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The first example of employing a mixed carboxylic-sulfonic anhydride in reaction with imines is reported. Unlike its well-studied isostere homophthalic anhydride, benzo[c][1,2]oxathiin-3(4H)-one 1,1-dioxide gave no product of a formal [4 + 2] cycloaddition and only followed an alternative reaction pathway toward β-lactams, presumably, via a formal [2 + 2] cycloaddition (a Staudinger-type reaction). Optimized reaction conditions involve the use of triethylamine as a base promoter, which also allows isolating the product β-lactam benzene sulfonic acids as respective triethylammonium salts by conventional column chromatography. The reaction shows some preference to trans-isomer formation; pure diastereomers can be isolated in some cases.

Resumen Las exacerbaciones pulmonares de causa infecciosa son una de las mayores complicaciones en los pacientes con fibrosis quística (FQ). Estas se asocian a un progresivo aumento en la morbilidad y mortalidad. El tratamiento antimicrobiano se realiza dependiendo del microorganismo aislado. Con frecuencia se utilizan antimicrobianos β-lactámicos, los cuales no están exentos de reacciones adversas. A continuación, se describen dos casos de neutropenia tras el uso prolongado de cefepime en pacientes con FQ.

A series of β-lactams containing the ferrocene moiety were synthesized through the Staudinger reaction between ferrocenylketene generated by the thermal Wolff rearrangement of the corresponding dia...

Stereoselective synthesis of novel monocyclic trans-3-halogenated-4-pyrazolyl-β-lactams 5 is described. The reaction of ketene derived from α-bromo/chloroethanoic acids 4 using POCl3 and Et3N with ...

Background Carbapenem-resistant Pseudomonas aeruginosa (CRPA) often results from multiple mechanisms, creating unique phenotypic patterns of resistance including retaining susceptibility to traditional antipseudomonal β-lactams: cefepime (FEP), ceftazidime (CAZ) and piperacillin-tazobactam (TZP). Outcomes of patients with CRPA susceptible to FEP, CAZ and TZP are unclear. Methods The Georgia Emerging Infections Programed performs active, population-based surveillance for CRPA (minimum inhibitory concentration [MIC] ≥ 8 µg/mL for doripenem, imipenem or meropenem) isolated from sterile sites, urine, lower respiratory tracts and wounds in metropolitan Atlanta. We created a retrospective cohort of adults without cystic fibrosis with their first episode of CRPA while hospitalized or hospitalized within 1 week, from 8/2016 – 7/2018. We compared patients with CRPA that remained susceptible to FEP, CAZ and TZP (“susceptible CRPA”) to those that were not (“resistant CRPA”) including multivariable logistic regression for 30-day mortality. Results Among 643 patients, 638 had susceptibility results available for FEP, CAZ or TZP. 60% were male, median age was 65 years, and median Charlson comorbidity index was 2 (Table 1). Most (66%) resided in a hospital or long-term care facility 4 days prior to culture. The most common source was urine (38%). Non-susceptibility to multiple antibiotic classes was common: 523 (81%) for 3 classes and 214 (33%) for 5 classes (Table 2). 220 (34%) patients had susceptible CRPA and compared to patients with resistant CRPA, were more likely to have lived in a private residence, have a community-associated infection, and less likely to be in the ICU previously (Table 1). Patients with susceptible CRPA had a similar crude 30-day mortality (16% vs 12%, p = 0.15) to those with resistant CRPA, but in a multivariable analysis had an increased 30-day mortality (OR 1.9; 95% CI 1.1–3.2). Table 1 (Part 1/2): Characteristics and outcomes of hospitalized patients with carbapenem-resistant Pseudomonas aeruginosa (CRPA) in metropolitan Atlanta, stratified by antipseudomonal β-lactam susceptibility Table 1 (Part 2/2): Characteristics and outcomes of hospitalized patients with carbapenem-resistant Pseudomonas aeruginosa (CRPA) in metropolitan Atlanta, stratified by antipseudomonal β-lactam susceptibility Table 2: Antibacterial susceptibility results for hospitalized patients with carbapenem-resistant Pseudomonas aeruginosa in metropolitan Atlanta Conclusion Over 1/3 of hospitalized patients with CRPA retained susceptibility to other antipseudomonal β-lactams, but had an increased mortality compared to CRPA resistant to other β-lactams. Further research into mechanisms of resistance or antibiotics received might help explain this unexpected finding. Disclosures Jessica Howard-Anderson, MD, Antibacterial Resistance Leadership Group (ARLG) (Other Financial or Material Support, The ARLG fellowship provides salary support for ID fellowship and mentored research training)

Due to the widespread emergence of resistant bacterial strains, an urgent need for the development of new antibacterial agents with novel modes of action has emerged. The discovery of naturally occurring monocyclic β-lactams in the late 1970s, mainly active against aerobic Gram-negative bacteria, has introduced a new approach in the design and development of novel antibacterial β-lactam agents. The main goal was the derivatization of the azetidin-2-one core in order to improve their antibacterial potency, broaden their spectrum of activity, and enhance their β-lactamase stability. In that respect, our review covers the updates in the field of monocyclic β-lactam antibiotics during the last three decades, taking into account an extensive collection of references. An overview of the relationships between the structural features of these monocyclic β-lactams, classified according to their N-substituent, and the associated antibacterial or β-lactamase inhibitory activities is provided. The different paragraphs disclose a number of well-established classes of compounds, such as monobactams, monosulfactams, monocarbams, monophosphams, nocardicins, as well as other known representative classes. Moreover, this review draws attention to some less common but, nevertheless, possibly important types of monocyclic β-lactams and concludes by highlighting the recent developments on siderophore-conjugated classes of monocyclic β-lactams.

Due to the emerging resistance against classical beta-lactam-based antibiotics, a growing number of bacterial infections has become harder to treat. This alarming tendency necessitates continued research on novel antibacterial agents. Many classes of b- lactam antibiotics are characterized by the presence of the 3- aminoazetidin-2-one core, which resembles the natural substrate of the target penicillin-binding proteins. In that re-spect, this Review summarizes the different synthetic pathways toward this key structure for the development of new antibacterial agents. The most extensively applied methods for 3-amino-beta-lactam ring formation are discussed, in addition to a few less common strategies. Moreover, approaches to introduce the 3-amino substituent after ring formation are also covered.

The δ-(l-α-aminoadipyl)-l-cysteinyl-d-valine (ACV) tripeptide is the first dedicated intermediate in the biosynthetic pathway leading to the penicillin and cephalosporin classes of β-lactam natural products in bacteria and fungi. It is synthesized nonribosomally by the ACV synthetase (ACVS) enzyme, which has been purified and partially characterized from many sources. Due to its large size and instability, many details regarding the reaction mechanism of ACVS are still not fully understood. In this review we discuss the chronology and associated methodology that led to the discovery of ACVS, some of the main findings regarding its activities, and some recent/current studies being conducted on the enzyme. In addition, we conclude with perspectives on what can be done to increase our understating of this very important protein in the future.

A series of ethanolamine-derived Ugi four-component-reaction adducts were subjected to a base-mediated cycloisomerization/rearrangement cascade to give functionalized 2,5-pyrrolidinediones in good-to-excellent yields. The method was extended to amino-acid-derived chiral ethanolamines to access enantiomerically pure 2,5-pyrrolidinediones. The reaction is diastereospecific, and mixtures of 2,5-pyrrolidinediones and β-lactams were formed with high enantiomeric excess. Mechanistic studies revealed that the reaction proceeds through the formation of a β-lactam intermediate by intramolecular cyclization in a 4-exo-dig fashion. This then rearranges further to give the 2,5-pyrrolidinedione with the help of the hydroxyethyl appendage. Computational analysis of the reaction profile demonstrated that the intramolecular 4-exo-dig cyclization is energetically favoured over the 5-endo-dig pathway, so this results in the formation of the β-lactam.

A simple and efficient protocol for the conversion of N-p-methoxyphenyl, N-p-ethoxyphenyl, N-p-methoxynaphthyl, N-3,4-dimethoxybenzyl and N-p-methoxybenzyl-2-azetidinones to N-unsubstituted 2-azetidinones using cerium(IV) tetrabutylammonium nitrate (CTAN) in dichloromethane is described. The method is compatible with a number of functional groups, and N-unsubstituted 2-azetidinones can be prepared under mild conditions at room temperature. The reaction is rapid, and pure products are obtained in good yields.

The efficient diastereoselective synthesis of 3-acetoxy/methoxy/phthalimido-β-lactams 2/2′ , 3/3′ and 4/4′ respectively was performed using chiral imines 1 obtained from chiral amines. Factors (solvent, temperature, substituent, steric bulk) influencing the stereoselectivity and the diastereomeric ratio were also studied in detail. The diastereoselectivity of the two isomers was determined from the ratio of integral values of doublets of C3–H and C4–H and from the integral values of H in –C H (Me/Et)Ph/Np of the two diastereomers. Representative pairs of cis -diastereomers were separated by efficient column chromatography.

Pd-Catalyzed sequential monoarylation/amidation of C(sp3)–H bonds of alanine enabled by a removable 5-methoxyquinolin-8-amine (MQ) auxiliary is described. This process is highly efficient and compatible with a variety of functional groups, providing a general and practical access to various α-amino-β-lactams. The synthetic potential of this protocol is further demonstrated by the stereoselective synthesis of orthogonally protected anti-α,β-diamino acids.

Background Mab is a MDR nontuberculous mycobacterium that causes lung infections in patients with structural lung disease. Mab harbors a chromosomally encoded class A β-lactamase, BlaMab, able to hydrolyze penicillins, cephalosporins and carbapenems. L,D- and D,D-transpeptidases (L,D TP and D,D TP) shape peptidoglycan (PG) synthesis and contribute to cell wall structure. Select combinations of β-lactams that inhibit L,D TP and D,D TPs and BlaMab are desirable as they can potentially improve treatment outcomes. DUR is a novel DBO β-lactamase inhibitor (BLI) with broad-spectrum activity against Ambler class A, C, and D β-lactamases (Fig.). Here, we investigated the mechanism of action and efficacy of DUR alone and combined with select β-lactams in restoring susceptibility of Mab to β-lactam antibiotics Methods Minimum inhibitory concentrations (MICs) of cefuroxime (CEF), imipenem (IMI) and amoxicillin (Amox) with or without DUR were determined using microdilution. Approximately 5 x 105 colony-forming units per milliliter were inoculated into Middlebrook 7H9 Broth supplemented with 10% (vol/vol) oleic albumin dextrose catalase and 0.05% (vol/vol) Tween 80. When more than 2 drugs were combined, Amox was added at fixed concentration of 8 µg/ml to serial dilutions of CEF-DUR or IMI-DUR. Mab isolates were incubated with test agents at 30°C for 48 h, and MIC was defined as lowest antibiotic concentration that prevented visible bacterial growth. Reaction intermediates in the inactivation pathway of BlaMab, L,D-TP and D,D-TPs with DUR Results One hundred clinically derived and previously characterized isolates were tested in these assays. MIC50 and MIC90 of DUR alone was 4 and 8 µg/ml, demonstrating intrinsic activity. Combinations of DUR-IMI or DUR-CEF plus 8 µg/mL Amox lowered MIC50 to < 0.06 µg/ml in all 100 clinical isolates (Table). Mass spectrometry analyses of BlaMab, L,D-TP and D,D-TPs Mab (2,4) inactivated by DUR showed formation of stable adducts of DUR to BlaMab, L,D-TP and D,D-TPs (Fig.) Chemical composition of durlobactam (DUR) and mass spectrometry of BlaMab, L,D TP and D,D TPs incubated with DUR MIC50 and MIC90 of 100 Mab clinical strains against DUR alone and in combination with Amox, CEF and IMI Conclusion We demonstrate that a novel DBO BLI, DUR, is an active agent with potent intrinsic activity against BlaMab and Mab L,D-TPs and D,D-TPs. We hypothesize that DUR improves b-lactam activity by protecting against the hydrolytic activity of BlaMab and by targeting multiple steps in PG synthesis Disclosures Alita Miller, PhD, Entasis Therapeutics (Employee) Robert A. Bonomo, MD, Entasis, Merck, Venatorx (Research Grant or Support)

Background ST258 K. pneumoniae and ST131 E. coli clones are considered vectors for the global spread of multidrug resistance. We evaluated the activity of β-lactams in combination with QPX7728, a novel β-lactamase inhibitor active against all β-lactamase classes, against a collection of 210 isolates belonging to these clones collected from a worldwide surveillance study. Methods A total of 118 ST258 K. pneumoniae and 92 ST131 E. coli (single loci variant also included) were susceptibility tested by reference broth microdilution against various β-lactams ± QPX7728 and comparator agents. All isolates were screened for β-lactamases using whole genome sequencing analysis. Results All β-lactam agents had limited activity against 118 ST258 K. pneumoniae (1.7–7.6% susceptible). Among these, 104 carried carbapenemase-encoding genes: 66 KPC variants, 20 NDM and 17 OXA-48-like. One isolate carried 2 carbapenemases. The addition of QPX7728 at 4 mg/L or 8 mg/L lowered the MICs for cefepime (MIC50/90, 0.25/1 mg/L and MIC50/90, 0.12/0.5 mg/L), ceftolozane (MIC50/90, 0.5/ > 32 mg/L and MIC50/90, 0.25/16 mg/L), ertapenem (MIC50/90, 0.12/2 mg/L and MIC50/90, 0.06/0.5 mg/L), and meropenem (MIC50/90, 0.06/0.5 mg/L and MIC50/90, 0.03/0.12 mg/L; Table). QPX7728 at 4 mg/L reduced the ceftibuten (MIC50/90, 0.25/8 mg/L) or tebipenem (MIC50/90, 0.12/2 mg/L) MICs for ST258 isolates. E. coli ST131 carried mainly CTX-M variant (85 isolates), but 6 isolates harbored carbapenemases. Carbapenems were the only β-lactams displaying > 80.0% activity against ST131 E. coli, followed by piperacillin-tazobactam (79.3% susceptible). Only 5.4%and 41.3% ST131 isolates were susceptible to cefepime and ceftibuten, respectively. MIC50/MIC90 values for these agents with QPX7728 were ≤ 0.015/≤ 0.015 mg/L for cefepime and ≤ 0.015/0.06 mg/L for ceftolozane with the inhibitor at 8 mg/L and ≤ 0.015/0.03 mg/L for ceftibuten with the inhibitor at 4 mg/L. Conclusion QPX7728 lowered the MICs for all agents tested to clinically achievable levels when tested against isolates multidrug resistant belonging to important clones responsible to the dissemination of KPC, CTX variants, and metallo-β-lactamases. The development of this broad β-lactamase inhibitor should be pursued. Table 1 Disclosures Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Jill Lindley, Allergan (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Timothy B. Doyle, Allergan (Research Grant or Support)Allergan (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Olga Lomovskaya, PhD, Qpex Biopharma (Employee)

International audience

The synthesis of a small set of β-lactams containing isocyanate precursors is described. The release of the isocyanate precursor in model hydrolysis experiments was substantiated by trapping experiments, thus confirming that β-lactams can be designed that are capable of releasing alternatively reactive species. Preliminary biological assessments are also briefly discussed.

Intramolecular C–H insertion reactions of α-diazocarbonyl compounds typically proceed with preferential five-membered ring formation. However, the presence of a heteroatom such as nitrogen can activate an adjacent C–H site towards insertion resulting in regiocontrol issues. In the case of α-diazoacetamide derivatives, both β- and γ-lactam products are possible owing to this activating effect. Both β- and γ-lactam products are powerful synthetic building blocks in the area of organic synthesis, as well as a common scaffold in a range of natural and pharmaceutical products and therefore C–H insertion reactions to form such compounds are attractive processes.

The cycloadditions of 2,2,2-trifluorodiazoethane with α-methylene-β-lactams were investigated. The reaction proceeded via a [3+2] cycloaddition mode under metal-free conditions, whereas the use of an iron catalyst enabled a cyclopropanation to occur. This protocol offers a facile access to a broad range of trifluoromethyl containing spirocyclic β-lactams.

A novel strategy to synthesize stereoselective β-lactams has been disclosed via cyclopropenium-ion-catalyzed reaction of substituted acetic acids with aldimines under mild conditions. Products are formed in high yields (86–95%) and good diastereoselectivity within 3–4 h. The new reaction is focused on the exploration of the scope of cyclopropenium-ion catalysis and introduction of a catalytic version of one-step Staudinger reaction for β-lactam synthesis. The reaction is effective for a range of substituted acetic acids and aldimines.

International audience; Mono- and disubstituted 4-CF3 β-lactams at the C-3 position have been obtained stereoselectively under basic conditions. A wide range of function such as alcohols, alkyls, aryls, esters, and double and triple bonds have been introduced.

The discovery of antibiotics to treat bacterial infections has had a dramatic and positive impact on human health. However, shortly after the introduction of a new antibiotic, bacteria often develop resistance. The bacterial cell envelope is essential for cell viability and is the target of many of the most commonly used antibiotics, including β-lactam antibiotics. Resistance to β-lactams is often dependent upon β-lactamases. In B. cereus, B. thuringiensis, and some B. anthracis strains, the expression of some β-lactamases is inducible. This inducible β-lactamase expression is controlled by activation of an alternative σ factor called σP. Here, we show that β-lactam antibiotics induce σP activation by degradation of the anti-σ factor RsiP., Bacteria can utilize alternative σ factors to regulate sets of genes in response to changes in the environment. The largest and most diverse group of alternative σ factors are the extracytoplasmic function (ECF) σ factors. σP is an ECF σ factor found in Bacillus anthracis, Bacillus cereus, and Bacillus thuringiensis. Previous work showed that σP is induced by ampicillin, a β-lactam antibiotic, and required for resistance to ampicillin. However, it was not known how activation of σP is controlled or what other antibiotics may activate σP. Here, we report that activation of σP is specific to a subset of β-lactams and that σP is required for resistance to these β-lactams. We demonstrate that activation of σP is controlled by the proteolytic destruction of the anti-σ factor RsiP and that degradation of RsiP requires multiple proteases. Upon exposure to β-lactams, the extracellular domain of RsiP is cleaved by an unknown protease, which we predict cleaves at site-1. Following cleavage by the unknown protease, the N terminus of RsiP is further degraded by the site-2 intramembrane protease RasP. Our data indicate that RasP cleavage of RsiP is not the rate-limiting step in σP activation. This proteolytic cascade leads to activation of σP, which induces resistance to β-lactams likely via increased expression of β-lactamases. IMPORTANCE The discovery of antibiotics to treat bacterial infections has had a dramatic and positive impact on human health. However, shortly after the introduction of a new antibiotic, bacteria often develop resistance. The bacterial cell envelope is essential for cell viability and is the target of many of the most commonly used antibiotics, including β-lactam antibiotics. Resistance to β-lactams is often dependent upon β-lactamases. In B. cereus, B. thuringiensis, and some B. anthracis strains, the expression of some β-lactamases is inducible. This inducible β-lactamase expression is controlled by activation of an alternative σ factor called σP. Here, we show that β-lactam antibiotics induce σP activation by degradation of the anti-σ factor RsiP.

Functionalized β-lactams are highly important motifs in synthetic chemistry. We report an efficient and novel approach to the synthesis of β-lactams via a copper(i)-catalyzed cascade process involving C(benzyl)-H radical abstraction, intermolecular alkene addition, and intramolecular amination reaction. Variously substituted alkenes were synthesized from vinylacetic acid, leading to the corresponding β-lactams in moderate to good yields. Preliminary studies indicate that the reaction undergoes a free radical mechanism via a Cu(i)/Cu(ii)/Cu(iii) catalytic cycle.

The treatment of 3-bromo β-lactams by an aryl Grignard, in the presence of CoCl2 (2 mol %) and TMEDA (2 mol %) in THF, produces 3-aryl β-lactams in good yields and excellent diastereoselectivity.

Configurationally stable e-amido-propargylindiums, generated in situ from N-Ts-4-ethynylazetidin-2-ones in the presence of InI, catalytic amounts of Pd(PPh3)4, and N-methylimidazole or pyridine ligand react with unusual regioselectivity with aromatic and aliphatic aldehydes to afford 2,6- syn- or 2,6- anti-allenediols with excellent central-to-axial chirality transfer and useful levels of acyclic remote 1,5-stereocontrol.

A new Kinugasa reaction protocol has been elaborated for the one-pot synthesis of 4-substituted β-lactams utilizing calcium carbide and nitrone derivatives. Calcium carbide is thereby activated by TBAF·3H2O in the presence of CuCl/NMI. The ease of synthesis and use of inexpensive chemicals provides rapid access of practical quantities of β-lactams exclusively substituted at position 4.

A novel three-component reaction of N-hydroxyanilines, enynones, and diazo compounds has been developed via a metal-organo relay catalysis, providing highly functionalized β-lactams containing two quaternary carbon centers in good yields and with excellent diastereoselectivities. This protocol features a sequential reaction of Rh-catalyzed imine formation, Wolff rearrangement, and benzoylquinine-catalyzed Staudinger cyclization using the stable, benign, and readily available N-hydroxyanilines as the N-resources.

Metallo-β-lactamase (MBL)-producing Enterobacteriaceae are of grave clinical concern, particularly as there are no metallo-β-lactamase inhibitors approved for clinical use. The discovery and development of MBL inhibitors to restore the efficacy of available β-lactams are thus imperative. We investigated a zinc-chelating moiety, 1,4,7-triazacyclononane (TACN), for its inhibitory activity against clinical carbapenem-resistant Enterobacteriaceae. MICs, minimum bactericidal concentrations (MBCs), the serum effect, fractional inhibitory concentration indexes, and time-kill kinetics were determined using broth microdilution techniques according to Clinical and Laboratory Standards Institute (CSLI) guidelines. Enzyme kinetic parameters and the cytotoxic effects of TACN were determined using spectrophotometric assays. The interactions of the enzyme-TACN complex were investigated by computational studies. Meropenem regained its activity against carbapenemase-producing Enterobacteriaceae, with the MIC decreasing from between 8 and 64 mg/liter to 0.03 mg/liter in the presence of TACN. The TACN-meropenem combination showed bactericidal effects with an MBC/MIC ratio of ≤4, and synergistic activity was observed. Human serum effects on the MICs were insignificant, and TACN was found to be noncytotoxic at concentrations above the MIC values. Computational studies predicted that TACN inhibits MBLs by targeting their catalytic active-site pockets. This was supported by its inhibition constant (K(i)), which was 0.044 μM, and its inactivation constant (K(inact)), which was 0.0406 min(−1), demonstrating that TACN inhibits MBLs efficiently and holds promise as a potential inhibitor. IMPORTANCE Carbapenem-resistant Enterobacteriaceae (CRE)-mediated infections remain a significant public health concern and have been reported to be critical in the World Health Organization’s priority pathogens list for the research and development of new antibiotics. CRE produce enzymes, such as metallo-β-lactamases (MBLs), which inactivate β-lactam antibiotics. Combination therapies involving a β-lactam antibiotic and a β-lactamase inhibitor remain a major treatment option for infections caused by β-lactamase-producing organisms. Currently, no MBL inhibitor–β-lactam combination therapy is clinically available for MBL-positive bacterial infections. Hence, developing efficient molecules capable of inhibiting these enzymes could be a promising way to overcome this phenomenon. TACN played a significant role in the inhibitory activity of the tested molecules against CREs by potentiating the activity of carbapenem. This study demonstrates that TACN inhibits MBLs efficiently and holds promises as a potential MBL inhibitor to help curb the global health threat posed by MBL-producing CREs.

Facile and efficient synthesis of sulfoxide esters using menthols as chiral auxiliary is described. Phenylthio/benzylthio/naphthylthioacetic esters act as an efficient substrate for chiral sulfoxides via oxidation in one step. The structural and stereochemical aspects of target product were established on the basis of various spectroscopic studies, namely FT-IR, NMR (1H NMR and 13C NMR) and elemental analysis. This method is simple, fast, convenient and very efficient.

Aim: The present study aims to determine the susceptibility of Aggregatibacter actinomycetemcomitans to amoxicillin by investigating a large collection of oral strains of diverse geographical origin. Methods: Two hundred and fifty-seven A. actinomycetemcomitans strains were serotyped using a multiplex polymerase chain reaction, and minimal inhibitory concentration (MIC) values of amoxicillin were determined using the agar dilution method (range 0.25–8.0 mg/L). The plates were spot-wise inoculated with approximately 10 4 colony-forming units, incubated in 5% CO 2 at 37 C°, and visually inspected after 24 and 48 hr. A MIC ≤ 2.00 mg/L was categorised as susceptible using EUCAST interpretative criteria for Haemophilus species. Results: Amoxicillin MIC values varied from 0.25 mg/L to 2.00 mg/L, and all tested strains, including strains previously reported as resistant, were susceptible to amoxicillin. The MIC 50 was 1.00 mg/L and the MIC 90 was 2.00 mg/L. Conclusion: Meticulous investigation of strains including isolates previously reported as resistant could not confirm the emergence of resistance to β-lactams in A. actinomycetemcomitans. Based on the present in vitro results, amoxicillin can be considered a key oral antimicrobial agent for treatment of A. actinomycetemcomitans.

Background Aztreonam is often given to patients with a documented β-lactam allergy in lieu of a first-line anti-pseudomonal β-lactam (APBL). However, aztreonam offers no gram positive coverage and data suggest that gram negative organisms have lower susceptibility rates to this antibiotic than to APBLs. Septic patients are especially vulnerable to poor outcomes since inappropriate initial antimicrobial therapy has been shown to be an independent predictor of increased mortality. The purpose of this study was to determine whether septic patients treated with aztreonam experience inferior outcomes compared to those treated with an APBL. Methods This was a retrospective, multicenter, cohort study of all adult patients in metro Charlotte Atrium Health facilities treated for sepsis or septic shock from January 2014 to October 2017. Patients receiving either aztreonam or an APBL were identified using the system-wide sepsis database and enrolled in a 1:2 ratio. Patients were excluded if there was no infection-related discharge ICD-9 or ICD-10 code, if they received both aztreonam and an APBL in the first 8 hours, or if they received fewer than 2 doses of the study antibiotic. The primary endpoint was in-hospital mortality. Results A total of 194 patients received aztreonam and 388 patients received an APBL. β-lactam allergies were more common in patients who received aztreonam compared to APBL (97% vs. 14.2%, p < 0.01). In-hospital mortality rates were greater in the patients who received aztreonam vs. APBL (22.7% vs. 12.9%, p = 0.0025). After adjusting for APACHE II score, initial aztreonam exposure remained independently associated with hospital mortality (OR = 1.74, 95% CI: 1.0 – 2.8, p = 0.02). Additionally, we identified an increase in combination therapy with the use of aminoglycosides (28.9% vs. 12.4%, p < 0.0001) and fluoroquinolones (50.5% vs. 25.8%, p < 0.0001) in patients receiving aztreonam. No difference was found in overall length of stay or ICU length of stay. Conclusion In septic patients, the use of aztreonam as the backbone of antimicrobial therapy may result in increased mortality. This highlights the importance of stewardship interventions that obtain an accurate allergy history and encourage the use of APBL antibiotics whenever feasible. Disclosures Kelly E. Pillinger, PharmD, BCIDP, Pharmacy Times (Other Financial or Material Support, Speaker)

3-Methylene-4-(trifluoromethyl)azetidin-2-ones were efficiently prepared from the corresponding 3-oxo-4-trifluoromethyl--lactams and successfully evaluated as novel building blocks in organic synthesis. In particular, Michael additions, electrophilic additions, and cycloadditions were applied to allow easy access to a broad variety of stereodefined mono- and spirocyclic 4-CF3-beta-lactams as useful synthetic intermediates en route to a variety of biologically relevant CF3-functionalized target structures.

The direct synthesis of (E)- and (Z)-3-allylidene-β-lactams from 3-allyl-3-phenylseleno-β-lactams under mild conditions has been described. 3-Allyl-3-phenylseleno-β-lactams acts as an efficient substrate for in situ oxidation and elimination in one step. This method is simple, convenient, fast, and very efficient.

An effective and stereoselective synthesis of 3-(1′-methyl/phenylallyl)-3-phenylthio-β-lactams (3/4) using substituted allylsilane and Lewis acid is described. The reaction leads to the formation of a mixture of C-3 substituted allyl β-Lactams. However, these compounds on desulphurisation using tri-n-butyltinhydride and Raney Ni provide two separable diastereomers of the reduced product.

The kinetics of the gas-phase thermolysis reaction of seven β-lactams and their thione analogues were investigated over the temperature range 533–603 K for the β-lactams and 463–542 K for the β-thiolactams. The average values of the energy of activation (Ea) (kJ mol−1) and Arrhenius log A (s–1) were, respectively, 170.8 ± 18.6 and 12.4 ± 1.6 for the lactams and 131.7 ± 18.2 and 11.0 ± 2.0 for the thione analogues. The entropy of activation (ΔS#) was negative for of the substrates and slightly positive for three. The rate constants (k) (s−1) were calculated for 510 K and compared for the two series of azetidinones. The effects of substituents on rates and the novel role played by the C=O and C=S moieties on the relative reactivities of the cyclic amides are rationalized on the basis of a formal retro[2+2]cycloaddition mechanism used earlier to explain the products of the gas-phase thermolysis reaction of the present azetidinones.

Ru-catalyzed cross-metathesis (CM) reaction between β-arylated α-methylidene-β-lactams and terminal olefins was developed. The CM reaction is effectively catalyzed with Hoveyda-Grubbs second-generation catalyst affording corresponding α-alkylidene-β-aryl-β-lactams in good isolated yields (41-83%) with exclusive Z-selectivity. The developed protocol was successfully applied for stereoselective preparation of Ezetimibe, the commercial cholesterol absorption inhibitor.