We
present self-assembled Pickering emulsions containing biocidal
phytochemical oils (carvacrol and terpinen-4-ol) and β-cyclodextrin
able to potentiate the antimicrobial and antibiofilm activity of miconazoctylium
bromide. The carvacrol-containing emulsion is 2-fold more sensitive
against C. albicans and S. aureus and highly active against E. coli, compared to
the commercial cream containing miconazole nitrate. Moreover, this
emulsion shows a synergistic effect against fungi, additive responses
against bacteria, and remarkable staphylococcal biofilm eradication.
These results are associated with membrane permeabilization, enzymes
inhibition, and the accumulation of reactive oxygen species in microorganisms.
The frequency of poor outcomes in relapsed leukemia patients underscores the need for novel therapeutic approaches. The FDA-approved immunosuppressant FTY720 limits leukemia progression by activating protein phosphatase 2A and restricting nutrient access. Unfortunately, FTY720 cannot be re-purposed for use in cancer patients due to on-target toxicity associated with S1P receptor activation at the elevated, anti-neoplastic dose. Here we show that the constrained azacyclic FTY720 analog SH-RF-177 lacks S1P receptor activity but maintains anti-leukemic activity in vitro and in vivo. SH-RF-177 was not only more potent than FTY720, but killed via a distinct mechanism. Phosphorylation is dispensable for FTY720’s anti-leukemic actions. However, chemical biology and genetic approaches demonstrated that the sphingosine kinase 2- (SPHK2) mediated phosphorylation of SH-RF-177 led to engagement of a pro-apoptotic target and increased potency. The cytotoxicity of membrane-permeant FTY720 phosphonate esters suggests that the enhanced potency of SH-RF-177 stems from its more efficient phosphorylation. The tight inverse correlation between SH-RF-177 IC50 and SPHK2 mRNA expression suggests a useful biomarker for SH-RF-177 sensitivity. In summary, these studies indicate that FTY720 analogs that are efficiently phosphorylated but fail to activate S1P receptors may be superior anti-leukemic agents compared to compounds that avoid cardiotoxicity by eliminating phosphorylation.
We designed and synthesized miconazole analogues containing a substituted imidazolium moiety. The structural modification of the miconazole led to a compound with high potency to prevent the formation and disrupt bacterial biofilms, as a result of accumulation in the biofilm matrix, permeabilization of the bacterial membrane and generation of reactive oxygen species in the cytoplasm.
The increased prevalence of antibiotic‐resistant bacteria is a critical issue for human health. Developing new antibiotic agents is vital for fighting persistent infections and lowering mortality rates. In this study, we designed lutidine‐disubstituted bis‐benzimidazolium salts (lutidine‐bis‐benzimidazolium core with octyl, adamantyl, and cholesteryl lipophilic side chains), and tested their antimicrobial activity, their capacity to inhibit planktonic bacterial and fungal growth, and their ability to inhibit the formation of or disrupt mature methicillin‐resistant Staphylococcus aureus (MRSA) biofilms. The antibiofilm activity of these salts was analyzed in terms of their lipophilicity, capacity to induce transmembrane ion transport, perturbation of the cellular membrane, and mechanism of action in the phospholipid bilayer. The synthesized compounds were not active against MRSA biofilms, as the formation of transmembrane channels had no effect on the integrity of the extracellular polymeric substance matrix and only octyl and adamantyl derivatives possessed the capacity to inhibit biofilm formation. The synthesized derivatives could be used as lead candidates for the development of anti‐MRSA agents.
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