An official website of the United States government
Abstract The World Health Organization has described the antimicrobial resistance crisis as one of the top ten global public health threats. New antimicrobial agents that can fight infections caused by antimicrobial resistant pathogens are therefore needed. A potential strategy is the development of small molecules that can selectively interact with bacterial membranes (or membranes of other microbial pathogens), and thereby rapidly kill the bacteria. Here, we report the structure‐activity relationship within a group of 22 compounds that were designed to bind the bacterial lipid phosphatidylethanolamine (PE). Liposome‐based studies reveal that the lipophilicity of the compounds has the strongest effect on both the affinity and selectivity for PE. The best results were obtained for compounds with logP≈3.75, which showed a 5x–7x selectivity for bacterial PE lipids over human PC (phosphatidylcholine) lipids. Furthermore, these compounds also showed potent antibacterial activity against the Gram‐positive bacteriumB. cereus, with minimum inhibitory concentrations (MICs) below 10 μM, a concentration where they showed minimal hemolytic activity against human red blood cells. These results not only show the possibility of PE‐binding small molecules to function as antibiotics, but also provide guidelines for the development of compounds targeting other types of biologically relevant membrane lipids.
more »
« less
Impact of Tralopyril and Triazolyl Glycosylated Chalcone in Human Retinal Cells’ Lipidome
Antifouling (AF) coatings containing booster biocides are used worldwide as one of the most cost-effective ways to prevent the attachment of marine organisms to submerged structures. Nevertheless, many of the commercial biocides, such as Econea® (tralopyril), are toxic in marine environments. For that reason, it is of extreme importance that new efficient AF compounds that do not cause any harm to non-target organisms and humans are designed. In this study, we measured the half-maximal inhibitory concentration (IC50) of a promising nature-inspired AF compound, a triazolyl glycosylated chalcone (compound 1), in an immortalized human retinal pigment epithelial cell line (hTERT-RPE-1) and compared the results with the commercial biocide Econea®. We also investigated the effects of these biocides on the cellular lipidome following an acute (24 h) exposure using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF/MS). Our results showed that compound 1 did not affect viability in hTERT-RPE-1 cells at low concentrations (1 μM), in contrast to Econea®, which caused a 40% reduction in cell viability. In total, 71 lipids were found to be regulated upon exposure to 10 µM of both compounds. Interestingly, both compounds induced changes in lipids involved in cell death, membrane modeling, lipid storage, and oxidative stress, but often in opposing directions. In general, Econea® exposure was associated with an increase in lipid concentrations, while compound 1 exposure resulted in lipid depletion. Our study showed that exposure to human cells at sublethal Econea® concentrations results in the modulation of several lipids that are linked to cell death and survival.
more »
« less
- Award ID(s):
- 2112201
- PAR ID:
- 10646921
- Publisher / Repository:
- MDPI
- Date Published:
- Journal Name:
- Molecules
- Volume:
- 27
- Issue:
- 16
- ISSN:
- 1420-3049
- Page Range / eLocation ID:
- 5247
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Invasive candidiasis (IC) remains as a major cause of morbidity and mortality in critically ill patients. Amphotericin B (AmB) is one of the most effective antifungal agents commonly used to treat this infection. However, it induces severe side effects such as nephrotoxicity, cardiac alterations, nausea, fever, and liver damage. The utilization of drug delivery systems has been explored to overcome these limitations. Several AmB lipid formulations have been developed and are currently available in the market. Although they have the ability to reduce the main side effects of free AmB, their high cost, necessity of repeated intravenous injections for successful treatment, and incidence of pulmonary toxicity have limited their use. In the last decades, alginate has gained significant interest in drug delivery applications as a cost-effective strategy to improve the safety and therapeutic effect of toxic drugs. In this work, the clinically relevant drug AmB was encapsulated into alginate microparticles using the emulsification/external gelation method. We hypothesize that this synthesis strategy may positively impact the antifungal efficacy of AmB-loaded MCPs toward Candida albicans cells while reducing the toxicity in human lung cells. To prove this hypothesis, the ability of the microplatform to disrupt the cellular membrane potential was tested and its antifungal effectiveness toward Candida albicans cells was evaluated using the cell counting and plate count methods. Moreover, the toxicity of the microplatform in human lung cells was evaluated using CellTiter 96® AQueous cell viability assay and qualitative diffusion analysis of acridine orange. Our results demonstrated that the platform developed in this work was able to induce antifungal toxicity against Candida albicans yeast cells at the same level of free AmB with minimal toxicity to lung cells, which is one of the main side effects induced by commercial drug delivery systems containing AmB. Overall, our data provides convincing evidence about the effectiveness of the alginate-based microplatform toward Candida albicans cells. In addition, this vehicle may not require several infusions for a successful treatment while reducing the pulmonary toxic effect induced by commercial lipid formulations.more » « less
-
null (Ed.)Abstract The plasma membrane of eukaryotic cells is asymmetric with respect to its phospholipid composition. Analysis of the lipid composition of the outer leaflet is important for understanding cell membrane biology in health and disease. Here, a method based on cyclodextrin-mediated lipid exchange to characterize the phospholipids in the outer leaflet of red blood cells (RBCs) is reported. Methyl-α-cyclodextrin, loaded with exogenous lipids, was used to extract phospholipids from the membrane outer leaflet, while delivering lipids to the cell to maintain cell membrane integrity. Thin layer chromatography and lipidomics demonstrated that the extracted lipids were from the membrane outer leaflet. Phosphatidylcholines (PC) and sphingomyelins (SM) were the most abundant phospholipids in the RBCs outer leaflet with PC 34:1 and SM 34:1 being the most abundant species. Fluorescence quenching confirmed the delivery of exogenous lipids to the cell outer leaflet. The developed lipid exchange method was then used to remove phosphatidylserine, a phagocyte recognition marker, from the outer leaflet of senescent RBCs. Senescent RBCs with reconstituted membranes were phagocytosed in significantly lower amounts compared to control cells, demonstrating the efficiency of the lipid exchange process and its application in modifying cell–cell interactions.more » « less
-
null (Ed.)Peptides that form nanoscale pores in lipid bilayers have potential applications in triggered release, but only if their selectivity for target synthetic membranes over bystander biomembranes can be optimized. Previously, we identified a novel family of α-helical pore-forming peptides called “macrolittins”, which release macromolecular cargoes from phosphatidylcholine (PC) liposomes at concentrations as low as 1 peptide per 1000 lipids. In this work, we show that macrolittins have no measurable cytolytic activity against multiple human cell types even at high peptide concentration. This unprecedented selectivity for PC liposomes over cell plasma membranes is explained, in part, by the sensitivity of macrolittin activity to physical chemical properties of the bilayer hydrocarbon core. In the presence of cells, macrolittins release all vesicle-entrapped cargoes (proteins and small molecule drugs) which are then readily uptaken by cells. Triggered release occurs without any direct effect of the peptide on the cells, and without vesicle–vesicle or vesicle–cell interactions.more » « less
-
The emerging fungal amphibian pathogen, Batrachochytrium salamandrivorans (Bsal), is currently spreading across Europe and given its estimated invasion potential, has the capacity to decimate salamander populations worldwide. Fungicides are a promising in situ management strategy for Bsal due to their ability to treat the environment and infected individuals. However, antifungal drugs or pesticides could adversely affect the environment and non-target hosts, thus identifying safe, effective candidate fungicides for in situ treatment is needed. Here, we estimated the inhibitory fungicidal efficacy of five plant-derived fungicides (thymol, curcumin, allicin, 6-gingerol, and Pond Pimafix®) and one chemical fungicide (Virkon® Aquatic) against Bsal zoospores in vitro. We used a broth microdilution method in 48-well plates to test the efficacy of six concentrations per fungicide on Bsal zoospore viability. Following plate incubation, we performed cell viability assays and agar plate growth trials to estimate the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of each fungicide. All six fungicides exhibited inhibitory and fungicidal effects against Bsal growth, with estimated MIC concentrations ranging from 60 to 0.156 μg/mL for the different compounds. Allicin showed the greatest efficacy (i.e., lowest MIC and MFC) against Bsal zoospores followed by curcumin, Pond Pimafix®, thymol, 6-gingerol, and Virkon® Aquatic, respectively. Our results provide evidence that plant-derived fungicides are effective at inhibiting and killing Bsal zoospores in vitro and may be useful for in situ treatment. Additional studies are needed to estimate the efficacy of these fungicides at inactivating Bsal in the environment and treating Bsal-infected amphibians.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/molecules27165247
