Eichler, Barrett

• Postdoctoral Fellow, University of California, Davis 

• Ph.D., Inorganic Chemistry, University of Wisconsin, Madison 

• B.A., Chemistry, University of Minnesota-Morris

Infectious diseases are one of the top five health challenges* facing humanity. Within the category of infectious diseases, antibiotic resistance is an increasingly threatening problem globally. Novel antimicrobial compounds are always needed to kill bacteria and yeast on surfaces and in solutions. Some antimicrobial compounds, such as cetylpyridinium chloride and benzalkonium chloride, have been used commercially for over 100 years. These antiseptic compounds are known as quaternary ammonium compounds (QACs). QACs work by disrupting the cell membranes of bacteria and yeast.

Cell membranes are phospholipid bilayers that have a hydrophilic head – hydrophobic tail-type structure (Fig.

1a). Most, if not all, antimicrobials that have been designed and reported have a “floppy” hydrophobic region,

which is meant to mimic the hydrophobic portion of the phospholipid bilayer, but also destroy the integrity of the bilayer by creating imperfections and therefore allowing water and other chemicals to leak into the interior and causing cells to lyse, thereby killing the cell.

We propose the hypothesis that if rigid, linear diarylacetylenes are turned into dicationic QACs, with each cation at opposite ends of the molecule (Fig. 1b), they will be more effective than currently used antimicrobials at disrupting the lipid bilayer because a hydrophilic positive charge must be forced down into the hydrophobic layer. This should be more effective at disrupting the cell membrane (Fig. 1c) than the “floppy” surfactants, which can bend to put all the ionic disruption toward the outside of the cell membrane, thus making them less effective than the proposed rigid surfactants. In 2023, we began to make rigid diarylacetyelene-based QACs using copper-assisted azide-alkyne click (CuAAC) chemistry. We previously published a synthetic method to efficiently synthesize symmetric diarylacetylenes, and this method, when combined with click chemistry, was used to make 1,2,3-triazoles, which are converted into QACs with benzyl bromide derivatives (Fig. 2). These compounds are tested using assays to determine their minimum inhibitory concentration (MIC) antibiotic properties versus gram-positive bacteria, gram-negative bacteria, and yeast/ derivatives.

*NIH…Turning discovery into health. https://www.nih.gov/about-nih/what-we-do/nih-turning-discovery-into-health/our-biggest-health-challenges, accessed 10/28/24.