Discovery of the First-in-Class Inhibitors of Hypoxia Up-Regulated Protein†1 (HYOU1) Suppressing Pathogenic Fibroblast Activation.

Fibroblasts are key regulators of inflammation, fibrosis, and cancer. Targeting their activation in these complex diseases has emerged as a novel strategy to restore tissue homeostasis. Here, we present a multidisciplinary lead discovery approach to identify and optimize small molecule inhibitors of pathogenic fibroblast activation. The study encompasses medicinal chemistry, molecular phenotyping assays, chemoproteomics, bulk RNA-sequencing analysis, target validation experiments, and chemical absorption, distribution, metabolism, excretion and toxicity (ADMET)/pharmacokinetic (PK)/in vivo evaluation. The parallel synthesis employed for the production of the new benzamide derivatives enabled us to a) pinpoint key structural elements of the scaffold that provide potent fibroblast-deactivating effects in cells, b) discriminate atoms or groups that favor or disfavor a desirable ADMET profile, and c) identify metabolic "hot spots". Furthermore, we report the discovery of the first-in-class inhibitor leads for hypoxia up-regulated protein 1 (HYOU1), a member of the heat shock protein 70 (HSP70) family often associated with cellular stress responses, particularly under hypoxic conditions. Targeting HYOU1 may therefore represent a potentially novel strategy to modulate fibroblast activation and treat chronic inflammatory and fibrotic disorders.

A combination of mild-moderate hypoxemia and low compliance is highly prevalent in persistent ARDS: a retrospective study.

BACKGROUND: The Acute Respiratory Distress Syndrome (ARDS) is characterized by lung inflammation and edema, impairing both oxygenation and lung compliance. Recent studies reported a dissociation between oxygenation and compliance (severe hypoxemia with preserved compliance) in early ARDS and COVID-19-related-ARDS (CARDS). During the pandemic, in patients requiring prolonged mechanical ventilation, we observed the opposite combination (mild-moderate hypoxemia but significantly impaired compliance). The purpose of our study was to investigate the prevalence of this combination of mild-moderate hypoxemia and impaired compliance in persistent ARDS and CARDS. METHODS: For this retrospective study, we used individual patient-level data from two independent cohorts of ARDS patients. The ARDSNet cohort included patients from four ARDS Network randomized controlled trials. The CARDS cohort included patients with ARDS due to COVID-19 hospitalized in two intensive care units in Greece. We used a threshold of 150 for PaO2/FiO2 and 30 ml/cmH2O for compliance, estimated the prevalence of each of the four combinations of oxygenation and compliance at baseline, and examined the change in its prevalence from baseline to day 21 in the ARDSNet and CARDS cohorts. RESULTS: The ARDSNet cohort included 2909 patients and the CARDS cohort included 349 patients. The prevalence of the combination of mild-moderate hypoxemia and low compliance increased from baseline to day 21 both in the ARDSNet cohort (from 22.2 to 42.7%) and in the CARDS cohort (from 3.1 to 33.3%). Among surviving patients with low compliance, oxygenation improved over time. The 60-day mortality rate was higher for patients who had mild-moderate hypoxemia and low compliance on day 21 (28% and 56% in ARDSNet and CARDS), compared to those who had mild-moderate hypoxemia and high compliance (20% and 50%, respectively). CONCLUSIONS: Among patients with ARDS who require prolonged controlled mechanical ventilation, regardless of ARDS etiology, a dissociation between oxygenation and compliance characterized by mild-moderate hypoxemia but low compliance becomes increasingly prevalent. The findings of this study highlight the importance of monitoring mechanics in patients with persistent ARDS.

Design, synthesis and antibacterial activity against pathogenic mycobacteria of conjugated hydroxamic acids, hydrazides and O-alkyl/O-acyl protected hydroxamic derivatives.

With the aim to discover new antituberculous molecules, three novel series of 23 hydroxamic acids, 13 hydrazides, and 9O-alkyl/O-acyl protected hydroxamic acid derivatives have been synthesized, and fully characterized by spectral 1H NMR, 13C NMR, HRMS) analysis. These compounds were further biologically screened for their in vitro antibacterial activities against three pathogenic mycobacteria - M. abscessus S and R, M. marinum, and M. tuberculosis - as well as for their toxicity towards murine macrophages by the resazurin microtiter assay (REMA). Among the 45 derivatives, 17 compounds (3 hydroxamic acids, 9 hydrazides, and 5O-alkyl/O-acyl protected hydroxamic acids) were nontoxic against murine macrophages. When tested for their antibacterial activity, hydroxamic acid 9 h was found to be the most potent inhibitor against M. abscessus S and R only. Regarding hydrazide series, only 7h was active against M. abscessus R, M. marinum and M. tuberculosis; while the O-acyl protected hydroxamic acid derivatives 14d and 15d displayed promising antibacterial activity against both M. marinum and M. tuberculosis. Since such hydroxamic- and hydrazide-chelating groups have been reported to impair the activity of the peptide deformylase, in silico molecular docking studies in M. tuberculosis peptide deformylase enzyme active site were further performed with 7h in order to predict the possible interaction mode and binding energy of this molecule at the molecular level.

Infective endocarditis by Acinetobacter species: a systematic review.

A. baumannii - A. calcoaceticus complex infections are increasingly frequent, especially in intensive care units. Such infections are associated with a mortality that can be as high as 62%. On the other hand, infective endocarditis (IE) is an uncommon disease with notable morbidity and mortality. Even though IE is rarely caused by Acinetobacter species, these infections can be particularly problematic due to increasing antimicrobial resistance. The purpose of this study was to systemically review all published cases of IE by Acinetobacter species in the literature. A systematic review of PubMed, Scopus and Cochrane library (through 25 April 2020) for studies providing epidemiological, clinical, microbiological as well as treatment data and outcomes of IE by Acinetobacter species was performed. A total of 35 studies, containing data of 37 patients, were included. A prosthetic valve was present in 40.5%, while the most common causative pathogen was A. baumannii - A. calcoaceticus complex, followed by A. lwoffii. Aortic valve was the commonest infected site, followed by mitral valve. Diagnosis was set with transthoracic echocardiography in 48.6%, while the diagnosis was set at autopsy in 20%. Fever and sepsis were the commonest clinical presentations, followed by heart failure and embolic phenomena. Aminoglycosides, cephalosporins and carbapenems were the commonest antimicrobials used. Clinical cure was noted in 70.3%, while overall mortality was 32.4%. Development of heart failure was independently associated with mortality by IE. This systematic review thoroughly describes IE by Acinetobacter and provides information on epidemiology, clinical presentation, treatment and outcomes.

Candida parapsilosis endocarditis. Report of cases and review of the literature.

INTRODUCTION: Infective endocarditis (IE) due to Candida species is a rare disease representing about 1-2% of all IE cases and carries a high mortality rate. Given the rarity of the disease, there are no clear guidelines on the type and duration of antifungal therapy. Thus, long-term or even life-long antifungal treatment is commonly used. CASE REPORT: We report two patients with prosthetic valve C. parapsilosis IE and persistent candidemia that failed conservative treatment and ultimately developed heart failure. They underwent prosthetic valve replacement and prolonged antifungal treatment with favorable outcome. DISCUSSION: Candida IE commonly occurs in the setting of underlying malignancy, chronic liver disease, previous endocarditis, previous antimicrobial exposure, previous abdominal surgery, intravenous drug use, presence of a central venous catheter, and previous cardiac surgery. Both present patients had undergone a cardiac surgery and had a prosthetic heart valve, while one patient had an underlying autoimmune disease that could be associated with higher risk of IE. In both patients transthoracic ultrasound failed to diagnose IE. In our patients, conservative treatment alone was not enough to control the infection, thus, both patients underwent valve replacement and were subsequently treated with antifungals for 6 weeks. Furthermore, both patients were put on long-term antifungal suppression treatment. CONCLUSIONS: Given the absence of controlled randomized trials, the treatment of Candida endocarditis mostly relies on experts' opinion, and, thus, future studies focusing on the type and duration of antifungal treatment are required.

Roseomonas species infections in humans: a systematic review.

Roseomonas species have been recognized to cause infections in immunocompromised individuals. The purpose of this study was to systemically review all published cases of Roseomonas infections in humans and describe the epidemiology, microbiology, antimicrobial susceptibility, treatment and outcomes of these infections in humans. We performed a systematic review of PubMed (through 20th Octrober 2019) for studies providing epidemiological, clinical, microbiological as well as treatment data and outcomes of Roseomonas species infections. A total of 37 studies, containing data of 99 patients, were included in the analysis. The most common Roseomonas infections were those of the bloodstream in 74.7% (74 patients), musculoskeletal infections in 8.1% (8 patients), skin and soft tissue infections (SSTIs) and peritoneal dialysis-associated peritonitis in 6.1% (6 patients) each. Epidemiology of these infections differed, with bacteremias being more prevalent in patients with malignancy and central venous lines, musculoskeletal infections being more prevalent after orthopedic surgery, and SSTIs occurring without any reported underlying cause. Resistance to beta-lactams was very high with penicillin, piperacillin/tazobactam resistance and cephalosporin resistance at 96.6%, 90.7% and 77.8% respectively, while quinolone resistance was 9.1%. Quinolones, carbapenems and cephalosporins are the most common agents used for treatment, irrespectively of the infection site. Overall mortality was 3% (3 patients), with the mortality attributed to Roseomonas being at 1% (1 patient).