Drug Design: Do Not Forget the Supramolecular Factor.

A major challenge currently facing medicinal chemists is designing agents that can selectively destroy drug resistant fungi and bacteria that have begun to emerge. One factor that has been overlooked by virtually all drug discovery/development approaches is the supramolecular factor, in which aggregated forms of a drug candidate exhibit low selectivity in destroying targeted cells while the corresponding monomers exhibit high selectivity. This Perspective discusses how we were led to the supramolecular factor through fundamental studies with simple model systems, how we reasoned that the selectivity of monomers of the antifungal agent amphotericin B should be much greater than the selectivity of the corresponding aggregates, and how we confirmed this hypothesis using derivatives of amphotericin B.

Creating Hyperthin Membranes for Gas Separations.

Interest in creating membranes that can separate gases has intensified in recent years owing, in large part, to climate change. Specifically, the need for separating CO and N from flue gas in an economically viable fashion is now considered urgent. This Perspective highlights two recent developments from my laboratory─defect repair of polyelectrolyte multilayers (PEMs) using micellar solutions of sodium dodecyl sulfate (SDS) and the surface modification of a highly permeable polymer, poly[1-(trimethylsilyl) propyne] (PTMSP)─which I believe have significant implications not only for this CO/N problem but also for the ever-growing area of layer-by-layer (LbL) thin films.

Cholesterol's Condensing Effect: Unpacking a Century-Old Mystery.

The ability of cholesterol to uncoil (i.e., condense) the acyl chains of phospholipids has been known for a century.

Membrane-Disrupting Molecules as Therapeutic Agents: A Cautionary Note.

Mechanistic studies have shown that aggregates of a common membrane disrupting molecule, Triton X-100, destroy the integrity of cholesterol-rich phospholipid bilayers via a catastrophic rupture process. In sharp contrast, attack on such membranes by monomers of Triton X-100 destroys their integrity through mild leakage events. This discovery of duplicity in the destruction of membrane integrity by a membrane-disrupting molecule has led to the design of derivatives of Amphotericin B that exhibit a lower tendency to aggregate and antifungal and hemolytic activities that are well-separated.

Defect Repair of Polyelectrolyte Bilayers Using SDS: The Action of Micelles Versus Monomers.

Defects within single, double, and triple polyelectrolyte bilayers derived from poly(sodium 4-styrenesulfonate) (PSS) and poly(diallyldimethyammonium chloride) (PDDA) have been repaired using aqueous solutions of sodium dodecyl sulfate (SDS), as evidenced by a reduction in their permeability and an increase in their permeation selectivity. In contrast to the use of monomer solutions of SDS, which were moderately effective in repairing only double and triple bilayers, micellar solutions proved highly effective for all three assemblies. Evidence for intact micelles or micellar fragments being deposited on the surface of single bilayers of PSS/PDDA has been obtained from a combination of atomic force microscopy, X-ray photoelectron spectroscopy, ellipsometry, and contact angle measurements.

Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming.

Antimicrobial resistance represents a significant world-wide health threat that is looming. To meet this challenge, new classes of antimicrobial agents and the redesign of existing ones will be required. This review summarizes some of the studies that have been carried out in my own laboratories involving membrane-disrupting agents.

The Origin of Lipid Rafts.

The time-averaged lateral organization of the lipids and proteins that make up mammalian cell membranes continues to be the subject of intense interest and debate. Since the introduction of the fluid mosaic model almost 50 years ago, the "lipid raft hypothesis" has emerged as a popular concept that has captured the imagination of a large segment of the biomembrane community. In particular, the notion that lipid rafts play a pivotal role in cellular processes such as signal transduction and membrane protein trafficking is now favored by many investigators.

Implementation of a pharmacist-led transitional care clinic.

Purpose: To describe a pharmacist-led transitional care clinic (TCC) for high-risk patients who were recently hospitalized or seen in the emergency department (ED).

Summary: The Memphis Veterans Affairs Medical Center (VAMC) established a pharmacist-led face-to-face and telephone follow-up TCC to improve posthospitalization follow-up care through medication optimization and disease state management, particularly for veterans with high-risk disease states such as chronic obstructive pulmonary disease (COPD) and heart failure (HF). The clinic's clinical pharmacy specialists (CPSs) ordered diagnostic and laboratory tests, performed physical assessments, and consulted other providers and specialty services in addition to performing medication reconciliation, compliance assessment, and evaluation of adverse drug events.

Clicking the Surface of Poly[1-(trimethylsilyl)propyne] (PTMSP) via a Thiol-Ene Reaction: Unexpected CO/N Permeability.

The surface modification of poly[1-(trimethylsilyl)propyne] (PTMSP) film via a thiol-ene click reaction with sodium 3-mercapto-1-propanesulfonate has yielded membranes having a CO permeance as high as 530 GPU with a CO/N selectivity of 21. This level of performance, together with the simplicity of this surface modification, suggests that such materials could become viable alternatives to some of the most promising membrane materials that are currently being explored for the practical capture of CO from flue gas.

The Fall Risk with Alpha blockers Given InitiaL dose or Elderly status (FRAGILE) Study.

α-1 adrenergic antagonists are commonly prescribed, but there is question regarding their safety in patients at increased fall risk. The purpose of the FRAGILE study was to determine the risk for developing adverse drug events (ADEs) in veterans prescribed α-1 blockers. A single-center, retrospective, observational cohort analysis was conducted of veterans newly initiated on α-1 antagonists.

Hyperthin Membranes for Gas Separations via Layer-by-Layer Assembly.

Thin film formation via the Layer-by-Layer method is now a well-established and broadly used method in materials science. We have been keenly interested in exploiting this technique in the area of gas separations. Specifically, we have sought to create hyperthin (<100 nm) polyelectrolyte-based membranes that have practical potential for the separation of CO from N (flue gas) and H from CO (syngas).

Layer-by-layer assembly of a polymer of intrinsic microporosity: targeting the CO/N separation problem.

A polymer of intrinsic microporosity, 1, has been incorporated into a series of polyelectrolyte multilayers via the layer-by-layer deposition method. One of these assemblies [a 6 nm multilayer derived from 1 plus poly(diallyldimethylammonium chloride)] showed exceptional permeation properties with respect to CO2 and N2. Specifically, this film exhibited a CO2 permeance of 130 GPU and a CO2/N2 selectivity of 33.

Net Interactions That Push Cholesterol Away from Unsaturated Phospholipids Are Driven by Enthalpy.

The exchangeable unsaturated phospholipids c-Phos and c-Phos, which bear one and three permanent kinks, respectively, in their acyl chains, are mimics of the biologically important, low-melting phosphatidylcholines (PCs) having one and three cis double bonds in their sn-2 chains (i.e., 16:0,18:1 PC and 16:0,18:3 PC, respectively).

A plug and socket approach for tightening polyelectrolyte multilayers.

A plug and socket approach for tightening polyelectrolyte multilayers is introduced based on the use pendant β-cyclodextrin groups. Prototypical multilayers derived from poly(sodium 4-styrene sulfonate) and β-cyclodextrin-containing poly(4-vinylbenzyltrimethylammonium chloride) are described. Evidence for tightened multilayers has been obtained from gas permeation, swelling and quartz crystal microbalance with dissipation (QCM-D) measurements.

Synthetic Immunotherapeutics against Gram-negative Pathogens.

While traditional drug discovery continues to be an important platform for the search of new antibiotics, alternative approaches should also be pursued to complement these efforts. We herein designed a class of molecules that decorate bacterial cell surfaces with the goal of re-engaging components of the immune system toward Escherichia coli and Pseudomonas aeruginosa. More specifically, conjugates were assembled using polymyxin B (an antibiotic that inherently attaches to the surface of Gram-negative pathogens) and antigenic epitopes that recruit antibodies found in human serum.

pK-Dependent Facilitated Transport of CO across Hyperthin Polyelectrolyte Multilayers.

Hyperthin (ca. 20-30 nm thick) polyelectrolyte multilayers have been fabricated that are capable of facilitated transport of CO. These membranes were fabricated from polycations bearing pendant groups of varying basicity plus poly(sodium 4-styrenesulfonate) as a polycounterion.

Lipid Raft Formation: Key Role of Polyunsaturated Phospholipids.

The forces that drive lipid raft formation are poorly understood. To date, most of the attention has focused on attractive interactions between cholesterol and high-melting lipids. Remarkably little attention has been paid to repulsive forces.

Simple Strategy for Taming Membrane-Disrupting Antibiotics.

A strategy has been devised for increasing the cellular selectivity of membrane-disrupting antibiotics based on the attachment of a facially amphiphilic sterol. Using Amphotericin B (AmB) as a prototype, covalent attachment of cholic acid bound to a series of α,ω-diamines has led to a dramatic reduction in hemolytic activity, a significant reduction in toxicity toward HEK293T cells, and significant retention of antifungal activity.

Tightening Polyelectrolyte Multilayers with Oligo Pendant Ions.

A series of polycations bearing one, two, and three pendant quaternary ammonium groups per repeat unit has been synthesized and combined with poly(sodium 4-styrenesulfonate) to produce hyperthin polyelectrolyte multilayers. Incremental addition of quaternary ammonium groups per repeat unit leads to decreased permeances for H, CO, and N and increased H/CO and CO/N permeation selectivities. These results, together with analysis of the composition from X-ray photoelectron spectra and values of Young's modulus from nanoindentation analysis, show that oligo pendant ions provide a means for increasing volume charge density and tightening polyelectrolyte multilayers.

Evidence for Surface Recognition by a Cholesterol-Recognition Peptide.

Two cholesterol recognition/interaction amino-acid consensus peptides, N-acetyl-LWYIKC-amide, and N-acetyl-CLWYIK-amide, have been coupled to exchangeable mimics of Chol (cholesterol) and Phos (1,2-dipalmitoyl-sn-glycerol-3-phospho-(1'rac-glycerol)) via disulfide bond formation. Equilibration between Chol and Phos via thiolate-disulfide interchange reactions has revealed that both peptides favor Chol as a nearest-neighbor in liquid-disordered (ld) bilayers to the same extent. In contrast, no Chol- or Phos-recognition could be detected by these peptides in analogous liquid-ordered (lo) bilayers.

Gas Permeability of Hyperthin Polyelectrolyte Multilayers Having Matched and Mismatched Repeat Units.

A series of polyelectrolyte multilayers (PEMs) has been fabricated using polyanions and polycations that have repeat units (i) similar in structure and composition (matched), (ii) partially similar in structure and composition (semimatched), and (iii) very different in structure and composition (mismatched). The primary aim of this investigation was to determine whether the matching of the polyelectrolytes can significantly influence the permeability properties of hyperthin PEMs. While matching, per se, was not found to be a key factor in defining membrane permeability, large differences in permeability were observed (the permeances of N varied by a factor of 20), which were correlated with the concentration of pendant aryl groups present, i.