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Supramolecular interactions are well recognized and many of them have been extensively studied in chemistry. The formation of supramolecular complexes that rely on weak force interactions are less well studied in bilayer membranes. Herein, a supported bilayer membrane is used to probe the penetration of a complex between tetracycline and a macrocyclic polyether. In a number of bacterial systems, the presence of the macrocycle has been found to significantly enhance the potency of the antimicrobial in vitro . The crown·tetracycline complex has been characterized in solution, neutron reflectometry has probed complex penetration, and the phenomena have been modeled by computational methods. 

Aims: The aim of the study was to determine whether and to what extent any of a family of amphiphilic heptapeptide synthetic anion transporters (SATs) affected the growth or root morphology of Arabidopsis thaliana. Study Design:  A. thaliana plants were grown from seedlings in PNS media in the absence or presence of one of 21 SATs. Place and Duration of Study: Departments of Chemistry & Biochemistry, University of Missouri – St. Louis, 1 University Blvd., St. Louis, MO 63121 U. S. A. The study was conducted 2017-2018. Methodology: Twenty one compounds of the form R2N-COCH2YCH2CO-(Aaa)3Pro(Aaa)3-O(CH2)6CH3 were prepared and studied. The amino acids included Ala, Gly, and Ser. R was normal alkyl having 6, 10, 12, or 18 carbons. Y was methylene, oxygen, sulfur, or absent. The PNS media was infused with various concentrations of the SAT and 21 plants in each group were allowed to grow for 11 days. Overall plant growth and root morphology were visualized and/or measured and the results recorded. Results: A comparison of primary root length and lateral root number revealed that the greatest alterations in lateral root densities were observed for peptide sequences of the type GGGPSGS, whether or not serine was protected by t-butyl. Differences were also observed for these peptide sequences according to the identity of Y in the ~COCH2YCH2CO~ chain. Conclusion: The presence of serine’s oxygen atoms on the C-terminal side of the heptapeptide interact with Cl¯ leading to a change in ion concentrations and alterations in primary root lengths and lateral root densities. 

Antimicrobial resistance is a world-wide health care crisis. New antimicrobials must both exhibit potency and thwart the ability of bacteria to develop resistance to them. We report the use of synthetic ionophores as a new approach to developing non-resistant antimicrobials and adjuvants. Most studies involving amphiphilic antimicrobials have focused on either developing synthetic amphiphiles that show ion transport, or developing non-cytotoxic analogs of such peptidic amphiphiles as colistin. We have rationally designed, prepared, and evaluated crown ether-based synthetic ionophores (‘hydraphiles’) that show selective ion transport through bilayer membranes and are toxic to bacteria. We report here that hydraphiles exhibit a broad range of antimicrobial properties and that they function as adjuvants in concert with FDA-approved antibiotics against multi-drug resistant (MDR) bacteria. Studies described herein demonstrate that benzyl C 14 hydraphile (BC 14 H) shows high efficacy as an antimicrobial. BC 14 H, at sub-MIC concentrations, forms aggregates of ∼200 nm that interact with the surface of bacteria. Surface-active BC 14 H then localizes in the bacterial membranes, which increases their permeability. As a result, antibiotic influx into the bacterial cytosol increases in the presence of BC n Hs. Efflux pump inhibition and accumulation of substrate was also observed, likely due to disruption of the cation gradient. As a result, BC 14 H recovers the activity of norfloxacin by 128-fold against resistant Staphylococcus aureus . BC 14 H shows extremely low resistance development and is less cytotoxic than colistin. Overall, synthetic ionophores represent a new scaffold for developing efficient and non-resistant antimicrobial-adjuvants. 

Hydraphiles are synthetic amphiphiles that form pores in bilayer membranes. A study was undertaken to determine if the formation of pores could assist the penetration of antibiotics into bacteria. The disruption of ion homeostasis by the pore-formers leads to microbial toxicity. Co-administration of hydraphiles at concentration ≤ ½ MIC and antimicrobials to E. coli or P. aeruginosa showed potency enhancements of up to 30-fold. A possible mechanism is the enhancement of antibiotic influx owing to membrane disruption and/or altering the ion balance within the bacterial cells.