Design Guidelines for Cationic Pillar[n]arenes that Prevent Biofilm Formation by Gram-Positive Pathogens

Abstract

Bacterial biofilms are a major threat to human health, causing persistent infections that lead to millions of fatalities worldwide every year. Biofilms also cause billions of dollars of damage annually by interfering with industrial processes. Recently, cationic pillararenes were found to be potent inhibitors of biofilm formation in Gram-positive bacteria. To identify the structural features of pillararenes that result in antibiofilm activity, we evaluated the activity of 16 cationic pillar[5]arene derivatives including that of the first cationic water-soluble pillar[5]arene-based rotaxane. Twelve of the derivatives were potent inhibitors of biofilm formation by Gram-positive pathogens. Structure activity analyses of our pillararene derivatives indicated that positively charged head groups are critical for the observed antibiofilm activity. Although certain changes in the lipophilicity of the substituents on the positively charged head groups are tolerated, dramatic elevation in the hydrophobicity of the substituents or an increase in steric bulk on these positive charges abolishes the antibiofilm activity. An increase in the overall positive charge from 10 to 20 did not affect the activity significantly, but pillararenes with 5 positive charges and 5 long alkyl chains had reduced activity. Surprisingly, the cavity of the pillar[n]arene is not essential for the observed activity, although the macrocyclic structure of the pillar[n]arene core, which facilitates the clustering of the positive charges, appears important. Interestingly, the compounds found to be efficient inhibitors of biofilm formation were nonhemolytic at concentrations that are ∼100-fold of their MBIC 50 (the minimal concentration of a compound at which at least 50% inhibition of biofilm formation was observed compared to untreated cells). The structure–activity relationship guidelines established here pave the way for a rational design of potent cationic pillar[n]arene-based antibiofilm agents.

Self-Assembling Systems Based on Pillar[5]arenes and Surfactants for Encapsulation of Diagnostic Dye DAPI

“…To obtain stable self-assembling systems based on Pillar [5]arenes and surfactants, the self-assembly of individual components of these systems, namely, macrocycles 1 and 2, and surfactants sodium dodecyl sulfate (SDS) and dodecyl trimethylammonium chloride (DTAC) was studied. Dynamic light scattering method shows the formation of polydispersity systems with submicron-sized associates for each component at the concentration range 1 × 10 −5 to 1 × 10 −3 M (Table S1).…”

“…The use of Pillar [5]arenes as a macrocyclic component is especially attractive due to the possibility of modification by various functional groups on both sides of the macrocyclic platform [4,5]. Pillar [5]arenes are capable of forming complexes with various biologically significant substrates using their hydrophobic macrocyclic cavity or substituents on both rims of the macrocycle [6][7][8][9][10]. Directed functionalization of Pillar [5]arenes allows one to control such important properties of molecules as bioavailability and water solubility [11][12][13][14][15].…”

“…Pillar [5]arenes are capable of forming complexes with various biologically significant substrates using their hydrophobic macrocyclic cavity or substituents on both rims of the macrocycle [6][7][8][9][10]. Directed functionalization of Pillar [5]arenes allows one to control such important properties of molecules as bioavailability and water solubility [11][12][13][14][15]. Effective binding of the substrate can be carried out either due to the hydrophobic cavity or due to functional groups [16][17][18][19][20][21][22].…”

“…It attracts great attention due to their potential application in various fields and especially in biomedicine as nanocontainers for medicinal and imaging agents [44][45][46][47][48][49][50][51]. Consequently, it becomes possible to obtain both host-guest complexes and polyelectrolyte aggregates of macrocycle-surfactants by varying the stoichiometric composition of a Pillar [5]arenesurfactant mixture on the analogy of interpolyelectrolyte complexes (IPEC) based on oppositely charged polymers [52][53][54][55][56][57].…”

“…Summarizing the above, it can be argued that such a strategy for the design of interpolyelectrolyte supramolecular Pillar[n]arene-surfactant systems will lead to a synergistic interaction of two components and will allow specific interaction with the third component (drug or fluorescent label), which will certainly be in demand in pharmaceuticals and biomedical diagnostics. Therefore, the aim of this work was to create supramolecular systems based on oppositely charged Pillar [5]arene and surfactants for encapsulating the dye 4',6-diamidino-2-phenylindole (DAPI), which is used for fluorescent staining of DNA in fluorescence microscopy [64,65]. We studied the aggregation behavior of synthesized macrocycles and surfactant molecules and investigated the encapsulating ability of mixed IPECs as nanocontainers for a fluorescent label.…”