Utilizing Paper‐Based Devices for Antimicrobial‐Resistant Bacteria Detection

Antimicrobial resistance (AMR), the ability of a bacterial species to resist the action of an antimicrobial drug, has been on the rise due to the widespread use of antimicrobial agents. Per the World Health Organization, AMR has an estimated annual cost of USD 34 billion in the US and is predicted to be the number one cause of death worldwide by 2050. One way AMR bacteria can spread, and by which individuals can contract AMR infections, is through contaminated water. Monitoring AMR bacteria in the environment currently requires that samples be transported to a central laboratory for slow and labor intensive tests. We have developed an inexpensive assay using paper‐based analytical devices (PADs) that can test for the presence of β‐lactamase‐mediated resistance. To demonstrate viability, the PAD was used to detect β‐lactam resistance in wastewater and sewage and identified resistance in individual bacterial species isolated from environmental water sources.     

19F‐NMR Reveals the Role of Mobile Loops in Product and Inhibitor Binding by the São Paulo Metallo‐β‐Lactamase

Resistance to β‐lactam antibiotics mediated by metallo‐β‐lactamases (MBLs) is a growing problem. We describe the use of protein‐observe ¹⁹F‐NMR (PrOF NMR) to study the dynamics of the São Paulo MBL (SPM‐1) from β‐lactam‐resistant Pseudomonas aeruginosa . Cysteinyl variants on the α3 and L3 regions, which flank the di‐Zn^II active site, were selectively ¹⁹F‐labeled using 3‐bromo‐1,1,1‐trifluoroacetone. The PrOF NMR results reveal roles for the mobile α3 and L3 regions in the binding of both inhibitors and hydrolyzed β‐lactam products to SPM‐1. These results have implications for the mechanisms and inhibition of MBLs by β‐lactams and non‐β‐lactams and illustrate the utility of PrOF NMR for efficiently analyzing metal chelation, identifying new binding modes, and studying protein binding from a mixture of equilibrating isomers.     

Recent Developments in the Field of β-Lactam Antibiotics

The era of β-lactam antibiotics, which represent the most important class of drugs against infectious diseases caused by bacteria, began more than fifty years ago with the discovery of penicillin G. Further improvements by isolation and structure elucidation of new natural compounds, and systematic chemical modification of these, is a striking example of to what extent chemistry can contribute to the progress of drug therapy. The complex relationship between structure and activity requires, even today, a largely empirical approach. The minimum structural unit for antibiotic activity had to be revised several times over decades. Both the activated β-lactam ring with an acidic group and the nature and spatial arrangement of the other substituents and rings decisively affect the potency, antibacterial spectrum, pharmacokinetics, and toxicity. Totally synthetic mono- and bicyclic compounds from the series of monobactams, penems, carbapenems, 1-oxacephems, and 1-carbacephems are increasingly joining the classic groups obtained by semisynthesis from 6-amino-penicillanic acid and 7-aminophalosporanic acid.     

Regio‐ and Enantioselective Rhodium‐Catalyzed Addition of 1,3‐Diketones to Allenes: Construction of Asymmetric Tertiary and Quaternary All Carbon Centers

An unprecedented highly regio‐ and enantioselective rhodium‐catalyzed addition of 1,3‐diketones to terminal and 1,1‐disubstituted allenes furnishing asymmetric tertiary and quaternary all‐carbon centers is reported. By applying a Rh^I/phosphoramidite/TFA catalytic system under mild conditions, the desired chiral branched α‐allylated 1,3‐diketones could be obtained in good to excellent yields, with perfect regioselectivity and in high enantioselectivity. The reaction shows a broad functional‐group tolerance on both reaction partners highlighting its synthetic potential.     

Detection of Carbapenemase‐Producing Organisms with a Carbapenem‐Based Fluorogenic Probe

Antibiotic resistance has become a major challenge to public health worldwide. This crisis is further aggravated by the increasing emergence of bacterial resistance to carbapenems, typically considered as the antibiotics of last resort, which is mainly due to the production of carbapenem‐hydrolyzing carbapenemases in bacteria. Herein, the carbapenem‐based fluorogenic probe CB‐1 with an unprecedented enamine–BODIPY switch is developed for the detection of carbapenemase activity. This reagent is remarkably specific towards carbapenemases over other prevalent β‐lactamases. Furthermore, the efficient imaging of live clinically important carbapenemase‐producing organisms (CPOs) with CB‐1 demonstrates its potential for the rapid detection of antibiotic resistance and timely diagnosis of CPO infections.     

Peptide N‐Amination Supports β‐Sheet Conformations

The conformational heterogeneity of backbone N‐substituted peptides limits their ability to adopt stable secondary structures. Herein, we describe a practical synthesis of backbone aminated peptides that readily adopt β‐sheet folds. Data derived from model N‐amino peptides suggest that extended conformations are stabilized through cooperative steric, electrostatic, and hydrogen‐bonding interactions.     

Reactions of 3, 5-Dimethyl-4-Carbethoxy-2-Cyclohexen-1-One at α-Position

3, 5-Dimethyl-4-carbethoxy-2-cyclohexen-1-one has been synthesized through the Knoevenagel condensation¹, which is then subjected to alkylation and acylation at α-position. The resulting products are hydrolyzed and decarboxylated to α-substituted cyclohexenones. 3, 5-Dimethyl-2-cyclohexen-1-one is converted by N-bromosuccinimide to phenol via enolization².     

Synthesis of β‐Haloketones by β‐Addition Reactions of α,β‐Unsaturated Ketones with BX3 (X = Br,Cl) as Halide Source

A series of β‐bromoketones and β‐chloroketones were synthesized by the addition reactions of α,β‐unsaturated ketones under BX₃ (X = Br, Cl) and ethylene glycol reaction system. The α,β‐unsaturated ester also was successfully converted to its corresponding β‐bromoester under the reaction condition.     

Reductive C−C Coupling from α,β‐Unsaturated Nitriles by Intercepting Keteniminates

We present an atom‐economic strategy to catalytically generate and intercept nitrile anion equivalents using hydrogen transfer catalysis. Addition of α,β‐unsaturated nitriles to a pincer‐based Ru?H complex affords structurally characterized κ‐N‐coordinated keteniminates by selective 1,4‐hydride transfer. When generated in situ under catalytic hydrogenation conditions, electrophilic addition to the keteniminate was achieved using anhydrides to provide α‐cyanoacetates in high yields. This work represents a new application of hydrogen transfer catalysis using α,β‐unsaturated nitriles for reductive C?C coupling reactions.     

Heat-resistant resins obtained from polymer precursors bearing β,β′-dicyanovinyl terminal groups

Certain polymer precursors of the general formula: where A is an aromatic structure bearing ester, amide, azomethine, or imide linkages were synthesized. Particularly, 4-hydroxybenzaldehyde was condensed with malonitrile to afford 4-hydroxy-β,β′-dicyanostyrene which reacted with a half molar amount of terephthaloyl dichloride in the presence of an acid acceptor. In addition, 3-nitrobenzaldehyde was condensed with malonitrile to yield 3-nitro-β,β′-dicyanostyrene that was catalytically hydrogenated to the corresponding amine. The latter reacted with a half molar amount of terephthaloyl dichloride, terephthaldehyde, pyromellitic dianhydride, or benzophenone tetracarboxylic dianhydride. The polymer precursors were characterized by elemental analyses as well as IR and ¹H-NMR spectroscopy. Their curing behavior was investigated by DTA. Crosslinked polymers were obtained by curing the monomers at 300°C for 24 h. They were stable up to 407–437°C in N₂ and afforded an anaerobic char yield of 65–50% at 800°C. The thermal stability of resins was correlated with their chemical structures. © 1993 John Wiley & Sons, Inc.     

Muropeptides in Pseudomonas aeruginosa and their Role as Elicitors of β‐Lactam‐Antibiotic Resistance

Muropeptides are a group of bacterial natural products generated from the cell wall in the course of its turnover. These compounds are cell‐wall recycling intermediates and are also involved in signaling within the bacterium. However, the identity of these signaling molecules remains elusive. The identification and characterization of 20 muropeptides from Pseudomonas aeruginosa is described. The least abundant of these metabolites is present at 100 and the most abundant at 55,000 molecules per bacterium. Analysis of these muropeptides under conditions of induction of resistance to a β‐lactam antibiotic identified two signaling muropeptides (N‐acetylglucosamine‐1,6‐anhydro‐N‐acetylmuramyl pentapeptide and 1,6‐anhydro‐N‐acetylmuramyl pentapeptide). Authentic synthetic samples of these metabolites were shown to activate expression of β‐lactamase in the absence of any β‐lactam antibiotic, thus indicating that they serve as chemical signals in this complex biochemical pathway.     

Access to Cyclic β‐Amino Acids by Amine‐Catalyzed Enantioselective Addition of the γ‐Carbon Atoms of α,β‐Unsaturated Imines to Enals

Disclosed herein is a new catalytic approach for an efficient access to cyclic β‐amino acids widely found in bioactive small molecules and peptidic foldamers. Our method involves addition of the remote γ‐carbon atoms of α,β‐unsaturated imines to enals by iminium organic catalysis. This highly chemo‐ and stereo‐selective reaction affords cyclic β‐amino aldehydes that can be converted to amino acids bearing quaternary stereocenters with exceptional optical purities. Our study demonstrates the unique power of organic catalytic remote carbon reactions in rapid synthesis of functional molecules.     

Syngas‐Free Highly Regioselective Rhodium‐Catalyzed Transfer Hydroformylation of Alkynes to α,β‐Unsaturated Aldehydes

The hydroformylation of alkynes is a fundamental and important reaction in both academic research and industry. Conventional methods focus on the conversion of alkynes, CO, and H₂ into α,β‐unsaturated aldehydes, but they often suffer from problems associated with operation, regioselectivity, and chemoselectivity. Herein, we disclose an operationally simple, mild, and syngas‐free rhodium‐catalyzed reaction for the hydroformylation of alkynes via formyl and hydride transfer from an alkyl aldehyde. This synthetic method uses inexpensive and easy‐to‐handle n‐butyraldehyde to overcome the challenge posed by the use of syngas in traditional approaches and employs a commercially available catalyst and ligand to transform a broad range of internal alkynes, especially alkynyl‐containing complex molecules, into versatile stereodefined α,β‐unsaturated aldehydes with excellent chemo‐, regio‐, and stereoselectivity.     

Enantioselective Synthesis of β-Lactam Carried C(3) Functionality via Ester Enolate-Imine Condensation

Enantioselective synthesis of optically active β-lactam via ester enolate-imine condensation using homochiral ester 16 and imine 17 provided β-lactam 18a in 77% cc. Lactam 18a, carried C(3) functionality on β-lactam nuclei, provided a potential precursor toward a synthesis of dipeptide antibiotic.