Chronic Antagonism of the Mineralocorticoid Receptor Ameliorates Hypertension and End Organ Damage in a Rodent Model of Salt-Sensitive Hypertension

We investigated the effects of chronic mineralocorticoid receptor blockade with eplerenone on the development and progression of hypertension and end organ damage in Dahl salt-sensitive rats. Eplerenone significantly attenuated the progressive rise in systolic blood pressure (SBP) (204 ± 3 vs. 179±3 mmHg, p < 0.05), reduced proteinuria (605.5 ± 29.6 vs. 479.7 ± 26.1 mg/24h, p < 0.05), improved injury scores of glomeruli, tubules, renal interstitium, and vasculature in Dahl salt-sensitive rats fed a high-salt diet. These results demonstrate that mineralocorticoid receptor antagonism provides target organ protection and attenuates the development of elevated blood pressure (BP) in a model of salt-sensitive hypertension

In Vivo Efficacy of a Novel Oxazolidinone Compound in Two Mouse Models of Infection▿

A novel oxazolidinone, AM 7359, was evaluated in two mouse models of Staphylococcus aureus infection. AM 7359 and linezolid were equally efficacious in a methicillin-susceptible S. aureus organ burden model and a methicillin-resistant S. aureus localized infection model. However, AM 7359 was eightfold more efficacious than linezolid against a linezolid- and methicillin-resistant S. aureus strain in this localized (thigh) infection model

Silicosis Among Immigrant Engineered Stone (Quartz) Countertop Fabrication Workers in California

ImportanceSilicosis associated with inhalation of respirable crystalline silica among engineered stone countertop fabrication workers is an emerging health concern.ObjectiveTo describe clinical, socioeconomic, and occupational characteristics of patients diagnosed with silicosis associated with engineered stone in California.Design, setting, and participantsThis case series included reported cases of silicosis associated with fabrication of engineered stone countertops, as identified by statewide surveillance by the California Department of Public Health (2019-2022). Data analysis was performed from October 2022 to March 2023.ExposuresPatient interviews and medical record abstractions were used to assess occupational exposure to respirable crystalline silica, including duration of work tenure and preventive measures undertaken.Main outcomes and measuresDemographics, clinical characteristics, health care utilization, and clinical outcomes were obtained, including vital status, hypoxia, and lung transplant.ResultsThis case series identified 52 male patients meeting inclusion criteria; median (IQR) age was 45 (40-49) years, and 51 were Latino immigrants. Ten (19%) were uninsured, and 20 (39%) had restricted-scope Medi-Cal; 25 (48%) presented initially to an emergency department. A delay in diagnosis occurred in 30 (58%) patients, most commonly due to alternative initial diagnoses of bacterial pneumonia (9 [30%]) or tuberculosis (8 [27%]). At diagnosis, 20 (38%) patients had advanced disease (progressive massive fibrosis) with severely or very severely reduced forced expiratory volume in 1 second in 8 (18%) and 5 (11%), respectively. Of the cases, 10 (19%) were fatal; median (IQR) age at death was 46 (38-51) years, and 6 patients (12%) were alive with chronic resting hypoxia. Eleven were referred for lung transplant: 3 underwent transplant with 1 fatality; 7 were declined transplant, with 6 fatalities; and 1 died prior to listing. Median (IQR) work tenure was 15 (10-20) years; 23 (45%) reported use of water suppression for dust mitigation, and 25 (48%) continued to fabricate stone after being diagnosed with silicosis.Conclusions and relevanceIn this case series performed in California, silicosis associated with occupational exposure to dust from engineered stone primarily occurred among young Latino immigrant men. Many patients presented with severe disease, and some cases were fatal

Silicosis Among Immigrant Engineered Stone (Quartz) Countertop Fabrication Workers in California

Key Points: Question: What are the characteristics of patients in California with silicosis from occupational exposure to dust from engineered stone (quartz), a popular material that is high in silica content and that is used to fabricate countertops? Findings: In this case series of 52 patients, the median age was 45 years at diagnosis, and nearly all were Latino immigrant men. Diagnosis was delayed in 58%, with 38% presenting with advanced disease (progressive massive fibrosis), and 19% died. Meaning: In California, silicosis associated with occupational exposure to dust from engineered stone primarily occurred among young Latino immigrant men; many patients presented with severe disease, and some cases were fatal

Chemical Genomics-Based Antifungal Drug Discovery: Targeting Glycosylphosphatidylinositol (GPI) Precursor Biosynthesis

Steadily increasing antifungal drug resistance and persistent high rates of fungal-associated mortality highlight the dire need for the development of novel antifungals. Characterization of inhibitors of one enzyme in the GPI anchor pathway, Gwt1, has generated interest in the exploration of targets in this pathway for further study. Utilizing a chemical genomics-based screening platform referred to as the Candida albicans fitness test (CaFT), we have identified novel inhibitors of Gwt1 and a second enzyme in the glycosylphosphatidylinositol (GPI) cell wall anchor pathway, Mcd4. We further validate these targets using the model fungal organism Saccharomyces cerevisiae and demonstrate the utility of using the facile toolbox that has been compiled in this species to further explore target specific biology. Using these compounds as probes, we demonstrate that inhibition of Mcd4 as well as Gwt1 blocks the growth of a broad spectrum of fungal pathogens and exposes key elicitors of pathogen recognition. Interestingly, a strong chemical synergy is also observed by combining Gwt1 and Mcd4 inhibitors, mirroring the demonstrated synthetic lethality of combining conditional mutants of GWT1 and MCD4. We further demonstrate that the Mcd4 inhibitor M720 is efficacious in a murine infection model of systemic candidiasis. Our results establish Mcd4 as a promising antifungal target and confirm the GPI cell wall anchor synthesis pathway as a promising antifungal target area by demonstrating that effects of inhibiting it are more general than previously recognized.Genome Canada (Firm)Genome Quebe

Arundifungin, a novel antifungal compound produced by fungi: biological activity and taxonomy of the producing organisms

Echinocandins, the lipopeptide class of glucan synthase inhibitors, are an alternative to ergosterol-synthesis inhibitors to treat candidiasis and aspergillosis. Their oral absorption, however, is low and they can only be used parenterally. During a natural product screening program for novel types of glucan synthesis inhibitors with improved bioavailability, a fungal extract was found that inhibited the growth of both a wild-type Saccharomyces cerevisiae strain and the null mutant of the FKS1 gene (fks1::HIS). The mutant strain was more sensitive to growth inhibition, suggesting that the fungal extract could contain an inhibitor of glucan synthesis. A novel acidic steroid, named arundifungin, was purified from a fungal extract obtained from a liquid culture of Arthrinium arundinis collected in Costa Rica. Arundifungin caused the same pattern of hallmark morphological alterations in Aspergillus fumigatus hyphae as echinocandins, further supporting the idea that arundifungin belongs to a new class of glucan synthesis inhibitors. Moreover, its antifungal spectrum was comparable to those of echinocandins and papulacandins, preferentially inhibiting the growth of Candida and Aspergillus strains, with very poor activity against Cryptococcus. Arundifungin was also detected in nine other fungal isolates which were ecologically and taxonomically unrelated, as assessed by sequencing of the ITS1 region. Further, it was also found in two more Arthrinium spp from tropical and temperate regions, in five psychrotolerant conspecific isolates collected on Macquarie Island South Pacific) and belonging to the Leotiales, and in two endophytes collected in central Spain a sterile fungus belonging to the Leotiales and an undetermined coelomycete)

Efficacy of Caspofungin in a Juvenile Mouse Model of Central Nervous System Candidiasis ▿

Neonatal candidiasis is an increasingly common occurrence causing significant morbidity and mortality and a higher risk of dissemination to the central nervous system (CNS) than that seen with older patients. The current understanding of optimal antifungal therapy in this setting is limited. We have developed a model of disseminated candidiasis with CNS involvement in juvenile mice to assess the efficacy of the echinocandin caspofungin relative to amphotericin B (AmB). Juvenile mice were inoculated intravenously with 5.64 × 104 CFU of Candida albicans MY1055. Treatment with caspofungin at 1, 2, 4, and 8 mg/kg of body weight/day, AmB at 1 mg/kg/day, or a vehicle control (VC) was initiated 30 h after infection and continued for 7 days. Pharmacokinetic parameters for caspofungin were also determined. Culture and histology showed evidence of disseminated candidiasis with multifocal encephalitis at the start of antifungal therapy. Survival was 100% in all treated groups, while mortality was 100% in the VC by day 11 after infection. By day 5, all mice in the caspofungin treatment (four doses) groups showed reductions in kidney and brain burden relative to the VC, while AmB treatment reduced kidney burden but gave no reduction of brain fungal burden. Systemic levels of caspofungin were similar in infected and uninfected mice, while brain levels were higher in infected animals. In this juvenile mouse model, caspofungin demonstrated dose-dependent activity, equivalent to or better than that of AmB at 1 mg/kg, against disseminated candidiasis with CNS involvement

Antifungal Spectrum, In Vivo Efficacy, and Structure–Activity Relationship of Ilicicolin H

Ilicicolin H is a polyketidenonribosomal peptide synthase (NRPS)natural product isolated from <i>Gliocadium roseum</i>, which exhibits potent and broad spectrum antifungal activity, with sub-μg/mL MICs against <i>Candida</i> spp., <i>Aspergillus fumigatus</i>, and <i>Cryptococcus</i> spp. It showed a novel mode of action, potent inhibition (IC₅₀ = 2–3 ng/mL) of the mitochondrial cytochrome bc1 reductase, and over 1000-fold selectivity relative to rat liver cytochrome bc1 reductase. Ilicicolin H exhibited in vivo efficacy in murine models of <i>Candida albicans</i> and <i>Cryptococcus neoformans</i> infections, but efficacy may have been limited by high plasma protein binding. Systematic structural modification of ilicicolin H was undertaken to understand the structural requirement for the antifungal activity. The details of the biological activity of ilicicolin H and structural modification of some of the key parts of the molecule and resulting activity of the derivatives are discussed. These data suggest that the β-keto group is critical for the antifungal activity