Amino acid-derived 1,2-benzisothiazolinone derivatives as novel small-molecule antifungal inhibitors: identification of potential genetic targets.

We have identified four synthetic compounds (DFD-VI-15, BD-I-186, DFD-V-49, and DFD-V-66) from an amino acid-derived 1,2-benzisothiazolinone (BZT) scaffold that have reasonable MIC(50) values against a panel of fungal pathogens. These compounds have no structural similarity to existing antifungal drugs. Three of the four compounds have fungicidal activity against Candida spp., Cryptococcus neoformans, and several dermatophytes, while one is fungicidal to Aspergillus fumigatus. The kill rates of our compounds are equal to those in clinical usage. The BZT compounds remain active against azole-, polyene-, and micafungin-resistant strains of Candida spp. A genetics-based approach, along with phenotype analysis, was used to begin mode of action (MOA) studies of one of these compounds, DFD-VI-15. The genetics-based screen utilized a homozygous deletion collection of approximately 4,700 Saccharomyces cerevisiae mutants. We identified mutants that are both hypersensitive and resistant. Using FunSpec, the hypersensitive mutants and a resistant ace2 mutant clustered within a category of genes related directly or indirectly to mitochondrial functions. In Candida albicans, the functions of the Ace2p transcription factor include the regulation of glycolysis. Our model is that DFD-VI-15 targets a respiratory pathway that limits energy production. Supporting this hypothesis are phenotypic data indicating that DFD-VI-15 causes increased cell-reactive oxidants (ROS) and a decrease in mitochondrial membrane potential. Also, the same compound has activity when cells are grown in a medium containing glycerol (mitochondrial substrate) but is much less active when cells are grown anaerobically.

Severe Maternal Morbidity and 30-Day Postpartum Readmission in the Military Health System.

Background: The Centers for Disease Control and Prevention (CDC) cite an increase of 200% in severe maternal morbidity (SMM) in the United States from 1993 to 2014. This study aims to identify the incidence of SMM in the Military Health System (MHS), along with factors that may be correlated with the risk of SMM and 30-day readmissions among universally insured, ethnically diverse women who delivered in military treatment facilities (MTFs). Methods: Using the MHS Data Repository, we conducted a cross-sectional study on all women 15 to 54 years of age who delivered at a MTF during fiscal years 2016 to 2018. Using the CDC's list of 21 indicators and corresponding International Classification of Diseases diagnostic and procedure codes, 10th revision (ICD-10) for SMM, hospitalizations with SMM were identified within our selected group at the time of the delivery, as well as the prevalence of overall 30-day maternal readmissions. Multivariable logistic regressions were conducted to determine the likelihood of SMM and 30-day readmissions, with patient demographics at each delivery as predictor variables. Results: Of the total deliveries, 2.58% had maternal readmissions within 30 days and 0.59% had SMM identified. Women 35-39 years of age and ages 40+ had significantly higher odds of SMM during delivery when compared with women 25-29 years of age. Black women were 1.39 times more likely than White women to be diagnosed with SMM during their delivery admission. Black women also had significantly greater odds of a 30-day postpartum readmission when compared with White women. Conclusions: The low rate of SMM in this population, compared with national data, is a significant finding. The overall 30-day readmission rate in this population is also lower than what has been reported in prior studies. In this study population, women 30-34 are also at higher risk for readmission, which is an area for further study to assess for potential risk factors and underlying causes that may be impacting the higher rates in this age group.