Repurposing host-guest chemistry to sequester virulence and eradicate biofilms in multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii

Abstract

The limited diversity in targets of available antibiotic therapies has put tremendous pressure on the treatment of bacterial pathogens, where numerous resistance mechanisms that counteract their function are becoming increasingly prevalent. Here, we utilize an unconventional anti-virulence screen of host-guest interacting macrocycles, and identify a water-soluble synthetic macrocycle, Pillar[5]arene, that is non-bactericidal/bacteriostatic and has a mechanism of action that involves binding to both homoserine lactones and lipopolysaccharides, key virulence factors in Gram-negative pathogens. Pillar[5]arene is active against Top Priority carbapenem- and third/fourth-generation cephalosporin-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, suppressing toxins and biofilms and increasing the penetration and efficacy of standard-of-care antibiotics in combined administrations. The binding of homoserine lactones and lipopolysaccharides also sequesters their direct effects as toxins on eukaryotic membranes, neutralizing key tools that promote bacterial colonization and impede immune defenses, both in vitro and in vivo. Pillar[5]arene evades both existing antibiotic resistance mechanisms, as well as the build-up of rapid tolerance/resistance. The versatility of macrocyclic host-guest chemistry provides ample strategies for tailored targeting of virulence in a wide range of Gram-negative infectious diseases.

Pillar[n]arenes in the Fight against Biofilms: Current Developments and Future Perspectives

“…(c) Schematic representation of HSL quorum sensing in Gram-negative bacteria (left), along with a virulence inhibition approach (right). Adapted from ref , which is an open access article distributed under the Creative Commons Attribution License (CC-BY 4.0), Springer Nature.…”

“…By inhibition of quorum sensing molecules through hydrogen bonding or other interactions, pillar­[ n ]­arenes can impede the formation of biofilms. Recently, Linder and their team conducted research with the objective of utilizing host–guest chemistry to combat bacterial virulence and eradicate biofilms, particularly in the context of multidrug-resistant P. aeruginosa and Acinetobacter baumannii . To explore potential interactions between cavity-containing macrocycles and bacterial signaling molecules, the authors screened a diverse family of macrocycles such as crown ethers, calix­[ n ]­arenes, resorcin­[ n ]­arenes, cucurbit­[ n ]­uril, cyclodextrins, and pillar[5]­arene with varying inner cavity sizes (1.5–11.7 Å) and molecular weights (172–2260 g/mol).…”

Macrocycle-Based Antibacterial Materials

“…Due to the dynamic and reversible noncovalent interactions, versatile host–guest recognition abilities, and stimuli-responsive features, supramolecular materials are favorable for fabricating smart platforms in various fields of science and technology. − A growing number of macrocycle-based materials have begun to play a remarkable role in combating bacterial infections, disrupting biofilms, and fighting against AMR, which effectively addressed some limitations impeding traditional antibiotics for clinical applications. ,− Although some related excellent reviews are available for readers’ perusal, they generally summarized the early advancements of macrocycle-based antibacterial materials based on different types of synthetic macrocycles, including crown ethers, cyclodextrins (CDs), cucurbiturils (CBs), calixarenes, pillararenes, and other macrocyclic molecules . These reviews afford a deeper understanding of the design of supramolecular antibacterial materials with macrocyclic skeletons.…”

Calculating Binding Free Energies in Model Host–Guest Systems with Unrestrained Advanced Sampling

“…5−7 These host−guest interactions are crucial to a variety of biological 5,8 and chemical processes, 9 including catalysis, 10,11 sensor design, 12,13 and molecular sequestration from solution. 14,15 It is crucial for the design of new materials and pharmaceuticals to have reliable knowledge of the degree of association between the host and guest, as captured by standard binding free energies. Large, negative binding free energies ΔG°indicate thermodynamically stable host−guest associations.…”

“…Host–guest systems are a particular class of binding interactions where one molecule (the host) contains a cavity into which a second molecule (the guest) inserts. − The interactions can involve significant specificity in matching molecular shapes and charge distributions and often lead to strong and selective interactions between the host and guest. − These host–guest interactions are crucial to a variety of biological , and chemical processes, including catalysis, , sensor design, , and molecular sequestration from solution. , …”