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. Our catalytic methods provided straightforward access, inspired by the innate structural features of lignin, to synthetically challenging biologically active molecules with the core structure of dopamine, namely, tetrahydroisoquinolines, quinazolinones, 3-arylindoles and the natural product tetrahydropapaveroline. Our diverse array of atom-economic transformations produces only harmless side products and uses benign reaction media, such as tunable deep eutectic solvents for modulating reactivity in challenging cyclization steps.

Inhibitors of the Elastase LasB for the Treatment of Pseudomonas aeruginosa Lung Infections.

Infections caused by the Gram-negative pathogen Pseudomonas aeruginosa are emerging worldwide as a major threat to human health. Conventional antibiotic monotherapy suffers from rapid resistance development, underlining urgent need for novel treatment concepts. Here, we report on a nontraditional approach to combat P. aeruginosa-derived infections by targeting its main virulence factor, the elastase LasB. We discovered a new chemical class of phosphonates with an outstanding in vitro ADMET and PK profile, auspicious activity both in vitro and in vivo. We established the mode of action through a cocrystal structure of our lead compound with LasB and in several in vitro and ex vivo models. The proof of concept of a combination of our pathoblocker with levofloxacin in a murine neutropenic lung infection model and the reduction of LasB protein levels in blood as a proof of target engagement demonstrate the great potential for use as an adjunctive treatment of lung infections in humans.

Structure-Based Design of α-Substituted Mercaptoacetamides as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa.

Antivirulence therapy has become a widely applicable method for fighting infections caused by multidrug-resistant bacteria. Among the many virulence factors produced by the Gram-negative bacterium Pseudomonas aeruginosa, elastase (LasB) stands out as an important target as it plays a pivotal role in the invasion of the host tissue and evasion of the immune response. In this work, we explored the recently reported LasB inhibitor class of α-benzyl-N-aryl mercaptoacetamides by exploiting the crystal structure of one of the compounds. Our exploration yielded inhibitors that maintained inhibitory activity, selectivity, and increased hydrophilicity. These inhibitors were found to reduce the pathogenicity of the bacteria and to maintain the integrity of lung and skin cells in the diseased state. Furthermore, two most promising compounds increased the survival rate of Galleria mellonella larvae treated with P. aeruginosa culture supernatant.

Inhibition of Collagenase Q1 of Bacillus cereus as a Novel Antivirulence Strategy for the Treatment of Skin-Wound Infections.

Despite the progress in surgical techniques and antibiotic prophylaxis, opportunistic wound infections with Bacillus cereus remain a public health problem. Secreted toxins are one of the main factors contributing to B. cereus pathogenicity. A promising strategy to treat such infections is to target these toxins and not the bacteria. Although the exoenzymes produced by B. cereus are thoroughly investigated, little is known about the role of B. cereus collagenases in wound infections. In this report, the collagenolytic activity of secreted collagenases (Col) is characterized in the B. cereus culture supernatant (csn) and its isolated recombinantly produced ColQ1 is characterized. The data reveals that ColQ1 causes damage on dermal collagen (COL). This results in gaps in the tissue, which might facilitate the spread of bacteria. The importance of B. cereus collagenases is also demonstrated in disease promotion using two inhibitors. Compound 2 shows high efficacy in peptidolytic, gelatinolytic, and COL degradation assays. It also preserves the fibrillar COLs in skin tissue challenged with ColQ1, as well as the viability of skin cells treated with B. cereus csn. A Galleria mellonella model highlights the significance of collagenase inhibition in vivo.

Validity of Self-reported Height, Weight, Body Mass Index, and Waist Circumference in Iranian Adults.

CONTEXT: The validity of self-reported anthropometric indices has been examined in previous studies in different populations. AIMS: The aim of our study was to evaluate the validity of self-reported height, weight, body mass index (BMI), and waist circumference (WC) for the first time in middle-age staffs of Isfahan University of Medical Sciences. SETTINGS AND DESIGN: In this cross-sectional study, a total of 171 men and women were selected from staffs of Isfahan University of Medical Sciences, Isfahan, Iran. METHODS AND MATERIALS: Technician- and self-reported measurements of height, weight, and WC were collected from all participants. BMI was calculated by dividing weight in kg by height in meters squared. Overweight and obesity were defined as BMI ≥25-<29.9 and ≥30 kg/m2, respectively. Abdominal obesity was defined as WC ≥94 and ≥80 cm in men and women, respectively. STATISTICAL ANALYSIS: Independent t-test, chi-square, Pearson and intraclass correlation coefficients (ICCs), as well as Kappa measurements, were used. RESULTS: Fifty and 19 percentages of the study population were overweight and obese, respectively. Self-reported height (r = 0.83, P < 0.001, ICC =0.89, 95% confidence interval (CI): 0.85-0.92), weight (r = 0.95, P < 0.001, ICC = 0.979, 95% CI: 0.971-0.98), BMI (r = 0.70, P < 0.001, ICC = 0.81, 95% CI: 0.74-0.86), and WC (r = 0.60, P < 0.001, ICC = 0.71, 95% CI: 0.51-0.81) were highly correlated with actually measured ones. Approximately 80% and 65% of individuals who were defined as overweight and obese, respectively, based on actually measured data were correctly diagnosed as overweight and obese, respectively, based on self-reported data. The Kappa coefficients for different categories of weight situation and abdominal obesity were 0.59 and 0.32, respectively. Fifty-seven percent of participants who were diagnosed with abdominal obesity based on actually measured data were correctly diagnosed with abdominal obesity based on self-reported data. Also, approximately 48% and 69% of men and women, respectively, who were diagnosed with abdominal obesity based on actually measured data were correctly diagnosed with abdominal obesity based on self-reported ones. CONCLUSIONS: We found that self-reported data of anthropometric measures are reasonable in middle-age staff of Isfahan University of Medical Sciences. Nevertheless, self-reported data on WC should be cautiously relined on, in particular, among men.