The University of Texas Health Science Center at Houston

Several Candida species such as C. albicans and C. auris have emerged as formidable multidrug-resistant pathogens, posing significant challenges to global healthcare.C. albicans can rapidly adapt its metabolism under nutrient-limited conditions, such as low-carbon environments, leading to virulence and drug resistance.Therefore, identifying novel compounds that can disrupt this metabolic adaptability is crucial for developing effective therapeutic strategies against this elusive pathogen.In this study, we first employed an in-silico dynamics approach to investigate the inhibitory effects of guaiazulene and aureusidin on C. albicans metabolic adaptability and virulence.By employing mol. docking and mol. dynamics simulations, we demonstrated that these compounds strongly interacted with crucial enzymes involved in the glyoxylate cycle, impairing their catalytic functions.Guaiazulene exhibited the highest binding affinity for malate synthase and isocitrate lyase, with a docking score of -8.5 and -9.3 kcal/mol, resp.The ADME properties of these mols. were also examined to evaluate the pharmacol. parameters.Furthermore, we investigated the impact of guaiazulene and aureusidin on C. albicans growth and biofilm formation.Our findings indicated that the targeting the glyoxylate cycle represents a promising strategy to counteract the metabolic adaptability of C. albicans and enhance the efficacy of antifungal agents.

The efficacy and safety of ensifentrine, a novel PDE3/PDE4 inhibitor, were previously evaluated in the ENHANCE-1 (NCT04535986) and ENHANCE-2 (NCT04542057) trials. Here, we present a pooled post-hoc subgroup analysis of patients according to background chronic obstructive pulmonary disease (COPD) maintenance medication regimens.

This analysis aimed to explore the efficacy and safety of ensifentrine in patients receiving long-acting muscarinic antagonists (LAMA) or long-acting beta-agonists with inhaled corticosteroids (LABA + ICS).

Eligible patients had moderate to severe COPD, were aged 40–80 years, and were symptomatic at randomization. Patients were randomized 5:3, receiving twice-daily ensifentrine 3 mg or placebo via standard jet nebulizer over 24 weeks.

The pooled post-hoc analysis included 485 LAMA patients and 272 LABA + ICS patients. Ensifentrine showed lung function improvement over placebo at week 12, including average FEV1 AUC0–12 h in the LAMA (placebo-corrected least squares mean change from baseline [LSMC], 92 mL; 95% CI, 54, 131; p < 0.001) and LABA + ICS subgroups (LSMC, 74 mL; 95% CI, 27, 121; p = 0.002). Ensifentrine reduced the rate and risk of exacerbations in both LAMA (48% and 50%, respectively) and LABA + ICS (51% and 56%, respectively) subgroups. Ensifentrine-treated patients reported improvement in symptoms and quality of life over 24 weeks. The safety profile of ensifentrine in each subgroup was similar to the profile in the pooled modified intention-to-treat population.

Nebulized ensifentrine offers a novel non-steroidal anti-inflammatory and bronchodilator treatment added to existing LAMA or LABA + ICS treatment options in patients with moderate to severe, symptomatic COPD.

Nematode-trapping fungi (NTF), most of which belong to a monophyletic lineage in Ascomycota, cannibalize nematodes and other microscopic animals, raising questions regarding the types and mechanisms of genomic changes that enabled carnivorism and adaptation to the carbon-rich and nitrogen-poor environment created by the Permian-Triassic extinction event. To address these questions, we conducted comparative genomic analyses of 21 NTF and 21 non-NTF. Carnivorism-associated changes include expanded genes for nematode capture, infection, and consumption (e.g., adhesive proteins, CAP superfamily, eukaryotic aspartyl proteases, and serine-type peptidases). Although the link between secondary metabolite (SM) production and carnivorism remains unclear, we found that the number of SM gene clusters in NTF was significantly lower than that in non-NTF. Significantly expanded cellulose degradation gene families (GH5, GH7, AA9, and CBM1) and contracted genes for carbon-nitrogen hydrolases (enzymes that degrade organic nitrogen to ammonia) are likely associated with adaptation to carbon-rich and nitrogen-poor environments. Through horizontal gene transfer events from bacteria, NTF acquired the Mur gene cluster (participating in synthesizing peptidoglycan of the bacterial cell wall) and Hyl (a virulence factor in animals). Disruption of MurE reduced NTF's ability to attract nematodes, supporting its role in carnivorism. This study provides new insights into how NTF evolved and diversified, presumably after the Permian-Triassic mass extinction event.