receptor binding, mGluR5 binding and function, acetylcholinesterase (AChE) inhibition, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, interference with the amyloid ß peptide (Aß) fibrillation process, and protection against Aß-induced toxicity in transgenic Caenorhabditis elegans strain GMC101 expressing full-length Aß42. Molecular modeling studies were also performed to predict the binding modes of most active compounds with NMDAR, mGluR5, and Aß42. Among the synthesized analogs, 3c, 5b, and 5c emerged as multifunctional compounds that act via multiple anti-AD mechanisms including AChE inhibition, free radical scavenging, NMDA receptor binding, mGluR5 binding, inhibition of Aß42 fibril formation, and disassembly of preformed Aß42 fibrils. Interestingly, 5c showed protection against Aß42-induced toxicity in transgenic C. elegans strain GMC101. Moreover, 5b and 5c displayed high permeability in an MDR1-MDCKII cell-based model of the blood-brain barrier (BBB). Compound 3b emerged with specific activity as a micromolar AChE inhibitor, however it had low permeability in the BBB model. This study highlights the opportunities that exist to develop analogs of endogenous molecules from the kynurenine pathway for therapeutic uses.

Effect of the Biphenyl Neolignan Honokiol on Aß42-Induced Toxicity in Caenorhabditis elegans, Aß42 Fibrillation, Cholinesterase Activity, DPPH Radicals, and Iron(II) Chelation.

The biphenyl neolignan honokiol is a neuroprotectant which has been proposed as a treatment for central nervous system disorders such as Alzheimer's disease (AD). The death of cholinergic neurons in AD is attributed to multiple factors, including accumulation and fibrillation of amyloid beta peptide (Aß) within the brain; metal ion toxicity; and oxidative stress. In this study, we used a transgenic Caenorhabditis elegans model expressing full length Aß42 as a convenient in vivo system for examining the effect of honokiol against Aß-induced toxicity. Furthermore, honokiol was evaluated for its ability to inhibit Aß42 oligomerization and fibrillation; inhibit acetylcholinesterase and butyrylcholinesterase; scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals; and chelate iron(II). Honokiol displayed activity similar to that of resveratrol and (-)-epigallocatechin gallate (EGCG) in delaying Aß42-induced paralysis in C. elegans, and it exhibited moderate-to-weak ability to inhibit Aß42 on-pathway aggregation, inhibit cholinesterases, scavenge DPPH radicals, and chelate iron(II). Moreover, honokiol was found to be chemically stable relative to EGCG, which was highly unstable. Together with its good drug-likeness and brain availability, these results suggest that honokiol may be amenable to drug development and that the synthesis of honokiol analogues to optimize these properties should be considered.

Discovery and Structure-Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening.

Structure-based virtual screening of two libraries containing 567 981 molecules was used to discover novel, selective BuChE inhibitors, which are potentially superior symptomatic treatments in late-stage Alzheimer's disease. Compound 16 was identified as a highly selective submicromolar inhibitor of BuChE (huBuChE IC50 = 0.443 µM) with high permeability in the PAMPA-BBB model. The X-ray crystal structure of huBuChE in complex with 16 revealed the atomic-level interactions and offers opportunities for further development of the series.

Biological and medicinal significance of benzofuran.

This article emphasizes on the importance of benzofuran as a biologically relevant heterocycle. It covers most of the physiologically as well as medicinally important compounds containing benzofuran rings. This article also covers clinically approved drugs containing benzofuran scaffold.

Use of ionic liquids as neoteric solvents in the synthesis of fused heterocycles.

Medicinal chemistry has been benefited by combinatorial chemistry and high-throughput parallel synthesis. Ionic liquids reduce the materials and energy intensity of chemical processes and products, minimize or eliminate the dispersion of harmful chemicals in the environment, maximize the use of renewable resources and extend the durability and recyclability of products. It is possible to tune the physical and chemical properties by varying the nature of the cations and anions. Ionic liquids can be easily recovered, cleaned up, and reused repeatedly.

Biological and Medicinal Significance of Purines.

This article outlines the biological significance of one of the most important heterocycles, the purines. An attempt has been made to cover most of the physiologically as well as medicinally important compounds containing the purine derivatives. Purines are the drug molecules, which possess a variety of biological and medicinal significance.

A Remarkably High-Speed Solution-Phase Combinatorial Synthesis of 2-Substituted-Amino-4-Aryl Thiazoles in Polar Solvents in the Absence of a Catalyst under Ambient Conditions and Study of Their Antimicrobial Activities.

Remarkably high-speed synthesis of 2-substituted amino-4-aryl thiazoles in polar solvents with a minimum threshold polarity index of 4.8 was found to proceed to completion in just 30-40 sec. affording excellent yields of thiazoles under ambient temperature conditions without the use of any additional catalyst. The purification-free procedure afforded libraries based around a known pharmacophore, namely, substituted arylthiazoles and generated samples of high purity. In terms of combinatorial synthesis in a single solution phase, our protocol is significantly better than those hitherto reported and is amenable for HTS. The in vitro biological tests of some thiazoles showed good activity towards gram-positive bacteria, gram-negative bacteria and fungi comparable with the standard drugs, nitrofurantoin and griseofulvin, for their antibacterial and antifungal activities, respectively.