Nanoarchitectonics-based model membrane platforms for probing membrane-disruptive interactions of odd-chain antimicrobial lipids

Abstract

The use of nanoscience tools to investigate how antimicrobial lipids disrupt phospholipid membranes has greatly advanced molecular-level biophysical understanding and opened the door to new application possibilities. Until now, relevant studies have focused on even-chain antimicrobial lipids while there remains an outstanding need to investigate the membrane-disruptive properties of odd-chain antimicrobial lipids that are known to be highly biologically active. Herein, using the quartz crystal microbalance-dissipation (QCM-D) and electrochemical impedance spectroscopy (EIS) techniques, we investigated how an 11-carbon, saturated fatty acid and its corresponding monoglyceride—termed undecanoic acid and monoundecanoin, respectively—disrupt membrane-mimicking phospholipid bilayers with different nanoarchitectures. QCM-D tracking revealed that undecanoic acid and monoundecanoin caused membrane tubulation and budding from supported lipid bilayers, respectively, and were only active above their experimentally determined critical micelle concentration (CMC) values. Monoundecanoin was more potent due to a lower CMC and electrochemical impedance spectroscopy (EIS) characterization demonstrated that monoundecanoin caused irreversible membrane disruption of a tethered lipid bilayer platform at sufficiently high compound concentrations, whereas undecanoic acid only induced transient membrane disruption. This integrated biophysical approach also led us to identify that the tested 11-carbon antimicrobial lipids cause more extensive membrane disruption than their respective 12-carbon analogues at 2 × CMC, which suggests that they could be promising molecular components within next-generation antimicrobial nanomedicine strategies.

Structure‐Activity Relationship Study to Develop Peptide Amphiphiles as Species‐Specific Antimicrobials

“…[18] For the hydrophobic core of the nanostructures, we explored alkyl tails with different lengths (14 to 18 carbons) and odd or even number of carbons. Alkyl chain with an odd number of carbons have been reported to have membranedisruptive properties [19] and increased antifungal activity. [20] Furthermore, since unsaturated alkyl tails have been shown to exhibit more potent bactericidal, higher biological stability, and selectivity to bacteria [21,22] some PAs (PA 7, PA 10, PA 32, and PA 33) contained such modification.…”

Membrane-Disruptive Effects of Fatty Acid and Monoglyceride Mitigants on E. coli Bacteria-Derived Tethered Lipid Bilayers

“…Herein, we conducted EIS measurements to comparatively evaluate the membrane-disruptive effects of medium-chain fatty acid and monoglyceride mitigants on E. coli tBLM platforms. Our approach builds on recent efforts to study antimicrobial lipid and detergent interactions with simplified tBLM platforms [ 28 , 29 , 30 ] and extends the measurement concept to investigate how various biologically important antimicrobial mitigants interact with reconstituted E. coli lipid membranes. As depicted in Figure 1 A, we selected two pairs of medium-chain fatty acids and monoglycerides—the 10-carbon long capric acid (CA) fatty acid and its monoglyceride equivalent monocaprin (MC), and the 12-carbon long lauric acid (LA) fatty acid and its monoglyceride equivalent glycerol monolaurate (GML)—for EIS testing because these mitigants are among the most potent, membrane-disruptive ones against Gram-positive bacteria [ 31 ], yet have varying levels of antibacterial activity against Gram-negative bacteria such as E. coli .…”