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The rise of antimicrobial resistance remains one of the greatest global health threats facing humanity. Furthermore, the development of novel antibiotics has all but ground to a halt due to a collision of intersectional pressures. Herein we determine the antimicrobial efficacy for 14 structurally related supramolecular self-associating amphiphiles against clinically relevant Gram-positive methicillin resistant Staphylococcus aureus and Gram-negative Escherichia coli. We establish the ability of these agents to selectively target phospholipid membranes of differing compositions, through a combination of computational host:guest complex formation simulations, synthetic vesicle lysis, adhesion and membrane fluidity experiments, alongside our novel 1H NMR CPMG nanodisc coordination assays, to verify a potential mode of action for this class of compounds and enable the production of evermore effective next-generation antimicrobial agents. Finally, we select a 7-compound subset, showing two lead compounds to exhibit ‘druggable’ profiles through completion of a variety of in vivo and in vitro DMPK studies.

Celebrating Supramolecular Chemistry and Mentoring: ChemPlusChem is pleased to publish a Special Collection on Supramolecular Chemistry: Young Talents and their Mentors, guest-edited by Anna McConnell, Cally Haynes, Claudia Caltagirone, and Jennifer Hiscock. The Special Collection features recent developments in supramolecular chemistry and highlights mentoring relationships between emerging investigators and their mentors.

An unreported d,l-tripeptide self-assembled into gels that embedded FeII4L4 metal–organic cages to form materials that were characterized by TEM, EDX, Raman spectroscopy, rheometry, UV/Vis and NMR spectroscopy, and circular dichroism. The cage type and concentration modulated gel viscoelasticity, and thus the diffusion rate of molecular guests through the nanostructured matrix, as gauged by 19F and 1H NMR spectroscopy. When two different cages were added to spatially separated gel layers, the gel–cage composite material enabled the spatial segregation of a mixture of guests that diffused into the gel. Each cage selectively encapsulated its preferred guest during diffusion. We thus present a new strategy for using nested supramolecular interactions to enable the separation of small molecules., Un tripéptido d,l no informado se autoensambló en geles que incrustaron jaulas metalorgánicas de Fe II 4 L 4 para formar materiales que se caracterizaron por TEM, EDX, espectroscopia Raman, reometría, espectroscopia UV/Vis y NMR, y dicroísmo circular. El tipo de jaula y la concentración modularon la viscoelasticidad del gel y, por lo tanto, la tasa de difusión de los huéspedes moleculares a través de la matriz nanoestructurada, medida por 19 F y 1Espectroscopía de RMN H. Cuando se agregaron dos jaulas diferentes a capas de gel separadas espacialmente, el material compuesto de jaula de gel permitió la segregación espacial de una mezcla de invitados que se difundió en el gel. Cada jaula encapsuló selectivamente a su huésped preferido durante la difusión. Por lo tanto, presentamos una nueva estrategia para utilizar interacciones supramoleculares anidadas para permitir la separación de moléculas pequeñas.

A comprehensive experimental and theoretical investigation of the transmembrane chloride transport promoted by four series of squaramide derivatives, with different degrees of fluorination, number of convergent N–H binding units and conformational shapes, is reported. The experimental chloride binding and transport abilities of these small synthetic molecules in liposomes were rationalised with quantum descriptors and molecular dynamics simulations in POPC bilayers. The tripodal tren-based compounds, with three squaramide binding motifs, have high chloride affinity, isolating the anion from water molecules within the membrane model and preventing its release to the aqueous phase, in agreement with the absence of experimental transport activity. In contrast, the symmetrical monosquaramides, with moderate chloride binding affinity, are able to bind and release chloride either in the aqueous phase or at the membrane interface level, in line with experimentally observed high transport activity. The PMF profiles associated with the diffusion of these free transporters and their chloride complexes across phospholipid bilayers show that the assisted chloride translocation is thermodynamically favoured. ARC, FCT, CICECO, EPSRC, Royal Society, Wolfson Foundation

Simple, highly fluorinated receptors are shown to function as effective transmembrane anion transporters with the most active transporters rivalling the transport efficacy of natural anion transporter prodigiosin for chloride/bicarbonate antiport.

Despite extensive interest in transmembrane anion carriers (anionophores), the factors that govern activity are still only partly understood. Herein we report a study which identifies a new principle for anionophore design, that of “lipophilic balance”. A series of simple thioureas with identical molecular formulae has been prepared and assayed for chloride/nitrate transport activity in synthetic vesicles. The molecules differ only in the positioning of the phenylthiourea binding unit within an 11-carbon linear chain. They are shown to possess very similar lipophilicities and anion affinities, while a test for leaching establishes that they locate almost exclusively in the vesicle membranes. Notwithstanding their close similarities, activities across the series show >5-fold variation, peaking when the phenylthiourea group is centrally located. The results suggest that transport is favoured by a balanced array of lipophilic substituents, possibly because this arrangement facilitates transfer of the complexed anion into the apolar membrane interior., info:eu-repo/semantics/published

Highly potent but structurally simple transmembrane anion transporters are reported that function at receptor to lipid ratios as low as 1 : 1 000 000. The compounds, based on the simple ortho-phenylenediamine-based bisurea scaffold, have been studied for their ability to facilitate chloride/nitrate and chloride/bicarbonate antiport, and HCl symport processes using a combination of ion selective electrode and fluorescence techniques. In addition, the transmembrane transport of dicarboxylate anions (maleate and fumarate) by the compounds was examined. Molecular dynamics simulations showed that these compounds permeate the membrane more easily than other promising receptors corroborating the experimental efflux data. Moreover, cell based assays revealed that the majority of the compounds showed cytotoxicity in cancer cells, which may be linked to their ability to function as ion transporters.

Two differently protected aldehydes, A and B, were demonstrated to deprotect selectively through the application of light and heat, respectively. In the presence of iron(II) and a triamine, two distinct FeII4L4 cages, 1 and 2, were thus observed to form from the deprotected A and B, respectively. The alkyl tails of B and 2 render them preferentially soluble in cyclopentane, whereas A and 1 remain in acetonitrile. The stimulus applied (either light or heat) thus determines the outcome of self-assembly and dictates whether the cage and its ferrocene cargo remain in acetonitrile, or transport into cyclopentane. Cage self-assembly and cargo transport between phases can in this fashion be programmed using orthogonal stimuli.