ABSTRACT The emergence of multidrug-resistant Candidozyma auris has created an urgent need for antifungals with novel mechanisms of action. We screened 121 nucleoside and nucleobase derivatives against C. auris and other clinically relevant Candida species to identify effective antimetabolite scaffolds. Among all compounds tested, only the C-5-fluorinated nucleosides 5-fluorouridine (5-FU) and 5-fluorocytidine exhibited potent antifungal activity. 5-FU demonstrated consistently low minimum inhibitory concentrations (0.5–10 µg/mL) across multiple Candida species, including fluconazole-resistant strains, and displayed fungicidal activity against C. auris at concentrations lower than several frontline antifungals. Uridine rescue assays confirmed competitive interference with endogenous uridine metabolism. Checkerboard assays revealed synergistic or additive interactions between 5-FU and clinically used azoles and echinocandins. Toxicity evaluation using plant, nematode, and human cell models showed minimal cytotoxicity even at concentrations far exceeding antifungal minimum inhibitory concentrations. In silico docking analyses revealed dual inhibition of thymidylate synthase and RNA polymerase III, explaining the fungicidal phenotype and broad-spectrum efficacy. These findings identify 5-fluorouridine as a promising antifungal candidate and establish C-5-halogenated nucleosides as a privileged scaffold for antifungal drug development.
Bharath Reddy Boya, Ezhaveni Sathiyamoorthi, Jin-Hyung Lee et al.· Antimicrobial Agents and Che...· 0 citations
Candida albicans biofilms are a major cause of persistent infections and contribute to antifungal resistance as well as limitations in drug delivery. Targeting virulence traits such as biofilm formation and hyphal transition represents an effective strategy for controlling fungal pathogenicity without exerting strong selective pressure on planktonic growth. In this study, a library of structurally diverse benzophenone derivatives was screened to identify compounds with antibiofilm and anti-hyphal activities against azole-resistant C. albicans. Most benzophenone derivatives exhibited weak antifungal activity (MIC ≥ 200 µg/mL). However, several halogenated benzophenones markedly suppressed biofilm formation. Among them, decafluorobenzophenone at 10 µg/mL displayed the strongest inhibition, reducing biofilm formation to approximately 1–2% of control levels while maintaining substantial planktonic cell viability. Microscopy confirmed hyphal suppression, while qRT-PCR showed a 36-fold reduction in ALS3 expression. These findings indicate that multi-halogenated benzophenones act primarily as anti-virulence agents targeting biofilm formation and hyphal development. Molecular docking suggested a possible interaction of decafluorobenzophenone with the Als3 binding pocket. Decafluorobenzophenone showed low toxicity, with unaffected Caenorhabditis elegans viability at 10 µg/mL, plant germination at 100 µg/mL, and only slight hemolysis at 100 µg/mL. The results highlight halogen substitution as a key structural determinant and identify benzophenone scaffolds as promising leads for developing novel antibiofilm strategies against azole-resistant Candida infections.
Juyeon Jo, Ziyad Abdelaal, Yong-Guy Kim et al.· International Journal of Mol...· 0 citations
Biofilm-associated Staphylococcus aureus infections remain difficult to treat using conventional antibiotics. Herein, we report the synthesis and biological evaluation of lauric acid- and BDSF-derived N-acyl sulfonamides as antibiofilm and antivirulence agents. Structure-activity relationship (SAR) analysis identified 4-tert-butylphenyl sulfonyldodecenamide (59) as a lead compound with a minimum inhibitory concentration of 5 μg/mL and >60% inhibition of MSSA and MRSA biofilm formation at sub-minimum inhibitory concentration levels. Microscopy confirmed marked reductions in biofilm biomass and thickness. The lead compound synergized with gentamicin and tobramycin, suppressed hemolysis, slime production, metabolic activity, and cell-surface hydrophobicity, and induced intracellular reactive oxygen species. qRT-PCR revealed downregulation of key virulence regulators (agrA, RNAIII, saeR, and seb), indicating disruption of quorum-sensing circuitry. SAR modeling rationalized steric and electronic requirements for activity. Low toxicity in plant, nematode, and mammalian models highlights bioisosteric N-acyl sulfonamides as promising antivirulence scaffolds for combating S. aureus biofilm infections.
Yong-Guy Kim, Michelle O'Driscoll, Conor Horgan et al.· Journal of Medicinal Chemist...· 0 citations
Acne vulgaris is a chronic inflammatory skin disorder in which Cutibacterium acnes contributes to disease persistence through biofilm formation, lipid metabolism, and production of inflammatory metabolites within the pilosebaceous unit. Targeting bacterial physiological pathways that sustain these processes represents a potential therapeutic strategy beyond conventional antibiotic approaches. In this study, we evaluated a panel of halogenated indole derivatives and identified 6-bromo-4-iodoindole as a potent inhibitor of C. acnes growth and biofilm formation. The compound exhibited a minimum inhibitory concentration of 20 μg/mL and disrupted biofilm architecture. Further analyses revealed that treatment markedly altered several virulence-associated phenotypes, including reductions in extracellular lipase activity, cell-surface hydrophobicity, extracellular polymeric substance production, and porphyrin levels, accompanied by increased intracellular reactive oxygen species. Because lipase activity plays a central role in sebum metabolism and follicular colonization by C. acnes, molecular docking was performed to evaluate potential target engagement. Docking simulations suggested that 6-bromo-4-iodoindole occupies the catalytic pocket of C. acnes triacylglycerol lipase, providing a structural basis for the observed suppression of lipase-dependent phenotypes. Importantly, the compound retained biofilm inhibitory activity in polymicrobial C. acnes + Staphylococcus aureus biofilms, exhibited broad-spectrum growth inhibition extending to S. epidermidis, and significantly reduced bacterial recovery in an ex vivo porcine skin model. In silico pharmacokinetic analyses further indicated physicochemical properties compatible with localized topical delivery. Together, these findings demonstrate that a dihalogenated indole reduces lipase-associated virulence related phenotypes in C. acnes and suppresses biofilm formation in skin-relevant environments, supporting further investigation of this scaffold as a therapeutic strategy targeting acne-associated microbial physiology.
S. Angulmaduwa, G.G. Roshan Pradeep Ratupaskatiye, Yong-Guy Kim et al.· Microbial Pathogenesis· 0 citations