Structural and Kinetic Studies of the Potent Inhibition of Metallo-ß-lactamases by 6-Phosphonomethylpyridine-2-carboxylates.

There are currently no clinically available inhibitors of metallo-ß-lactamases (MBLs), enzymes that hydrolyze ß-lactam antibiotics and confer resistance to Gram-negative bacteria. Here we present 6-phosphonomethylpyridine-2-carboxylates (PMPCs) as potent inhibitors of subclass B1 (IMP-1, VIM-2, and NDM-1) and B3 (L1) MBLs. Inhibition followed a competitive, slow-binding model without an isomerization step (IC50 values of 0.3-7.2 µM; Ki values of 0.03-1.5 µM). Minimum inhibitory concentration assays demonstrated potentiation of ß-lactam (Meropenem) activity against MBL-producing bacteria, including clinical isolates, at concentrations at which eukaryotic cells remain viable. Crystal structures revealed unprecedented modes of binding of inhibitor to B1 (IMP-1) and B3 (L1) MBLs. In IMP-1, binding does not replace the nucleophilic hydroxide, and the PMPC carboxylate and pyridine nitrogen interact closely (2.3 and 2.7 Å, respectively) with the Zn2 ion of the binuclear metal site. The phosphonate group makes limited interactions but is 2.6 Å from the nucleophilic hydroxide. Furthermore, the presence of a water molecule interacting with the PMPC phosphonate and pyridine N-C2 π-bond, as well as the nucleophilic hydroxide, suggests that the PMPC binds to the MBL active site as its hydrate. Binding is markedly different in L1, with the phosphonate displacing both Zn2, forming a monozinc enzyme, and the nucleophilic hydroxide, while also making multiple interactions with the protein main chain and Zn1. The carboxylate and pyridine nitrogen interact with Ser221 and -223, respectively (3 Å distance). The potency, low toxicity, cellular activity, and amenability to further modification of PMPCs indicate these and similar phosphonate compounds can be further considered for future MBL inhibitor development.

Self-adaptive Bioinspired Hummingbird-wing Stimulated Triboelectric Nanogenerators.

Bio-inspired technologies have remarkable potential for energy harvesting from clean and sustainable energy sources. Inspired by the hummingbird-wing structure, we propose a shape-adaptive, lightweight triboelectric nanogenerator (TENG) designed to exploit the unique flutter mechanics of the hummingbird for small-scale wind energy harvesting. The flutter is confined between two surfaces for contact electrification upon oscillation. We investigate the flutter mechanics on multiple contact surfaces with several free-standing and lightweight electrification designs. The flutter driven-TENGs are deposited on simplified wing designs to match the electrical performance with variations in wind speed. The hummingbird TENG (H-TENG) device weighed 10 g, making it one of the lightest TENG harvesters in the literature. With a six TENG network, the hybrid design attained a 1.5 W m-2 peak electrical output at 7.5 m/s wind speed with an approximately linear increase in charge rate with the increased number of TENG harvesters. We demonstrate the ability of the H-TENG networks to operate Internet of Things (IoT) devices from sustainable and renewable energy sources.

Multiple and regioselective introduction of protected sulfates into carbohydrates using sulfuryl imidazolium salts.

Selective incorporation of trichloroethyl (TCE)-protected sulfates into monosaccharides was examined using reagent 2. In general, sulfation of 4,6-O-benzylidene acetals of galactosides and glucosides (2-OH versus 3-OH sulfations) proceeded in good to excellent yield and selectivity. Sulfation occurred predominantly at the 2-OH in 4,6-O-benzylidene acetals of alpha-glucosides and at the 3-OH in 4,6-O-benzylidene acetals of beta-galactosides and beta-glucosides. Good yields and selectivity was also achieved for the 3-OH in 3,4-diols of glucosides and galactosides. A glucoside bearing a 2-amino moiety and 6-OH group gave mainly the N-sulfated product in good yield. Selective sulfation of the primary 6-OH in galactose and glucose derivatives bearing one or two free secondary hydroxyl groups was also achieved usually in good yield and selectivity. Reagent 2 was also effective for the direct disulfation of diols of glucosides and galactosides, and trisulfated monosaccharides could be prepared from the disulfated compounds.