Poly(2-oxazoline) surfactants allow for the stabilization and functionalization of hydrocarbon- and perfluorocarbon-in-water nanoemulsions.

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Emulsions are dynamic materials that have been extensively employed within pharmaceutical, food and cosmetics industries. However, their use beyond conventional applications has been hindered by difficulties in surface functionalization, and an inability to selectively control physicochemical properties. Here, we employ custom poly(2-oxazoline) block copolymers to overcome these limitations. We demonstrate that poly(2-oxazoline) copolymers can effectively stabilize nanoscale droplets of hydrocarbon and perfluorocarbon in water. The living polymerization allows for the incorporation of chemical handles into the surfactants such that covalent modification of the emulsion surfaces can be performed. Through post-emulsion modification, we are able to access nanoemulsions with modified surface chemistries, yet consistent sizes. By decoupling size and surface charge, we explore structure-activity relationships involving the cellular uptake of nanoemulsions.

Cationic polymers are an interesting class of macromolecules due to their versatility and emerging properties that can be used for various industrial and biomedical purposes. This report is focused on investigating the use of microwave heating in the reversible addition–fragmentation chain transfer polymerization of functional cationic monomers, N‐(3‐aminopropyl)methacrylamide hydrochloride (APMA) and N‐[3‐(dimethylamino)propyl]methacrylamide (DMAPMA). Under comparable polymerization reaction conditions, the microwave‐assisted reaction achieves up to 270% (APMA) and 375% (DMAPMA) rate enhancement over conventional oil‐bath mediated set‐up. Linear relationships are observed between number average molecular weight and monomer conversion for different target degrees of polymerization to give low‐ to high‐molecular‐weight cationic polymers. Chain extension experiments show increase in molecular weight of the cationic polymers with narrow dispersities (Ð < 1.2) indicating retention of the chain transfer agent with no observable aminolysis or hydrolysis during polymerization.

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Despite the widespread emergence of multidrug‐resistant nosocomial Gram‐negative bacterial infections and the major public health threat it brings, no new class of antibiotics for Gram‐negative pathogens has been approved over the past five decades. Therefore, there is an urgent medical need for developing effective novel antibiotics against multidrug‐resistant Gram‐negative pathogens by targeting previously unexploited pathways in these bacteria. To fulfill this crucial need, we have been investigating a series of sulfonyl piperazine compounds targeting LpxH, a dimanganese‐containing UDP‐2,3‐diacylglucosamine hydrolase in the lipid A biosynthetic pathway, as novel antibiotics against clinically important Gram‐negative pathogens. Inspired by a detailed structural analysis of our previous LpxH inhibitors in complex with K. pneumoniae LpxH (KpLpxH), here we report the development and structural validation of the first‐in‐class sulfonyl piperazine LpxH inhibitors, JH‐LPH‐45 (8) and JH‐LPH‐50 (13), that achieve chelation of the active site dimanganese cluster of KpLpxH. The chelation of the dimanganese cluster significantly improves the potency of JH‐LPH‐45 (8) and JH‐LPH‐50 (13). We expect that further optimization of these proof‐of‐concept dimanganese‐chelating LpxH inhibitors will ultimately lead to the development of more potent LpxH inhibitors for targeting multidrug‐resistant Gram‐negative pathogens.

The UDP‐2,3‐diacylglucosamine pyrophosphatase, LpxH, is an essential enzyme in the biosynthesis of the lipid A, which functions as the hydrophobic anchor of lipopolysaccharides or lipooligosaccharides in the outer leaflet of the outer membrane of Gram‐negative bacteria. This enzyme is conserved in the majority of Gram‐negative bacterial pathogens and is an excellent novel antibiotic target. Here we report the development of a coupled, nonradioactive and colorimetric LpxH assay suitable for high‐throughput analysis of LpxH inhibition and screening. Using this new assay, we have established a pharmacophore model for the recently reported LpxH inhibitor by AstraZeneca (dubbed as AZ1 below). Our crystal structure of Klebsiella pneumoniae LpxH (KpLpxH) in complex with AZ1 shows that AZ1 fits snugly into the L‐shaped acyl chain‐binding chamber of LpxH with its indoline ring situating adjacent to the active site, its sulfonyl group adopting a sharp kink, and its N‐CF3‐phenyl substituted piperazine group reaching out to the far side of the LpxH acyl chain‐binding chamber. Our solution NMR investigation later revealed the presence of a second ligand conformation that was unseen in the crystalline state, delineating a cryptic inhibitor envelope that expands the observed footprint of AZ1 in the LpxH‐bound crystal structure. Utilizing these discoveries, we designed new AZ1‐derivatives that display striking improvement in antibiotic activity over AZ1 against wild‐type K. pneumoniae. Co‐administration with outer membrane permeability enhancers profoundly sensitizes E. coli to our designed LpxH inhibitors. As none of these first sulfonyl piperazine compounds occupied the active site of LpxH, we designed a new series of sulfonyl piperazine analogs and discovered an extended N‐acyl chain analog that additionally occupied the untapped polar binding pocket near the manganese cluster of the LpxH active site. We expect that this work will provide guiding design principles for new LpxH inhibitors and establish important frameworks for the future development of antibiotics against multi‐drug resistant Gram‐negative pathogens