Significance: There is a critical lack of therapeutic agents to treat infections caused by nongrowing persister forms of methicillin-resistant Staphylococcus aureus (MRSA). Although membrane-disrupting agents can kill persister cells, their therapeutic potential has been mostly overlooked because of low selectivity for bacterial versus mammalian membranes. We report that the clinically approved anthelmintic drug bithionol kills MRSA persisters by disrupting membrane lipid bilayers at concentrations that exhibit low levels of toxicity to mammalian cells. The selectivity of bithionol results from the presence of cholesterol in mammalian but not in bacterial membranes. We also show that the antipersister potency of membrane-active antimicrobial agents correlates with their ability to increase membrane fluidity. Our results significantly enhance our understanding of bacterial membrane disruption and membrane selectivity.

The ongoing SARS-CoV-2 pandemic has highlighted the importance of the rapid development of vaccines and antivirals. However, the potential for the emergence of antibiotic resistances due to the increased use of antibacterial cleaning products and therapeutics presents an additional, underreported threat. Most antibacterial cleaners contain simple quaternary ammonium compounds (QACs); however, these compounds are steadily becoming less effective as antibacterial agents. QACs are extensively used in SARS-CoV-2-related sanitization in clinical and household settings. Similarly, due to the danger of secondary infections, antibiotic therapeutics are increasingly used as a component of COVID-19 treatment regimens, even in the absence of a bacterial infection diagnosis. The increased use of antibacterial agents as cleaners and therapeutics is anticipated to lead to novel resistances in the coming years.

Efficient construction of architecturally complex natural and unnatural products is the hallmark of organic chemistry. Anion relay chemistry (ARC)—a multi-component coupling protocol—has the potential to provide the chemist with a powerful synthetic tactic, enabling efficient, rapid elaboration of structurally complex scaffolds in a single operation with precise stereochemical control. The ARC tactic can be subdivided into two main classes, comprising the relay of negative charge either through bonds or through space, the latter with aid of a transfer agent. This review will present the current state of through-space anion relay, in conjunction with examples of natural and unnatural product syntheses that illustrate the utility of this synthetic method.