Cyclic Boronate Research Articles

11B NMR Together with Infrared Spectroscopy Provides Insight into Structural Elucidation of Quadrivalent Diazaborines & Cyclic Boronate Esters: Intriguing & Little-Explored

Imidazo-fused diazaborines, which serve as intermediary structures somewhat alongside benzene and borazine, had been of particular interest to Dewar and Snyder more than 60 years ago. To this end, Dewar utilised his ‘π-complex theory’so as to represent ‘borazaros’as a ‘quadrivalent’ species; however, sadly, modern representations have deviated and leapt into ‘trivalent’ counterparts. Bonding in boron species has never been straightforward, to such an extent that the orthodox ‘ethane’ like diborane, i.e., H3B–BH3, which conformed to the paradigmatic rules of molecular structure, in particular, hybridisation and electronegativity, was later evolved to a more realistic ‘3-centre 2-electron’ bonding so as to give the lie to the purported diborane structures of X-ray diffractors. Herein 11B NMR together with IR spectroscopy sheds light on the nature of bonding in borazaros, and ‘caged’ cyclic oxazaborons so as to reinforce, and reinvigorate the old literature, which could be of interest to both the synthetic, and medicinal chemist alike.

A Highly Efficient Fluorescent Turn-Off Nanosensor for Quantitative Detection of Teicoplanin Antibiotic from Humans, Food, and Water Based on the Electron Transfer between Imprinted Quantum Dots and the Five-Membered Cyclic Boronate Esters.

Teicoplanin has been banned in the veterinary field due to the drug resistance of antibiotics. However, teicoplanin residue from the antibiotic abuse of humans and animals poses a threat to people's health. Therefore, it is necessary to develop an efficient way for the highly accurate and reliable detection of teicoplanin from humans, food, and water. In this study, novel imprinted quantum dots of teicoplanin were prepared based on boronate affinity-based precisely controlled surface imprinting. The imprinting factor (IF) for teicoplanin was evaluated and reached a high value of 6.51. The results showed excellent sensitivity and selectivity towards teicoplanin. The relative fluorescence intensity was inversely proportional to the concentration of teicoplanin, in the range of 1.0-17 μM. And its limit of detection (LOD) was obtained as 0.714 μM. The fluorescence quenching process was mainly controlled by a static quenching mechanism via the non-radiative electron-transfer process between QDs and the five-membered cyclic boronate esters. The recoveries for the spiked urine, milk, and water samples ranged from 95.33 to 104.17%, 91.83 to 97.33, and 94.22 to 106.67%, respectively.

Approachable Synthetic Methodologies for Second-Generation β-Lactamase Inhibitors: A Review.

Some antibiotics that are frequently employed are β-lactams. In light of the hydrolytic process of β-lactamase, found in Gram-negative bacteria, inhibitors of β-lactamase (BLIs) have been produced. Examples of first-generation β-lactamase inhibitors include sulbactam, clavulanic acid, and tazobactam. Many kinds of bacteria immune to inhibitors have appeared, and none cover all the β-lactamase classes. Various methods have been utilized to develop second-generation β-lactamase inhibitors possessing new structures and facilitate the formation of diazabicyclooctane (DBO), cyclic boronate, metallo-, and dual-nature β-lactamase inhibitors. This review describes numerous promising second-generation β-lactamase inhibitors, including vaborbactam, avibactam, and cyclic boronate serine-β-lactamase inhibitors. Furthermore, it covers developments and methods for synthesizing MβL (metallo-β-lactamase inhibitors), which are clinically effective, as well as the various dual-nature-based inhibitors of β-lactamases that have been developed. Several combinations are still only used in preclinical or clinical research, although only a few are currently used in clinics. This review comprises materials on the research progress of BLIs over the last five years. It highlights the ongoing need to produce new and unique BLIs to counter the appearance of multidrug-resistant bacteria. At present, second-generation BLIs represent an efficient and successful strategy.

Ring Expansion of Cyclic Boronates via Oxyboration of Arynes.

The oxyboration of arynes was achieved for the first time. A series of 2-aryl-1,3,2-dioxaborolane derivatives were reacted with aryne precursors in the presence of CsF to give the corresponding ring-expanded seven-membered borinic acid esters via selective boron-oxygen bond activation. Preliminary experimental mechanistic studies and density functional theory (DFT) calculations suggest that this unprecedented aryne oxyboration proceeds through the formation of boron ate complexes of arylboronates with CsF, followed by aryne insertion into the boron-oxygen bond.

Drug Discovery in the Field of β-Lactams: An Academic Perspective.

β-Lactams are the most widely prescribed class of antibiotics that inhibit penicillin-binding proteins (PBPs), particularly transpeptidases that function in peptidoglycan synthesis. A major mechanism of antibiotic resistance is the production of β-lactamase enzymes, which are capable of hydrolyzing β-lactam antibiotics. There have been many efforts to counter increasing bacterial resistance against β-lactams. These studies have mainly focused on three areas: discovering novel inhibitors against β-lactamases, developing new β-lactams less susceptible to existing resistance mechanisms, and identifying non-β-lactam inhibitors against cell wall transpeptidases. Drug discovery in the β-lactam field has afforded a range of research opportunities for academia. In this review, we summarize the recent new findings on both β-lactamases and cell wall transpeptidases because these two groups of enzymes are evolutionarily and functionally connected. Many efforts to develop new β-lactams have aimed to inhibit both transpeptidases and β-lactamases, while several promising novel β-lactamase inhibitors have shown the potential to be further developed into transpeptidase inhibitors. In addition, the drug discovery progress against each group of enzymes is presented in three aspects: understanding the targets, screening methodology, and new inhibitor chemotypes. This is to offer insights into not only the advancement in this field but also the challenges, opportunities, and resources for future research. In particular, cyclic boronate compounds are now capable of inhibiting all classes of β-lactamases, while the diazabicyclooctane (DBO) series of small molecules has led to not only new β-lactamase inhibitors but potentially a new class of antibiotics by directly targeting PBPs. With the cautiously optimistic successes of a number of new β-lactamase inhibitor chemotypes and many questions remaining to be answered about the structure and function of cell wall transpeptidases, non-β-lactam transpeptidase inhibitors may usher in the next exciting phase of drug discovery in this field.

A palladium-catalyzed synthesis of cyclic alkenyl boronates from alkenyl chlorides.

A palladium-catalyzed borylation of cyclic alkenyl chlorides with B2pin2 is reported. This transformation allows for the conversion of diverse cyclic alkenyl chlorides into synthetically versatile alkenyl boronates with moderate to excellent yields. The utility of this reaction has been demonstrated with practical Suzuki-Miyaura coupling and aziridination reactions, which allow access to functionalized olefins and valuable boron-substituted aziridines.

Visualized sensing of erythritol using a simple enzyme-free catechol-based hydrogel film.

Based on the versatile properties of bio-derived materials, non-enzymatic assays in combination with electronic devices have attracted increasing interest. Here, we report a novel enzyme-free visualization approach for the detection of erythritol, which is a zero-calorie natural sweetener and serves as an ideal sucrose substitute for diabetics or overweight people who need sugar control. The recognition element of the electrochemical biosensor was constructed by catechol modification on a chitosan-based hydrogel film. The signal transduction was achieved by the competitive binding assay of sweeteners. The results show that 2-fluorophenylboronic acid (FPBA) can form a cyclic boronate ester with the ortho-hydroxyls of both reduced catechol and oxidized quinone, impeding the electron transfer and leading to redox signal attenuation. The addition of sweeteners caused a competitive reaction resulting in bonding between the 1,2-diols and FPBA moieties, and in the recovery of the redox signals. Importantly, the pattern of redox signal changes of catechol can be detected optically, as the oxidized quinone state is darker in color than the reduced catechol state. Using a simple cell phone imaging application, we demonstrate that erythritol can be distinguished from other sweeteners in real samples using the oxidized catechol-Chit0/agarose hydrogel film. Thus, we envision that this method could allow diabetics and people who need to control their sugar intake to detect whether the product contains only erythritol in the field or at home. In addition, this work further illustrates the potential of bio-derived materials for performing redox-based functions and enzyme-free visualization assays.

In vitro potency of xeruborbactam in combination with multiple β-lactam antibiotics in comparison with other β-lactam/β-lactamase inhibitor (BLI) combinations against carbapenem-resistant and extended-spectrum β-lactamase-producing Enterobacterales.

Recently, several β-lactam (BL)/β-lactamase inhibitor (BLI) combinations have entered clinical testing or have been marketed for use, but limited direct comparative studies of their in vitro activity exist. Xeruborbactam (XER, also known as QPX7728), which is undergoing clinical development, is a cyclic boronate BLI with potent inhibitory activity against serine (serine β-lactamase) and metallo-β-lactamases (MBLs). The objectives of this study were (i) to compare the potency and spectrum of β-lactamase inhibition by various BLIs in biochemical assays using purified β-lactamases and in microbiological assays using the panel of laboratory strains expressing diverse serine and metallo-β-lactamases and (ii) to compare the in vitro potency of XER in combination with multiple β-lactam antibiotics to that of other BL/BLI combinations in head-to-head testing against recent isolates of carbapenem-resistant Enterobacterales (CRE). Minimal inhibitory concentrations (MICs) of XER combinations were tested with XER at fixed 4 or 8 µg/mL, and MIC testing was conducted in a blinded fashion using Clinical and Laboratory Standards Institute reference methods. Xeruborbactam and taniborbactam (TAN) were the only BLIs that inhibited clinically important MBLs. The spectrum of activity of xeruborbactam included several MBLs identified in Enterobacterales, e.g., and various IMP enzymes and NDM-9 that were not inhibited by taniborbactam. Xeruborbactam potency against the majority of purified β-lactamases was the highest in comparison with other BLIs. Meropenem-xeruborbactam (MEM-XER, fixed 8 µg/mL) was the most potent combination against MBL-negative CRE with MIC90 values of 0.125 µg/mL. MEM-XER and cefepime-taniborbactam (FEP-TAN) were the only BL/BLIs with activity against MBL-producing CREs; with MEM-XER (MIC90 of 1 µg/mL) being at least 16-fold more potent than FEP-TAN (MIC90 of 16 µg/mL). MEM-XER MIC values were ≤8 µg/mL for >90% of CRE, including both MBL-negative and MBL-positive isolates, with FEP-TAN MIC of >8 µg/mL. Xeruborbactam also significantly enhanced potency of other β-lactam antibiotics, including cefepime, ceftolozane, ceftriaxone, aztreonam, piperacillin, and ertapenem, against clinical isolates of Enterobacterales that carried various class A, class C, and class D extended-spectrum β-lactamases and carbapenem-resistant Enterobacterales, including metallo-β-lactamase-producing isolates. These results strongly support further clinical development of xeruborbactam combinations.

IN SILICO STUDY OF NEW SCHIFF BASE-AND AMIDE-BORONIC ACID DERIVATIVES AS POTENTIAL INHIBITORS OF Β-LACTAMASES

Bacteria are becoming more and more resistant to β-lactam antibiotics. One approach to lower such resistance involves combining inhibitors of β-lactamase with β-lactams antibiotics. As such, the need for innovative inhibitors of β-lactamases is urgent. therefore, the aim of this research was to design and dock two new series of amides and Schiff bases of the cyclic and noncyclic boronate derivatives into four subtypes from two different classes of the β-lactamase enzymes. In silico prediction of the pharmacokinetic profile of the designed compounds was also performed. the results revealed possible enhanced activity of 15 out of the 82 compounds, when matched with 4 existing β-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam and vaborbactam). the 15 compounds showed favorable docking interactions with the residues in the active site of all enzymes. the predicted pharmacokinetic characteristics also showed that the 15 compounds are promising as oral agents. the designed compounds have the potential to act as inhibitors of β-lactamase as shown by their docking results on 4 β-lactamase crystal structures. the pharmacokinetic profile of 15 compounds is also promising, making them suitable candidates for synthesis and in vitro testing.

Alternative boronic acids in the detection of Mycolactone A/B using the thin layer chromatography (f-TLC) method for diagnosis of Buruli ulcer

BackgroundMycobacterium ulcerans is the causative agent of Buruli ulcer. The pathology of M. ulcerans disease has been attributed to the secretion of a potent macrolide cytotoxin known as mycolactone which plays an important role in the virulence of the disease. Mycolactone is a biomarker for the diagnosis of BU that can be detected using the fluorescent-thin layer chromatography (f-TLC) technique. The technique relies on the chemical derivatization of mycolactone A/B with 2-naphthylboronic acid (BA) which acts as a fluorogenic chemosensor. However, background interferences due to co-extracted human tissue lipids, especially with clinical samples coupled with the subjectivity of the method call for an investigation to find an alternative to BA.MethodsTwenty-six commercially available arylboronic acids were initially screened as alternatives to BA using the f-TLC experiment. UV–vis measurements were also conducted to determine the absorption maximum spectra of mycolactone A/B and myco-boronic acid adducts followed by an investigation of the fluorescence-enhancing ability of the boronate ester formation between mycolactone A/B and our three most promising boronic acids (BA15, BA18, and BA21). LC–MS technique was employed to confirm the adduct formation between mycolactone and boronic acids. Furthermore, a comparative study was conducted between BA18 and BA using 6 Polymerase Chain Reaction (PCR) confirmed BU patient samples.ResultsThree of the boronic acids (BA15, BA18, and BA21) produced fluorescent band intensities superior to BA. Complexation studies conducted on thin layer chromatography (TLC) using 0.1 M solution of the three boronic acids and various volumes of 10 ng/µL of synthetic mycolactone ranging from 1 µL – 9 µL corresponding to 10 ng – 90 ng gave similar results with myco-BA18 adduct emerging with the most visibly intense fluorescence bands. UV–vis absorption maxima (λmax) for the free mycolactone A/B was observed at 362 nm, and the values for the adducts myco-BA15, myco-BA18, and myco-BA21 were at 272 nm, 270 nm, and 286 nm respectively. The comparable experimental λmax of 362 nm for mycolactone A/B to the calculated Woodward-Fieser value of 367 nm for the fatty acid side chain of mycolactone A/B demonstrate that even though 2 cyclic boronates were formed, only the boronate of the southern side chain with the chromophore was excited by irradiation at 365 nm. Fluorescence experiments have demonstrated that coupling BA18 to mycolactone A/B along the 1,3-diols remarkably enhanced the fluorescence intensity at 537 nm. High-Resolution Mass Spectrometer (HR-MS) was used to confirm the formation of the myco-BA15 adduct. Finally, f-TLC analysis of patient samples with BA18 gave improved BA18-adduct intensities compared to the original BA-adduct.ConclusionTwenty-six commercially available boronic acids were investigated as alternatives to BA, used in the f-TLC analysis for the diagnosis of BU. Three (3) of them BA15, BA18, and BA21 gave superior fluorescence band intensity profiles. They gave profiles that were easier to interpret after the myco-boronic acid adduct formation and in experiments with clinical samples from patients with BA18 the best. BA18, therefore, has been identified as a potential alternative to BA and could provide a solution to the challenge of background interference of co-extracted human tissue lipids from clinical samples currently associated with the use of BA.

In Vitro Activity of Cefepime-Taniborbactam and Comparators against Clinical Isolates of Gram-Negative Bacilli from 2018 to 2020: Results from the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) Program.

Taniborbactam is a novel cyclic boronate β-lactamase inhibitor in clinical development in combination with cefepime. We assessed the in vitro activity of cefepime-taniborbactam and comparators against a 2018-2020 collection of Enterobacterales (n = 13,731) and Pseudomonas aeruginosa (n = 4,619) isolates cultured from infected patients attending hospitals in 56 countries. MICs were determined by CLSI broth microdilution. Taniborbactam was tested at a fixed concentration of 4 μg/mL. Isolates with cefepime-taniborbactam MICs of ≥16 μg/mL underwent whole-genome sequencing. β-lactamase genes were identified in meropenem-resistant isolates by PCR/Sanger sequencing. Against Enterobacterales, taniborbactam reduced the cefepime MIC90 value by >64-fold (from >16 to 0.25 μg/mL). At ≤16 μg/mL, cefepime-taniborbactam inhibited 99.7% of all Enterobacterales isolates; >97% of isolates with multidrug-resistant (MDR) and ceftolozane-tazobactam-resistant phenotypes; ≥90% of isolates with meropenem-resistant, difficult-to-treat-resistant (DTR), meropenem-vaborbactam-resistant, and ceftazidime-avibactam-resistant phenotypes; 100% of VIM-positive, AmpC-positive, and KPC-positive isolates; 98.7% of extended-spectrum β-lactamase (ESBL)-positive; 98.8% of OXA-48-like-positive; and 84.6% of NDM-positive isolates. Against P. aeruginosa, taniborbactam reduced the cefepime MIC90 value by 4-fold (from 32 to 8 μg/mL). At ≤16 μg/mL, cefepime-taniborbactam inhibited 97.4% of all P. aeruginosa isolates; ≥85% of isolates with meropenem-resistant, MDR, and meropenem-vaborbactam-resistant phenotypes; >75% of isolates with DTR, ceftazidime-avibactam-resistant, and ceftolozane-tazobactam-resistant phenotypes; and 87.4% of VIM-positive isolates. Multiple potential mechanisms, including carriage of IMP, certain alterations in PBP3, permeability (porin) defects, and possibly, upregulation of efflux were present in most isolates with cefepime-taniborbactam MICs of ≥16 μg/mL. We conclude that cefepime-taniborbactam exhibited potent in vitro activity against Enterobacterales and P. aeruginosa and inhibited most carbapenem-resistant isolates, including those carrying serine carbapenemases or NDM/VIM metallo-β-lactamases (MBLs).

1693. Meropenem-Xeruborbactam: In Vitro Potency against Gram-Negative Bacteria in Comparison with Marketed and Investigational Beta-lactam (BL)/Beta-lactamase Inhibitor (BLI) Combinations

Abstract Background Several BLI combinations have entered into clinical testing or been approved for use but there are few comparative studies of their in vitro activity. Xeruborbactam (XER, formerly QPX7728) is a cyclic boronate BLI with potent inhibitory activity against serine and metallo-beta-lactamases (MBL). It is in clinical development in combination with meropenem (MEM). The objective of this study was to compare in vitro potency of MEM-XER to that of other investigational and approved BL/BLI combinations in head-to-head testing against recent isolates of carbapenem-resistant Enterobacterales (CRE) and Acinetobacter baumannii (CRAB) as well as Pseudomonas aeruginosa (PA). Methods The test panel of recent worldwide isolates consisted of 507 CRE including 168 MBL producers (157 NDM, 11 VIM, 1 IMP), 506 CRAB, and 506 PA that were representative of current isolates and included 65 MDR (resistant to ≥ 3 antimicrobial classes) strains. MEM-XER was tested with XER at a fixed 8 mg/L conc. and other BL/BLI combinations at their recommended BLI concentrations. MIC testing was conducted blinded to drug identity using CLSI reference methods and controlled using approved quality control bacterial strains and ranges. Results The MIC50 and MIC90 for MEM-XER vs CRE ranged from ≤ 0.03 mg/L to 0.06 mg/L and 0.06 mg/L to 1 mg/L, respectively. MEM-XER and cefepime-taniborbactam (FEP-TANI) were the only BL/BLIs with activity against MBL-producers; based on MIC90, MEM-XER (MIC90 of 1 mg/L) was 16-fold more potent than FEP-TANI (MIC90 of 16 mg/L). MEM-XER and sulbactam-durlobactam (SUL-DUR) were the only agents with high potency against CRAB, with MIC50/MIC90 of 0.5/4 mg/L and 1/2 mg/L. For the representative panel of PA, the potency of MEM-XER, FEP-TAN, ceftolozane-tazobactam (TOL-TAZ), imipenem-relebactam (IMP-REL), and CAZ-AVI was similar with MIC90s ranging between 2-8 mg/L; for the MDR panel, MIC90‘s were > 8 mg/L for all combinations, with MER-XER, IMP-REL, TOL-TAZ, and CAZ-AVI having MIC50’s of 2-4 mg/L. Conclusion Compared to the marketed or investigational BL/BLIs, MEM-XERU had the broadest coverage of carbapenem-resistant gram-negative bacteria, with the most differentiating property being activity against multiple strains of MBL-producing CRE and CRAB. Disclosures Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Jill Lindley, BS, AbbVie: Grant/Research Support.

A fluorescent turn on/off probe for glucose detection based on a boronic acid-capped 1,1′-ferrocenedicarboxylic acid functional graphene oxide

The accurate determination of glucose in the human body is highly desired because excessive ingestion of glucose may lead to obesity, diabetes and other diseases. This work demonstrates a fluorescent probe for sugar detection using the unique affinity of boronates for cis -diols. The fluorescent sensing system is composed of two components: 1) Aminated graphene oxide (GON) decorated with phenylboronic acid (BPA) and 1,1'-ferrocenedicarboxylic acid (FCA) as a fluorescence quencher (FCA–GON–BPA); and 2) fluorophores of a cis -diol modified tetraphenylethylene derivative (TPBD) with aggregation-induced emission (AIE) characteristics as the luminescence. FCA–GON–BPA can selectively bind cis -diol-containing fluorogens, such as TPBD, resulting in fluorescence quenching of the probe system. Upon addition of glucose, a new cyclic boronate ester is formed, resulting in the cis -diol-containing fluorogen dissociating from the quenched system, and TPBD fluorescence is recovered. The probe has an obvious response to the presence of glucose and a low limit of detection (LOD, 4.36 mg/mL). • The fluorophore has the characteristics of aggregation-induced emission. • The reaction platform is graphene oxide with high adsorption surface area. • Glucose preempts binding of fluorophore and quencher to release fluorescence.

Enantiopure β-isocyano-boronic esters: synthesis and exploitation in isocyanide-based multicomponent reactions

Various boron-containing isocyanides have been efficiently synthesized from the corresponding enantiopure β-substituted β-amino boronic acid pinacol esters, without need for protecting group interconversion, through a two-step, purification-free procedure. They were employed in a variety of isocyanide-based multicomponent reactions, proving to be reliable components for all of them and allowing the efficient synthesis of unprecedented, boron-containing peptidomimetics and heteroatom-rich small molecules, including biologically relevant cyclic boronates. Jointing together the β-amido boronic acid moiety, deriving from the isocyanide component, with prominent pharmacophoric rings emerging from the multicomponent process, a successful application of the molecular hybridization concept could be realized.Graphical abstract

Intrinsic Antibacterial Activity of Xeruborbactam In Vitro: Assessing Spectrum and Mode of Action.

ABSTRACTXeruborbactam (formerly QPX7728) is a cyclic boronate inhibitor of numerous serine and metallo-beta-lactamases. At concentrations generally higher than those required for beta-lactamase inhibition, xeruborbactam has direct antibacterial activity against some Gram-negative bacteria, with MIC50/MIC90 values of 16/32 μg/mL and 16/64 μg/mL against carbapenem-resistant Enterobacterales and carbapenem-resistant Acinetobacter baumannii, respectively (the MIC50/MIC90 values against Pseudomonas aeruginosa are >64 μg/mL). In Klebsiella pneumoniae, inactivation of OmpK36 alone or in combination with OmpK35 resulted in 2- to 4-fold increases in the xeruborbactam MIC. In A. baumannii and P. aeruginosa, AdeIJK and MexAB-OprM, respectively, affected xeruborbactam’s antibacterial potency (the MICs were 4- to 16-fold higher in efflux-proficient strains). In Escherichia coli and K. pneumoniae, the 50% inhibitory concentrations (IC50s) of xeruborbactam’s binding to penicillin-binding proteins (PBPs) PBP1a/PBP1b, PBP2, and PBP3 were in the 40 to 70 μM range; in A. baumannii, xeruborbactam bound to PBP1a, PBP2, and PBP3 with IC50s of 1.4 μM, 23 μM, and 140 μM, respectively. Treating K. pneumoniae and P. aeruginosa with xeruborbactam at 1× and 2× MIC resulted in changes of cellular morphology similar to those observed with meropenem; the morphological changes observed after treatment of A. baumannii were consistent with inhibition of multiple PBPs but were unique to xeruborbactam compared to the results for control beta-lactams. No single-step xeruborbactam resistance mutants were obtained after selection at 4× MIC of xeruborbactam using wild-type strains of E. coli, K. pneumoniae, and A. baumannii; mutations selected at 2× MIC in K. pneumoniae did not affect antibiotic potentiation by xeruborbactam through beta-lactamase inhibition. Consistent with inhibition of PBPs, xeruborbactam enhanced the potencies of beta-lactam antibiotics even against strains that lacked beta-lactamase. In a large panel of KPC-producing clinical isolates, the MIC90 values of meropenem tested with xeruborbactam (8 μg/mL) were at least 4-fold lower than those in combination with vaborbactam at 64 μg/mL, the concentration of vaborbactam that is associated with complete inhibition of KPC. The additional enhancement of the potency of beta-lactam antibiotics beyond beta-lactamase inhibition may contribute to the potentiation of beta-lactam antibiotics by xeruborbactam.

The Optimal Permeation of Cyclic Boronates to Cross the Outer Membrane via the Porin Pathway.

We investigated the diffusion of three cyclic boronates formulated as beta-lactamase inhibitors through the porin OmpF to evaluate their potential to cross OM via the porin pathway. The three nonbeta-lactam molecules diffuse through the porin eyelet region with the same mechanism observed for beta-lactam molecules and diazobicyclooctan derivatives, with the electric dipole moment aligned with the transversal electric field. In particular, the BOH group can interact with both the basic ladder and the acidic loop L3, which is characteristic of the size-constricted region of this class of porins. On one hand, we confirm that the transport of small molecules through enterobacter porins has a common general mechanism; on the other, the class of cyclic boronate molecules does not seem to have particular difficulties in diffusing through enterobacter porins, thus representing a good scaffold for new anti-infectives targeting Gram-negative bacteria research.

Diastereodivergent Synthesis of Cyclopentyl Boronic Esters Bearing Contiguous Fully Substituted Stereocenters.

The synthesis of molecules bearing two or more contiguous, quaternary stereocenters is challenging, owing to the difficulty in controlling stereochemistry whilst simultaneously constructing a sterically congested motif. Herein, we report the electrophile‐induced ring contractive 1,2‐metallate rearrangement of 6‐membered cyclic alkenyl boronate complexes for the synthesis of cyclopentyl boronic esters bearing two contiguous, fully substituted stereocenters with high levels of stereocontrol. Remarkably, simple variation of the reaction solvent enabled their diastereodivergent construction with facile access to complementary diastereomeric pairs. The utility of our methodology is demonstrated in the asymmetric total synthesis of (+)‐herbertene‐1,14‐diol.

Diastereodivergent Synthesis of Cyclopentyl Boronic Esters Bearing Contiguous Fully Substituted Stereocenters

AbstractThe synthesis of molecules bearing two or more contiguous, quaternary stereocenters is challenging, owing to the difficulty in controlling stereochemistry whilst simultaneously constructing a sterically congested motif. Herein, we report the electrophile‐induced ring contractive 1,2‐metallate rearrangement of 6‐membered cyclic alkenyl boronate complexes for the synthesis of cyclopentyl boronic esters bearing two contiguous, fully substituted stereocenters with high levels of stereocontrol. Remarkably, simple variation of the reaction solvent enabled their diastereodivergent construction with facile access to complementary diastereomeric pairs. The utility of our methodology is demonstrated in the asymmetric total synthesis of (+)‐herbertene‐1,14‐diol.

Meropenem-vaborbactam: a critical positioning for the management of infections by Carbapenem-resistant Enterobacteriaceae

Introduction The review aims to review the positioning of meropenem-vaborbactam in clinical practice, taking into consideration the characteristics of other available drugs, namely ceftazidime-avibactam, plazomicin and colistin. Areas covered The search terms “meropenem-vaborbactam” or RX7009 for the years 2006 until 2021 were used. Expert opinion Coupling of meropenem with the cyclic boronate derivative varobactam enhances considerably the in vitro intrinsic activity of meropenem against isolates producing KPC (Klebsiella pneumoniae-producing carbapenemase). The drug has linear elimination and the ratio of the area under the curve of the free drug to the minimum inhibitory concentration is the main pharmacodynamics variable determining bacterial clearance. Meropenem-vaborbactam is currently approved for the management of complicated urinary tract infections including acute pyelonephritis, complicated intraabdominal infections and hospital-acquired pneumonia including ventilator-associated pneumonia.

Predicting the Activity of Boronate Inhibitors Against Metallo-beta-lactamase Enzymes

Potency of boronate inhibitors against metallo-β-lactamases (MβLs) has been found to be dependent on the electrophilicity of the boron atom. It forms a covalent bond with the oxygen atom of the catalytic OH− ion in the active site of the enzyme. The ability of the boronate inhibitor to influence the protein conformation also affects the binding potency. Molecular dynamics (MD) simulations of cyclic and non-cyclic boronate complexes with NDM-1 MβL show their higher impact on the inhibitor efficiency compared with the electrophilicity of the boron atom. Therefore, we focus on the hardware impact on the computational speedup of the GPU-accelerated MD. Using this data, we propose a comprehensive protocol for in silico prediction of the activity of boronate molecules against MβL enzymes, which includes MD simulations, combined quantum mechanics / molecular mechanics (QM/MM) computations and molecular dynamics simulations with the QM/MM potentials (QM/MM MD).