Biofilm inhibitors(Naval Medical University)

Biofilms commonly develop in immunocompromised patients, which leads to persistent infections that are difficult to treat.In the biofilm state, bacteria are protected against both antibiotics and the host's immune system; currently, there are no therapeutics that target biofilms.In this study, we screened a chem. fraction library representing the natural product capacity of the microbiota of marine egg masses, namely, the moon snail egg collars.This led to the identification of active fractions targeting both Pseudomonas aeruginosa and Staphylococcus aureus biofilms.Subsequent anal. revealed that a subset of these fractions were capable of eradicating pre-formed biofilms, all against S. aureus.Bioassay-guided isolations led to identifying pseudochelin A, a known siderophore, as a S. aureus biofilm inhibitor with an IC₅₀ of 34.1μg/mL.Mass spectrometry-based metabolomic analyses revealed widespread production of pseudochelin A among fractions possessing S. aureus antibiofilm properties.In addition, a key biosynthetic gene involved in producing pseudochelin A was detected on 30% of the moon snail egg collars and pseudochelin A is capable of inhibiting the formation of biofilms (IC₅₀ 19.5μg/mL) produced by ecol. relevant bacterial strains.All suggesting that pseudochelin A may have a role in shaping the microbiome or protecting the egg collars from microbiofouling.

Invasive fungal infections pose a serious threat to public health and are associated with high mortality and incidence rates. The development of novel antifungal agents is urgently needed. Based on hit-to-lead optimization, a series of 2,4,6-trisubstituted triazine hydrazone compounds were designed, synthesized, and biological evaluation was performed, leading to the identification of compound 28 with excellent in vitro synergy (FICI range: 0.094-0.38) and improved monotherapy potency against fluconazole-resistant Candida albicans and Candida auris (MIC range: 1.0-16.0 μg/mL). Moreover, 28 exhibited broad-spectrum antifungal activity against multiple pathogenic strains. Furthermore, 28 could inhibit hyphal and biofilm formation, which may be related to its ability to disrupt the fungal cell wall. Additionally, 28 significantly reduced the CFU in a mouse model of disseminated infection with candidiasis at a dose of 10 mg/kg. Overall, the triazine-based hydrazone compound 28 with low cytotoxicity, hemolysis, and favorable ADME/T characteristics represents a promising lead to further investigation.