A major resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent β-lactamases can now confer ...resistance to other β-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of β-lactamase-producing multi-drug-resistant “superbugs” has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-β-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided 20 (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum β-lactamase inhibitor. In vitro and in vivo studies demonstrated that 20 restored the activity of β-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum β-lactamase inhibitor to enter clinical development.
Alternative chemicals to diverse fossil-fuel-based products is urgently needed to mitigate the adverse impacts of fossil fuel depletion on human development. To this end, researchers have focused on ...the production of biochemical from readily available and affordable waste biomass. This is consistent with current guidelines for sustainable development and provides great advantages related to economy and environment. The search for suitable biochemical products is in progress worldwide. Therefore, this review recommends a biochemical (i.e., medium chain carboxylic acids (MCCAs)) utilizing an emerging biotechnological production platform called the chain elongation (CE) process. This work covers comprehensive introduction of the CE mechanism, functional microbes, available feedstock types and corresponding utilization strategies, major methods to enhance the performance of MCCAs production, and the challenges that need to be addressed for practical application. This work is expected to provide a thorough understanding of the CE technology, to guide and inspire researchers to solve existing problems in depth, and motivate large-scale MCCAs production.
•Medium chain carboxylic acid (MCCAs) recovery is promising to reuse waste biomass.•Three feedstock types and corresponding utilization strategies are summarized.•Strategies for enhancing MCCAs production performance are discussed.•Future perspectives for MCCAs production are recommended.
Despite major advances in the β-lactamase inhibitor field, certain enzymes remain refractory to inhibition by agents recently introduced. Most important among these are the class B (metallo) enzyme ...NDM-1 of Enterobacteriaceae and the class D (OXA) enzymes of Acinetobacter baumannii. Continuing the boronic acid program that led to vaborbactam, efforts were directed toward expanding the spectrum to allow treatment of a wider range of organisms. Through key structural modifications of a bicyclic lead, stepwise gains in spectrum of inhibition were achieved, ultimately resulting in QPX7728 (35). This compound displays a remarkably broad spectrum of inhibition, including class B and class D enzymes, and is little affected by porin modifications and efflux. Compound 35 is a promising agent for use in combination with a β-lactam antibiotic for the treatment of a wide range of multidrug resistant Gram-negative bacterial infections, by both intravenous and oral administration.
A pretreatment of lignocellulosic biomass to produce biofuels, polymers, and other chemicals plays a vital role in the biochemical conversion process toward disrupting the closely associated ...structures of the cellulose-hemicellulose-lignin molecules. Various pretreatment steps alter the chemical/physical structure of lignocellulosic materials by solubilizing hemicellulose and/or lignin, decreasing the particle sizes of substrate and the crystalline portions of cellulose, and increasing the surface area of biomass. These modifications enhance the hydrolysis of cellulose by increasing accessibilities of acids or enzymes onto the surface of cellulose. However, lignocellulose-derived byproducts, which can inhibit and/or deactivate enzyme and microbial biocatalysts, are formed, including furan derivatives, lignin-derived phenolics, and carboxylic acids. These generation of compounds during pretreatment with inhibitory effects can lead to negative effects on subsequent steps in sugar flat-form processes. A number of physico-chemical pretreatment methods such as steam explosion, ammonia fiber explosion (AFEX), and liquid hot water (LHW) have been suggested and developed for minimizing formation of inhibitory compounds and alleviating their effects on ethanol production processes. This work reviews the physico-chemical pretreatment methods used for various biomass sources, formation of lignocellulose-derived inhibitors, and their contributions to enzymatic hydrolysis and microbial activities. Furthermore, we provide an overview of the current strategies to alleviate inhibitory compounds present in the hydrolysates or slurries.
Environmental pressures caused by population growth and consumerism require the development of resource recovery from waste, hence a circular economy approach. The production of chemicals and fuels ...from organic waste using mixed microbial cultures (MMC) has become promising. MMC use the synergy of bio-catalytic activities from different microorganisms to transform complex organic feedstock, such as by-products from food production and food waste. In the absence of oxygen, the feedstock can be converted into biogas through the established anaerobic digestion (AD) approach. The potential of MMC has shifted to production of intermediate AD compounds as precursors for renewable chemicals. A particular set of anaerobic pathways in MMC fermentation, known as chain elongation, can occur under specific conditions producing medium chain carboxylic acids (MCCAs) with higher value than biogas and broader applicability. This review introduces the chain elongation pathway and other bio-reactions occurring during MMC fermentation. We present an overview of the complex feedstocks used, and pinpoint the main operational parameters for MCCAs production such as temperature, pH, loading rates, inoculum, head space composition, and reactor design. The review evaluates the key findings of MCCA production using MMC, and concludes by identifying critical research targets to drive forward this promising technology as a valorisation method for complex organic waste.
We report a stereoselective conversion of terminal alkynes to α‐chiral carboxylic acids using a nickel‐catalyzed domino hydrocarboxylation‐transfer hydrogenation reaction. A simple nickel/BenzP* ...catalyst displayed high activity in both steps of regioselective hydrocarboxylation of alkynes and subsequent asymmetric transfer hydrogenation. The reaction was successfully applied in enantioselective preparation of three nonsteroidal anti‐inflammatory profens (>90 % ees) and the chiral fragment of AZD2716.
A simple nickel catalyst converts terminal alkynes and formic acid to α‐chiral carboxylic acids in high enantioselectivity. The reaction proceeds via the hydrocarboxylation of alkynes and enantioselective transfer hydrogenation of acrylic acids.
In this study, we aimed to develop a polyethylene glycol (PEG)-conjugated third generation polyamidoamine (PAMAM) dendrimer with multiple carboxylic acids as a bone-targeting carrier for the ...treatment of bone diseases. We conjugated PAMAM backbones to various carboxylic acids aspartic acid (Asp), glutamic acid (Glu), succinic acid (Suc), or aconitic acid (Aco) to obtain four different types of carboxylic acid-modified PAMAMs. PEG was covalently bound to carboxylic acid-modified PAMAMs to obtain PEGylated carboxylic acid-modified PAMAMs. In a tissue distribution study, the amount of 111In-labeled unmodified PAMAM taken up by the bone after intravenous injection in mice was 11.3%. In contrast, the dose of 111In-labeled PEG(5)-Asp-PAMAM, PEG(5)-Glu-PAMAM, PEG(5)-Suc-PAMAM, or PEG(5)-Aco-PAMAM that accumulated in the bone after injection was approximately 46.0, 15.6, 22.6, and 24.5%, respectively. The bone clearance rates of 111In-labeled PEGylated carboxylic acid-modified PAMAMs were proportional to their affinities to hydroxyapatite and Ca2+. An intra-bone distribution study showed that fluorescein isothiocyanate-labeled PEG(5)-Asp-PAMAM predominantly accumulated on eroded and quiescent surfaces, a pattern associated with the pathogenesis of bone diseases, such as rheumatoid arthritis and osteoporosis. Our findings indicate that PEG(5)-Asp-PAMAM is a promising drug carrier for efficient drug targeting to the bones.
Efficient bone targeting by a polyamidoamine (PAMAM) dendrimer was successfully achieved by carboxylic acids. A combination of Asp and PEG modifications represented an optimal approach for effective bone targeting. Display omitted
Generation of non-stabilized β-ester diazos and their applications in carboxylic acid O-H insertion reactions have been reported, which afford β-acyloxy esters in excellent yield. Varieties of aryl- ...and alkyl-substituted diazos are well tolerated in this insertion reaction under mild and convenient conditions. Moreover, structural modification of the natural product and molecular drug can also be achieved in this reaction. This protocol not only realizes the reaction involving unstable β-ester diazos but also provides an efficient strategy for the synthesis of β-acyloxy esters.
The first enantioselective synthesis of (
)-meptazinol in 14 steps from commercially available ethyl 4-oxo-3,4-dihydropyridine-1(2
)-carboxylate, being widely used in racemic form for pain treatment, ...and, en route, the formal synthesis of two anti-Alzheimer's agents are reported. A novel ring expansion of 2-azabicyclo4.1.0heptanes, readily available via the stereoselective cyclopropanation of 1,2,3,4-tetrahydropyridine-4-ols, provides an effective entry to 3,3-disubstituted azepanes that represent the core for a variety of approved drugs.
PDF
