Membrane Adaptations and Cellular Responses of Sulfolobus acidocaldarius to the Allylamine Terbinafine

Abstract

Cellular membranes are essential for compartmentalization, maintenance of permeability, and fluidity in all three domains of life. Archaea belong to the third domain of life and have a distinct phospholipid composition. Membrane lipids of archaea are ether-linked molecules, specifically bilayer-forming dialkyl glycerol diethers (DGDs) and monolayer-forming glycerol dialkyl glycerol tetraethers (GDGTs). The antifungal allylamine terbinafine has been proposed as an inhibitor of GDGT biosynthesis in archaea based on radiolabel incorporation studies. The exact target(s) and mechanism of action of terbinafine in archaea remain elusive. Sulfolobus acidocaldarius is a strictly aerobic crenarchaeon thriving in a thermoacidophilic environment, and its membrane is dominated by GDGTs. Here, we comprehensively analyzed the lipidome and transcriptome of S. acidocaldarius in the presence of terbinafine. Depletion of GDGTs and the accompanying accumulation of DGDs upon treatment with terbinafine were growth phase-dependent. Additionally, a major shift in the saturation of caldariellaquinones was observed, which resulted in the accumulation of unsaturated molecules. Transcriptomic data indicated that terbinafine has a multitude of effects, including significant differential expression of genes in the respiratory complex, motility, cell envelope, fatty acid metabolism, and GDGT cyclization. Combined, these findings suggest that the response of S. acidocaldarius to terbinafine inhibition involves respiratory stress and the differential expression of genes involved in isoprenoid biosynthesis and saturation.

Archaea membranes in response to extreme acidic environments

“…Macrocyclic conformation per se has a condensation effect on membranes (Bulacu et al, 2012). In both GDGT and GDNT, up to four cyclopentane rings can be synthesized in each biphytanyl chain (Rao et al, 2023). The average number and distribution of cyclopentane rings in the isoprenoid chains depend upon the growth temperature (De Rosa et al, 1980), pH (Shimada et al, 2008;Boyd et al, 2011;Chiu et al, 2023), growth rate (Quehenberger et al, 2020) and growth phase (Jensen et al, 2015;Chiu et al, 2023).…”

“…Therefore, BTL membranes are "durable" (rigid and tight) yet "liquid" (Chugunov et al, 2014). In short, BTL membranes exhibit tight and rigid packing in both the hydrophobic core and the polar headgroup regions, yet, they have certain fluidity for membrane functions which together contribute significantly to thermoacidophilic archaea's capability to thrive in extreme environments such as low pHs [recently reviewed in (Rao et al, 2023;Řezanka et al, 2023)].…”

Transcriptome Analysis Reveals the Important Role of Vitamin B12 in the Response of Natronorubrum daqingense to Salt Stress

“…(2) Microorganisms modify the cellular membrane permeability by adjusting the composition and ratio of membrane lipid constituents within cell membranes to enhance their adaptability to high-salinity environments [5,6]. (3) Accumulation of compatible solutes is one of the main mechanisms by which halophilic microorganisms tolerate osmotic stress, which is mainly achieved by ingesting compatible solutes from a medium or synthesizing them intracellularly.…”

Characterization of Two Na+(K+, Li+)/H+ Antiporters from Natronorubrum daqingense

“…In environments with a high salt concentration, the damage of Na + stress to organisms is mainly manifested as water loss, ion toxicity, and imbalance in osmotic pressure. In order to adapt to the toxicity, microorganisms have formed three major salt tolerance mechanisms: (1) microorganisms change the permeability of their cell membranes to adapt to high-salinity environments by changing the proportion of membrane lipid components in the cell membrane [ 1 , 2 ]; (2) microorganisms accumulate a high concentration of compatible substances within cells as osmotic regulators to maintain osmotic balance [ 3 ]; (3) microorganisms extrude Na + from cells while accumulating KCl to maintain an osmotic balance within the cells [ 4 ]. These proteins are named Na + /H + exchangers (NHEs) [ 5 ], can extrude Na + , and can be divided into primary Na + pumps [ 6 ] and secondary Na + /H + pumps [ 7 ].…”