Introduction: Candidozyma auris (Cz. auris) has emerged globally, and diseases caused by it are associated with a mortality rate of 30–72%. This yeast is often multidrug-resistant and challenging to treat. A synthetic peptide, consisting of 11 amino acids of human lactoferrin (hLF1-11), offers a new therapy that is active against Candida albicans, non-albicans Candida yeasts, as well as Cz. auris. The current study examined the susceptibility of clinically relevant Candida species to hLF(1-11) in vitro and investigated the synergistic interaction of this peptide with fluconazole (FLU) and anidulafungin (ANI). Methods: Susceptibility of the yeasts to hLF(1-11) was tested with a microdilution method to determine minimum inhibitory concentrations (MICs). A total of 59 strains belonging to 16 species of Candida or Candidozyma were tested. The treatment cohort included 20 strains of Cz. auris originating from six different countries. Results: Mean MIC values of all susceptible strains ranged from 16.66 ± 6.46 μg/mL to 45.83 ± 10.21 μg/mL. There were no statistical differences in the susceptibility of hLF(1-11) for Cz. auris across geographic origins. In the combinatory tests, drugs acting together, the fractional inhibitory concentration indexes [FIC] < 1.0, showed a synergistic or additive effect on the efficacy of FLU and ANI when used in combination with hLF(1-11). [FIC] indexes 1–2 were interpreted as intermediate. MIC values in combinatory use were 1–2 titer steps lower than when used alone. Conclusions: hLF(1-11) inhibits the growth of yeasts that belong to the genus Candida, including Cz. auris. The combinatory use may be further investigated to treat infections caused by resistant yeasts.

Background/Objectives: In the last few decades, the dengue virus, a prevalent flavivirus, has demonstrated various epidemiological, economic, and health impacts around the world. Dengue virus serotype 2 (DENV2) plays a vital role in dengue-associated mortality. The RNA-dependent RNA polymerase (RdRp) of DENV2 is a charming druggable target owing to its crucial function in viral reproduction. In recent years, streptomycetes natural products (NPs) have attracted considerable attention as a potential source of antiviral drugs. Methods: Seeking prospective inhibitors that inhibit the DENV2 RdRp allosteric site, in silico mining of the Streptome database was executed. AutoDock4.2.6 software performance in predicting docking poses of the inspected inhibitors was initially conducted according to existing experimental data. Upon the assessed docking parameters, the Streptome database was virtually screened against DENV2 RdRp allosteric site. The streptomycetes NPs with docking scores less than the positive control (68T; calc. −35.6 kJ.mol⁻¹) were advanced for molecular dynamics simulations (MDS), and their binding affinities were computed by employing the MM/GBSA approach. Results: SDB9818 and SDB4806 unveiled superior inhibitor activities against DENV2 RdRp upon MM/GBSA//300 ns MDS than 68T with ΔG_binding values of −246.4, −242.3, and −150.6 kJ.mol⁻¹, respectively. A great consistency was found in both the energetic and structural analyses of the identified inhibitors within the DENV2 RdRp allosteric site. Furthermore, the physicochemical characteristics of the identified inhibitors demonstrated good oral bioavailability. Eventually, quantum mechanical computations were carried out to evaluate the chemical reactivity of the identified inhibitors. Conclusions: As determined by in silico computations, the identified streptomycetes NPs may act as DENV2 RdRp allosteric inhibitors and mandate further experimental assays.

As the second most deadly infectious disease worldwide after COVID‐19, tuberculosis (TB) remains a pressing global health issue, further aggravated by multidrug‐resistant TB (MDR‐TB) and extensively drug‐resistant TB (XDR‐TB) strains. There is an urgent need to identify new anti‐TB treatments and novel therapeutics to confront drug resistance. The decaprenylphosphoryl‐D‐ribose oxidase (DprE1) is an essential protein for the biosynthesis of the mycobacterial cell wall, and its inhibition features a promising antitubercular strategy. NPAtlas was utilized as a reference database, comprising natural products with confirmed biological effects. The aim of the current study is to identify and prioritize promising nitro‐containing natural products from the NPAtlas as potential covalent DprE1 inhibitors using advanced in silico approaches. Herein, the docking scores of 133 nitro‐containing NPAtlas compounds were assessed using a covalent docking technique. Thereafter, NPAtlas compounds with docking scores lower than PBTZ169 (calc. −7.8 kcal·mol ⁻¹ ) were subjected to molecular dynamics simulation (MDS), accompanied by binding energy estimations utilizing the MM‐GBSA approach. Based on MM‐GBSA//250 ns MDS, NPA011203, NPA013234, NPA016048, NPA012944, NPA001712, and NPA002823 demonstrated higher binding affinities against DprE1 with Δ G _binding values of −75.6, −62.7, −61.6, −57.6, −54.8, and −50.7 kcal·mol ⁻¹ , respectively, than PBTZ169 (calc. −49.4 kcal·mol ⁻¹ ). The identified NPAtlas compounds also demonstrated structural and energetic stability within the DprE1 active site throughout 250 ns MDS. Physicochemical and ADMET predictions of the identified NPAtlas compounds indicated a suitable molecular size, favorable absorption, and negligible toxicity, suggesting their potential oral bioavailability. These in silico outcomes provide preliminary insights into the identified NPAtlas compounds as potential DprE1 inhibitors and can guide subsequent in vitro/in vivo experiments.