ß-Cyclodextrin Encapsulation of Synthetic AHLs: Drug Delivery Implications and Quorum-Quenching Exploits.

Many bacteria, such as Pseudomonas aeruginosa, regulate phenotypic switching in a population density-dependent manner through a phenomenon known as quorum sensing (QS). For Gram-negative bacteria, QS relies on the synthesis, transmission, and perception of low-molecular-weight signal molecules that are predominantly N-acyl-l-homoserine lactones (AHLs). Efforts to disrupt AHL-mediated QS have largely focused on the development of synthetic AHL analogues (SAHLAs) that are structurally similar to native AHLs. However, like AHLs, these molecules tend to be hydrophobic and are poorly soluble under aqueous conditions. Water-soluble macrocycles, such as cyclodextrins (CDs), that encapsulate hydrophobic guests have long been used by both the agricultural and pharmaceutical industries to overcome the solubility issues associated with hydrophobic compounds of interest. Conveniently, CDs have also demonstrated anti-AHL-mediated QS effects. Here, using fluorescence spectroscopy, NMR spectrometry, and mass spectrometry, we evaluate the affinity of SAHLAs, as well as their hydrolysis products, for ß-CD inclusion. We also evaluated the ability of these complexes to inhibit wild-type P. aeruginosa virulence in a Caenorhabditis elegans host infection study, for the first time. Our efforts confirm the potential of ß-CDs for the improved delivery of SAHLAs at the host/microbial interface, expanding the utility of this approach as a strategy for probing and controlling QS.

Molybdenum(VI)-Catalyzed Rearrangement of Prebiotic Carbohydrates in Formamide, a Candidate Prebiotic Solvent.

It has been four decades since formamide was first suggested to perform roles as a precursor and/or a solvent in prebiotic chemistry. However, little work has sought to integrate formamide into larger prebiotic schemes that might create prebiotic RNA, often proposed to have been the first Darwinian biopolymer. Here, we report that formamide can be used as a solvent to perform the Bílik reaction, which uses molybdenum(VI) oxo species as catalysts at near-neutral pH to rearrange branched carbohydrates to give linear carbohydrates; the branched carbohydrates are produced from formaldehyde (HCHO) in alkaline mixtures containing borate, whereas the linear carbohydrates are the precursors needed for ribonucleosides and ribonucleotides. Under conditions wherein the Bílik reaction does this rearrangement, carbohydrate reaction products do not require stabilization by borate. These results, therefore, connect aqueous and formamide-based processes for the prebiotic formation of RNA components. Based on data from Hadean zircons that show that the mantle of the early Earth was near the fayalite-quartz-magnetite fugacity, molybdenum in its 6+ oxidation state was likely available in the Hadean. Together, these allow us to conjecture a process that delivers ribonucleosides and ribonucleotides from hydrogen cyanide and HCHO from a Hadean atmosphere on a Hadean geosphere, without needing precisely timed transitions from one solvent system to the other.