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Based on sequential organic transformations, that is, diimine formation, Staudinger [2 + 2] ketene-imine cycloaddition, and ring-closing metathesis (RCM) reactions, the synthesis with full structural identification including NMR and HRMS spectral data along with single X-ray diffraction analysis (for

Among the acquired mechanisms of resistance to antibiotics of microorganisms, the production of beta-lactamases, enzymes that inactivate penicillins, cephalosporins, carbapenems, and monobactams, is widespread. Most often, such beta-lactamases, in particular ESBL (extended-spectrum beta-lactamases), are capable of destroying III and IV generations of cephalosporins. One of the important ESBL producers is Escherichia coli and, to a lesser extent, Salmonella enteritidis, which are clinically significant in animals and humans. The purpose of the study was to screen ESBL DDM using cephalosporin markers and screening of mobile extrachromosomal factors of bacterial heredity – plasmids (potentially dangerous factors of genetic transport) in isolates of E. coli and S. enteritidis, polyresistant to aminoderms, from environmental objects, patho- and biological material, raw materials and products of animal origin. Results of our studies have shown the level of their distribution among animals, poultry, since from 13 field isolates of E. coli isolated from the milk of cows with mastitis and pathological material from pigs, ESBL production was found in 3 strains (23.1%) and from 18 field isolates of S. enteritidis isolated from pathological material from poultry, ESBL production was found in 2 strains (11.1%). Based on the results of molecular genetics studies, the presence of resistance plasmids (R-plasmids) in 9 field E. coli isolates was confirmed, 4 of which produced acquired beta-lactamases, incl. ESBL and 8 field isolates of S. enteritidis, 7 of which confirmed the presence of acquired carbapenemases.

A convenient and versatile one-pot method for synthesis of 1,3-bis-aryl spirooxindolo-β-lactams from isatin Schiff bases and substituted phenylacetic acids using ketene-imine cycloaddition reaction with TsCl for a ketene generation has been developed. The reaction procedure does not require absolute solvents and unstable starting reagents. The studied reactions lead to cis-diastereoselective β-lactam formation for all tested phenylacetic acids except 4-MeOC6H4CH2COOH. An increase of trans-diastereomers yields with increasing temperature and solvent polarity was demonstrated.

β-Lactam compounds play a key role in medicinal chemistry, specifically as the most important class of antibiotics. Here, we report a novel one-step approach for the synthesis of α-(trifluoromethyl)-β-lactams and related products from fluorinated olefins, anilines and CO. Utilization of an advanced palladium catalyst system with the Ruphos ligand allows for selective cycloaminocarbonylations to give diverse fluorinated β-lactams in high yields., β-Lactam compounds play a key role in medicinal chemistry, specifically as the most important class of antibiotics.

Mycobacterium avium is an emerging opportunistic pathogen, globally. Infections caused by M. avium are laborious to treat and could result in drug resistance. This review discusses the importance of many factors including the cell wall in M. avium pathogenesis, since this unique structure modulates the pathogen’s ability to thrive in various hosts and environmental niches including conferring resistance to killing by antimicrobials. More research efforts in future are solicited to develop novel therapeutics targeting M. avium. The complete eradication of M. avium infection in immunocompromised individuals would need a deeper understanding of the source of infection, unique underlying mechanisms and its uncharacterized pathways. This could, perhaps in future, hold the key to target and treat M. avium more effectively.

Organic electrochemistry is a technique that allows for the heterogeneous redox reactions avoiding both the use of stoichiometric amounts of redox reagents and the resulting formation of stoichiometric by-products. In fact, the redox reagent in these reactions is the electron, which is naturally eco-friendly and produces no side compounds. It is therefore quite obvious that electrochemistry can be classified as a “green” technology. The use of this methodology in the synthesis of β-lactams is not a novelty, but the growing interest in this class of biologically active compounds, due to the discovery of new fields of application (after a moment of decrease in interest due to antibiotic resistance) has been a stimulus for the search for more efficient electrochemical ways to synthesize and transform β-lactams. Thus, this review deals with the twenty-first-century applications of electroorganic technique to the chemistry of β-lactams, by analyzing first the syntheses classified by the type of reactions (cyclization, cycloaddition, etc.) and then by manipulating the β-lactam structure, using it as a synthon. Lastly, the importance of this technique is demonstrated by a study of a pilot plant scale reduction of a cephalosporanic acid derivative to a commercially important antibiotic.

3 pags, 1 fig, Recently, Martelli and colleagues reported on the structural and functional characterization of new antimycobacterials based on N-thio-β-lactams. Surprisingly, the inhibitory mechanism follows a path unexpected for β-lactams, providing an alternative route to defeat drug-resistant strains of Mycobacterium tuberculosis.

A detailed mechanistic study of the diastereoselective CsOH-promoted cyclization of interlocked fumaramides to give β-lactams is described. The mechanistic analysis comprises the experimental evaluation of the structure-reactivity relationship for a wide range of fumaramides [2]rotaxanes (Hammet-plots), KIE studies with deuterium-labelled interlocked fumaramides and computational analysis of two alternative mechanistic pathways for the cyclization process. The obtained results confirm that: (a) the rate-determining step is the deprotonation of the N-benzyl group of the thread by the amidate group of the macrocycle generated by the external base, (b) the polyamide macrocycle plays an important role not only as activating element but also as the stereodifferenciating factor responsible for the observed diastereoselection and (c) the higher flexibility of the adamantyl core speeds up the cyclization process in diadamantyl-derived rotaxanes., A mechanistic study of the diastereoselective cyclization of interlocked fumaramides to give β-lactams unveils the key factors for successfully taming the process.

Antibiotic resistance in Pseudomonas aeruginosa is a serious concern in healthcare systems. Among the determinants of antibiotic resistance in P. aeruginosa , efflux pumps belonging to the resistance–nodulation–division (RND) family confer resistance to a broad range of antibacterial compounds. The MexXY efflux system is widely overexpressed in P. aeruginosa isolates from cystic fibrosis (CF) patients. MexXY can form functional complexes with two different outer membrane factors (OMFs), OprA and OprM. In this study, using state-of-the-art genetic tools, the substrate specificities of MexXY–OprA and MexXY–OprM complexes were determined. Our results show, for the first time, that the substrate profile of the MexXY system from P. aeruginosa PA7 can vary depending on which OM factor (OprM or OprA) it complexes with. While both MexXY–OprA and MexXY–OprM complexes are capable of effluxing aminoglycosides, the bi-anionic β-lactam molecules carbenicillin and sulbenicillin were found to only be the substrate of MexXY–OprA. Our study therefore shows that by partnering with different OMF proteins MexY can expand its substrate profile.

International audience; Purpose Staphylococcus aureus causes severe forms of community-acquired pneumonia (CAP), namely staphylococcal pleuropneumonia in young children and staphylococcal necrotising pneumonia in older patients. Methicillin resistance and the Panton–Valentine leukocidin (PVL) toxin, as well as less specific factors, have been associated with poor outcome in severe CAP, but their roles are unclear. Methods A prospective multicentre cohort study of severe staphylococcal CAP was conducted in 77 paediatric and adult intensive care units in France between January 2011 and December 2016. After age-clustering, risk factors for mortality, including pre-existing conditions, clinical presentation, laboratory features, strain genetic lineage, PVL, other virulence factors and methicillin resistance were assessed using univariate and multivariable Cox and LASSO (least absolute shrinkage and selection operator) regressions. Results Out of 163 included patients, aged 1 month to 87 years, 85 (52.1%) had PVL-positive CAP; there were 20 (12.3%) patients aged

An efficient protocol for the stereoselective synthesis of pyrazolo[5,1-b]thiazole-3-carboxylate tethered β-lactam conjugates 8a–j from novel pyrazolo [5,1-b]thiazole-3-carboxylate substituted Schiff’s bases 6a–f is reported here. The reaction between various ketene precursors and novel Schiff’s bases 6a–f afforded exclusive formation of trans-β-lactams 8a–j. The substrate scope of this approach was investigated extensively by varying different groups (R, Z). All the novel compounds were characterized using various spectroscopic techniques, such as FT-IR, 1H NMR, 13C NMR, elemental analysis, 13C NMR (DEPT-135), and mass spectrometry in representative cases. Single crystal X-ray crystallographic study of trans-ethyl 7-(1-(4-methoxyphenyl)-4-oxo-3-phenoxyazetidin-2-yl)-6-methyl-2-(methylthio)pyrazolo[5,1-b]thiazole-3-carboxylate 8a has confirmed the molecular structure and the stereochemical outcome. To the best of our knowledge, the synthesis of such types of Schiff’s bases and β-lactam conjugates has not been reported so far.

A series of novel isolated β-lactams 3a-c and thiazolidinone derivatives 4a-c were successfully synthesized from reactions of new Schiff's bases 2a-c with chloroacetyl chloride and thioglycolic acid. The chemical structures of the new compounds were confirmed through different spectroscopic techniques including IR, 1H NMR, 13C NMR, mass spectrometry and elemental analysis. The antimicrobial activity of the obtained compounds was assessed in-vitro against gram-positive Staphylococcus aureus and gram-negative Escherichia coli bacteria and Aspergillus flavus and Candida albicans fungi. Furthermore, a molecular docking study was carried out and the results indicated that compounds 3b and 4b displayed comparable binding affinity scores as that of glutamate. These two compounds are promising candidates as antibacterial and antifungal agents that would deserve further investigations.

A simple and efficient protocol for the synthesis of Schiff bases via condensation reaction of electron rich heterocyclic amines with electrophilic carbon of the carbonyl compound. Recently an impressive and important area in catalysis involved organic synthesis is the best implementation of Lewis acids as a acid catalyst for Schiff base synthesis. The higher acidic property and proper loading of catalyst leads to proper participation in reaction as a catalyst. The reactions of these Lewis acids are enhanced by porous solid support as heterogeneous catalyst. We report herein an efficient concise green synthesis of a new kind of β-lactam derivatives of 2-amino-6-nitro-benzothiazole via SiO2/P2O5 Lewis acid catalyzed Schiff bases. The reaction was carried out by the preparation of Schiff base through the condensation reaction of various aromatic aldehydes with substituted aromatic amines in the presence of P2O5/SiO2 under green conditions by simple conventional methods. Further this Schiff base used for the green synthesis of β-lactams by the reaction with chloro-acetyl chloride. The advantage of this reaction is good dispersion of active reagent sites, associated selectivity and easier work up with reusable catalyst. These qualities combined together prove these processes as truly eco-friendly green protocol with high product yields and short reaction time.

Microwave-induced bismuth nitrate-catalyzed reaction of 3-amino β-lactams with unsaturated ketones is performed in order to obtain substituted amino β-lactams. Amino β-lactams were obtained through the strategy of [2+2] ketene-imine cycloaddition followed by deprotection of phthalimido β-lactams with ethylene diamine.

Two new visible-light-mediated strategies are described starting from aryldiazoacetates. The first approach describes their reaction with azides to afford the corresponding imines, and then reaction with aryldiazoketones produces alkyl 2-carboxylate-2,3,3-trisubstituted β-lactams. The second approach describes the reaction with sulfoxides to afford the corresponding sulfoxonium ylides, followed by reaction with aryldiazoketones to produce 5-alkoxy-2,2,4-trisubstituted furan-3(2H)-ones. These protocols take advantage of the photolysis of aryldiazoacetates and the photochemically promoted Wolff rearrangement of aryldiazoketones.

Objectives: Carbapenemase-producing organisms (CPOs) are associated with high mortality rates. The recent development of β-lactamase inhibitors (BLIs) has made it possible to control CPO infections safely and effectively with β-lactams (BLs). This study aims to explicate the quantitative relationship between BLI’s β-lactamase inhibition and CPO’s BL susceptibility restoration, thereby providing the infectious disease society practical scientific grounds for regulating the use of BL/BLI in CPO infection treatment.Methods: A diverse collection of human CPO infection isolates was challenged by three structurally representative BLIs available in the clinic. The resultant β-lactamase inhibition, BL susceptibility restoration, and their correlation were followed quantitatively for each isolate by coupling FIBA (fluorescence identification of β-lactamase activity) and BL antibiotic susceptibility testing.Results: The β-lactamase inhibition and BL susceptibility restoration are positively correlated among CPOs under the treatment of BLIs. Both of them are dependent on the target CPO’s carbapenemase molecular identity. Of note, without sufficient β-lactamase inhibition, CPO’s BL susceptibility restoration is universally low across all tested carbapenemase molecular groups. However, a high degree of β-lactamase inhibition would not necessarily lead to a substantial BL susceptibility restoration in CPO probably due to the existence of non-β-lactamase BL resistance mechanisms.Conclusion: BL/BLI choice and dosing should be guided by quantitative tools that can evaluate the inhibition across the entire β-lactamase background of the CPO upon the BLI administion. Furthermore, rapid molecular diagnostics for BL/BLI resistances, especially those sensitive to β-lactamase independent BL resistance mechanisms, should be exploited to prevent ineffective BL/BLI treatment.

The specific concentrations of amoxicillin and penicillin V in non-target feed for food-producing animals, below which there would not be an effect on the emergence of, and/or selection for, resistance in bacteria relevant for human and animal health, as well as the specific antimicrobial concentrations in feed which have an effect in terms of growth promotion/increased yield were assessed by EFSA in collaboration with EMA. Details of the methodology used for this assessment, associated data gaps and uncertainties, are presented in a separate document. To address antimicrobial resistance, the Feed Antimicrobial Resistance Selection Concentration (FARSC) model developed specifically for the assessment was applied. However, due to the lack of data on the parameters required to calculate the FARSC, it was not possible to conclude the assessment until further experimental data become available. To address growth promotion, data from scientific publications obtained from an extensive literature review were used. Levels in feed that showed to have an effect on growth promotion/increased yield were reported for amoxicillin, whilst for penicillin V no suitable data for the assessment were available. It was recommended to carry out studies to generate the data that are required to fill the gaps which prevented the calculation of the FARSC for these two antimicrobials. info:eu-repo/semantics/publishedVersion

Therapeutic drug monitoring (TDM) and continuous infusion strategies are effective interventions in clinical practice, but these practices are still largely unknown in Colombia, especially in the critical care setting. This study aims to describe the practices involved in the administration and TDM of β-lactams and vancomycin reported by specialists in critical care in Colombia and to explore the factors that are related to the use of extended infusion. An online nationwide survey was applied to 153 specialists, who were selected randomly. A descriptive, bivariate analysis and a logistic regression model were undertaken. In total, 88.9% of the specialists reported TDM availability and 21.57% reported access to results within 6 h. TDM was available mainly for vancomycin. We found that 85.62% of the intensivists had some type of institutional protocol, however, only 39.22% had a complete and socialized protocol. The odds of preferring extended infusions among those who did not have institutional protocols were 80% lower than those with complete protocols, OR 0.2 (95% CI: 0.06−0.61). The most important perceived barriers to performing continuous infusions and TDM were the lack of training and technologies. This pioneering study in Colombia could impact the quality of care and outcomes of critically ill patients in relation to the threat of antimicrobial resistance.

exo-Methylene-β-lactams were synthesized in two steps from commercially available 3-bromo-2-(bromomethyl)propionic acid and reacted with arene diazonium salts in a Heck-type arylation in the presence of catalytic amounts of Pd(OAc)2 under ligand-free conditions. The products, arylidene-β-lactams, were obtained in high yields as single isomers. The β-hydride elimination step of the Pd-catalyzed coupling reaction proceeds with high exo-regioselectivity and E-stereoselectivity. With aryl iodides, triflates, or bromides, the coupling products were isolated only in low yields, due to extensive decomposition of the starting material at elevated temperatures. This underlines that arene diazonium salts can be superior arylating reagents in Heck-type reactions and yield coupling products in synthetically useful yields and selectivities when conventional conditions fail.\ud \ud

Background and objective The global spread of antimicrobial-nonsusceptible Streptococcus pneumoniae is a major concern. Molecular epidemiology of those strains in relation to vaccine serotype remains to be explored in Japan. This study aimed to elucidate the distribution of molecular types with the serotypes and antimicrobial susceptibility of pneumococcus strains isolated from adult pneumonia patients. Methods We enrolled adult pneumonia patients from four sites in Japan between September 2011 and August 2014. S. pneumoniae isolates from sputum and blood were analyzed for serotyping by the Quellung reaction and for antimicrobial susceptibility by the agar dilution method and e-test and for multilocus sequence typing. Results In total, 204 isolates were analyzed from 200 patients with a median age of 72.5 years, of whom 55 (27.5%) patients had received a 23-valent pneumococcal polysaccharide vaccine (PPSV23). We detected 41 clonal complexes (CCs) and 62 sequence types (STs), including 10 new STs: CC/ST 180 of serotype 3 was the most common followed by CC/ST 236 of serotype 19F and CC/ST 99 of serotype 11A; 144 (70.6%) isolates were PPSV23 serotypes; 40 (19.6%) and 121 (59.3%) isolates were b-lactam nonsusceptible (bNS) and multidrug-nonsusceptible strains, respectively. Among the bNS strains, 18 (45%) were nonvaccine serotypes, and 4 CCs (CC236, CC63, CC242, and CC558) comprised of 62.5% of them.Conclusion Multiple CCs of bNS strains, including nonvaccine serotype are spreading. It is crucial to monitor the antimicrobial susceptibility, serotypes, and molecular types of pneumococci to predict the effectiveness of vaccines in preventing pneumonia by bNS pneumococci strains.

The peptidoglycan (PG) cell wall is an essential polymer for the shape and viability of bacteria. Its protective role is in great part provided by its mesh-like character. Therefore, PG-cross-linking enzymes like the penicillin-binding proteins (PBPs) are among the best targets for antibiotics. However, while PBPs have been in the spotlight for more than 50 years, another class of PG-cross-linking enzymes called LD-transpeptidases (LDTs) seemed to contribute less to PG synthesis and, thus, has kept an aura of mystery. In the last years, a number of studies have associated LDTs with cell wall adaptation to stress including β-lactam antibiotics, outer membrane stability, and toxin delivery, which has shed light onto the biological meaning of these proteins. Furthermore, as some species display a great abundance of LD-cross-links in their cell wall, it has been hypothesized that LDTs could also be the main synthetic PG-transpeptidases in some bacteria. In this review, we introduce these enzymes and their role in PG biosynthesis and we highlight the most recent advances in understanding their biological role in diverse species.

Domino 1,4- and 1,6-addition reactions of ketene silyl acetals to dialkynyl imines are disclosed. Aluminum chloride promoted domino 1,4- and 1,6-addition reactions of ketene silyl acetals to dialkynyl imines to give a variety of alkenyl iminocyclobutenones in moderate to good yields. The chemoselective reduction of alkenyl iminocyclobutenones and the subsequent thermal rearrangement of resulting alkenyl aminocyclobutenones in the presence of appropriate amines provided cis or trans multifunctionalized β-lactams in moderate to high yields with good to high diastereoselectivities.

Microbial biofilms are ubiquitous in nature, and they pose a serious threat to public health. Staphylococcus epidermidis is the most common clinical isolate from healthcare-and medical device-related biofilm infections. No antibiotic currently on the market can eradicate pathogenic biofilms, which contain complex defense mechanisms composed of slimelike extracellular polymeric substances. Understanding the need to develop alternative approaches, we examine 600 Da branched polyethylenimine (BPEI) against methicillin-resistant Staphylococcus epidermidis (MRSE) bio-films. Here, a microtiter biofilm model is used to test the synergistic effects between the two components of our combination treatment: BPEI and β-lactam antibiotics. Electron microscopy was used to confirm the growth of MRSE biofilms from the model. Minimum biofilm eradication concentration assays, crystal violet assays, and biofilm kill curves suggest that BPEI exhibits antibiofilm activity and can potentiate β-lactams to eradicate MRSE biofilms.

[Image: see text] β-Lactams are used routinely to treat Staphylococcus aureus infections. However, the emergence of methicillin-resistant S. aureus (MRSA) renders them clinically precarious. We describe a class of cinnamonitrile adjuvants that restore the activity of oxacillin (a penicillin member of the β-lactams) against MRSA. The lead adjuvants were tested against six important strains of MRSA, one vancomycin-intermediate S. aureus (VISA) strain, and one linezolid-resistant S. aureus strain. Five compounds out of 84 total compounds showed broad potentiation. At 8 μM (E)-3-(5-(3,4-dichlorobenzyl)-2-(trifluoromethoxy)phenyl)-2-(methylsulfonyl)acrylonitrile (26) potentiated oxacillin with a >4000-fold reduction of its MIC (from 256 to 0.06 mg·L(–1)). This class of adjuvants holds promise for reversal of the resistance phenotype of MRSA.

The study investigated the prevalence of virulent and antibiotic resistant Salmonella (S) in retail chicken meat (CM) and pooled giblets (PG) in Egypt. Seventy-two and 64 % of examined CM and PG samples harbored Salmonellae, respectively. When S. Infantis was the most predominant serovar, followed by S. Kentucky, and then S. Virchow. The antibiotic resistance experiment showed a high rate of multiple drug resistant (MDR) Salmonellae. Remarkably, 64.7% of the isolates were resistant to ciprofloxacin (the drug of choice for Salmonella infection). Molecularly, a noteworthy correlation between the MDR and the presence of integrons class 1 and 3. When, integrons 1 and 3 were detected in 100 and 92 % of identified MDR isolates, respectively, while class 2 integrons were not found. Surprisingly, 53.8 and 100% of the molecularly identified isolates were resistant to ciprofloxacin and nalidixic acid, despite the absence of plasmid-mediated quinolone resistance (PMQR)-associated genes (qnrA, qnrB and qnrS, aac(6′)-Ib-cr and qepA) from all MDR isolates. This indicates that other genetic factors could be incriminated in this pattern. Beta-lactam resistance was explored by the existence of blaTEM, blaCTX, and blaCMY-2 genes in most MDR isolates. Additionally, 4 virulence genes were detected in almost all serovars. Concerning virulence genes, invA, hilA, sopB, and stn were detected in 100, 100, 100 and 94.7 % of MDR serovars, respectively. While, spvC was detected in only 7.6 %, and pef was absent. The high prevalence of MDR virulent Salmonella strains in retail chicken meat and giblets in Egypt should be faced with a great worry, as consumers could be under a great public health risk.

β-Lactams are highly valuable compounds due to their antibiotic activity. Among the number of well-established methodologies for building this privileged scaffold, our research group has settled on a novel synthetic approach for their preparation. This Account focuses on our latest progress in the synthesis of these compounds through a novel base-promoted intramolecular cyclization of benzylfumaramide-based rotaxanes. The mechanical bond plays a significant role in the process by activating the cyclization inside the macrocycle void, avoiding the formation of byproducts and fully controlling the diastereoselectivity. Further investigations on this transformation led to the formation of ­enantioenriched 2-azetidinones. The cyclization of enantiopure interlocked α-methylbenzylfumaramides allows the formation of two new stereogenic centers in the lactamic four-membered ring, one of them a quaternary carbon, keeping the initial configuration of the chiral group of the starting material.1 Introduction1.1 Mechanically Interlocked Molecules and Applications1.2 Chemical Stabilization of the Mechanical Bond2 Literature Methods for 4-exo-trig Ring Closures of Fumaramides for the Synthesis of β-Lactams3 Our First Encounter with Interlocked β-Lactams3.1 An Unexpected Result in Our Laboratory3.2 Finding the Optimal Reaction Conditions3.3 Elucidating the Effects of the Mechanical Bond4 Diastereoselective Synthesis of Interlocked and Non-Interlocked β-Lactams5 Asymmetric Cyclization of Enantiopure Interlocked Fumaramides6 Conclusions

Background Streptococcus agalactiae also known as Group B Streptococcus (GBS) is a major cause of disease in pregnant women and new born babies where it causes early and late onset disease characterised by sepsis, pneumonia and meningitis. Ten to 37 % of pregnant women in the world are colonised with GBS while intrapartum antibiotic prophylaxis has led to significant reduction in early onset disease. The increase in drug resistant microorganisms has become a major threat. Development of vaccines is still in progress so there is need for new and safer alternatives to treatment. Methods Benzyl penicillin, Ampicillin, Cefotaxime, Ceftriaxone, Levofloxacin, Erythromycin, Clindamycin, Linezolid, Vancomycin, Tetracycline and Cotrimoxazole, Olea europaea leaf extracts and essential oil were tested against GBS isolates from South Africa and Namibia. Results The isolates showed 100% sensitivity to benzyl penicillin, ampicillin, ceftriaxone, levofloxacin, linezolid, vancomycin, O. europaea leaf extracts and essential oils. Only one isolate (0.6%) was resistant to cefotaxime and 23.4 and 10.4% were resistant to clindamycin and erythromycin respectively. Conclusion GBS isolates showed sensitivity to O. europaea extracts at low minimum inhibitory concentrations. Β lactams are still the drugs of choice for treatment of GBS disease but O. europaea extracts potent as an alternative source of antimicrobials.

This study aimed to characterize Aeromonas spp. isolated from ten popular species of pet turtles and their environment to evaluate the potential risk of pet turtles as a source of virulence-associated genes, and tetracycline and β-lactams resistance determinants. Presence of eight virulence genes ( ser, aer, exu, lip, fla, ascV, ahyB and gcat ), and tetracycline ( tetA, tetB and tetE ) and β-lactams ( bla TEM , bla SHV , bla OXA and bla CTX-M ) resistance genes were evaluated by conventional PCR assays. The aerA gene showed the highest frequency of occurrence (92%), followed by fla (75%), gcaT (68%), ahyB (59%), ser (39%), lip (37%) and ascV (25%) genes. None of the isolates carried amplicon of DNase-associated exu gene. A. hydrophila, A. dharkensis, A. veronii and A. caviae were carried seven tested virulence genes except for exu while only four virulence genes were detected in A. enteropelogenes . Among the 75 tetracycline-resistant isolates, tetA, tetE and tetB genes were detected in 38, 26 and 6 isolates, respectively. Among the tested β-lactam resistance genes, bla OXA and bla TEM genes were detected in 54% and 36% of β-lactam resistant isolates, respectively. No bla CTX-M and bla SHV genes were detected. Our results indicate that pet turtle-associated aeromonads, exhibiting potential virulence and antimicrobial (tetracycline and β-lactams) resistance genes, may pose a serious health risk to pet turtle owners, particularly to immunocompromised individuals. Key words: Aeromonas spp.; virulence-associated genes; tetracycline resistance; β-lactams resistance; pet turtle PRISOTNOST DETERMINANT ZA DOLOCITEV DOMNEVNE VIRULENCE TER GENOV ZA ODPORNOST NA TETRACIKLIN IN β-LAKTAM VRST Aeromonas IZOLIRANIH IZ LJUBITELJSKIH VRST ŽELV IN IZ NJIHOVEGA OKOLJA Izvlecek: Namen studije je bil dolociti bakterije Aeromonas spp., izolirane iz desetih priljubljenih vrst hisnih želv in njihovega okolja, z namenom ocenjevanja potencialnega tveganje hisnih želv kot vira genov, povezanih z virulenco, ter determinante odpornosti proti tetraciklinom in β-laktamom. Prisotnost osmih virulentnih genov ( ser, aer, exu, lip, fla, ascV, ahyB in gcat ) ter genov za odpornost na tetracikline ( tetA, tetB in tetE ) in β-laktame (b la TEM , bla SHV , bla OXA in bla CTX-M ) je bila ocenjena s konvencionalnimi testi PCR. Najbolj pogost je bil Gen aerA (92 %), sledili so geni fla (75 %), gcaT (68 %), ahyB (59 %), ser (39 %), lip (37 %) in ascV (25 %). Nobeden od izolatov ni imel pomnoženega gena exu , povezanega z DNAzo. A. hydrophila , A. dharkensis , A. veronii in A. caviae so vsebovali sedem testiranih genov virulence, razen exu , medtem ko so bili v A. enteropelogenih odkriti le stirje virulencni geni. Med 75 izolati, odpornimi na tetracikline, so bili geni tetA , tetE in tetB odkriti v 38, 26 oziroma 6 izolatih. Med preizkusenimi geni za odpornost proti β-laktamu so bili geni bla OXA in bla TEM odkriti pri 54 % oziroma 36 % izolatov, odpornih proti β-laktamu. V nobenem vzorcu nista bila zaznana gena bla CTX-M in bla SHV . Rezultati studije kažejo, da bakterije Aeromonas spp. iz hisnih želv lahko imajo potencialne virulencne gene in gene za odpornost proti tetraciklinu in β-laktamom, in lahko potencialno ogrožajo zdravje lastnikov hisnih želv, zlasti imunsko oslabljenih posameznikov. Kljucne besede: Aeromonas spp.; geni povezani z virulenco; odpornost na tetracikline; rezistenca na β-laktami; ljubiteljske vrste želv

Background: Whether vancomycin (VAN) plus piperacillin-tazobactam (PTZ) could increase the risk of acute kidney injury (AKI) is still controversial in critically ill patients. The purpose of this study was to compare the risk of developing AKI and risk of developing AKI and treatment cost among this population receiving VAN/PTZ to a matched group receiving VAN/other antipseudomonal β-lactams. Methods: This multicenter, retrospective, matched study included 700 critically ill patients who received ≥48 hours of VAN/PTZ or VAN/other antipseudomonal β-lactams. The risk of developing AKI was compared between these two combination therapies using propensity-adjusted analysis. Furthermore, a pharmacoeconomic decision-analytic model was performed.Results: According to three AKI-defined criteria, VAN/PTZ was associated with significantly higher incidence of than VAN/other antipseudomonal β-lactams (all P < 0.001). In multivariate analysis, regardless of any VAN/other antipseudomonal β-lactams, VAN/PTZ was an independent predictor for stage 2 or 3 AKI. In the empiric treatment, the incremental cost-effectiveness ratios per additional nephrotoxic episode of 1147.35$, 1845.11$, and 3989.95$ were found for VAN/PTZ relative to, vancomycin plus imipenem-cilastatin, vancomycin plus meropenem, and vancomycin plus cefoperazone-sulbactam, respectively. Conclusion: In critically ill patients, VAN/PTZ was associated with both higher AKI risk and treatment cost when considering AKI occurence compared to VAN/other antipseudomonal β-lactams.Trial registration: retrospectively registered, ClinicalTrials.gov number: NCT03776409.

Determining phenotypic antimicrobial susceptibilities of Pseudomonas aeruginosa is particularly valuable due to the complexity of resistance mechanisms this organism can harbor. The Accelerate PhenoTest BC kit (AXDX) provides a fast phenotypic antimicrobial susceptibility testing (AST) method for

© 2021 Elsevier Masson SAS. All rights reserved., The synthesis and antimicrobial activity of new spiro-β-lactams is reported. The design of the new molecules was based on the structural modulation of two previously identified lead spiro-penicillanates with dual activity against HIV and Plasmodium. The spiro-β-lactams synthesized were assayed for their in vitro activity against HIV-1, providing relevant structure-activity relationship information. Among the tested compounds, two spirocyclopentenyl-β-lactams were identified as having remarkable nanomolar activity against HIV-1. Additionally, the same molecules showed promising antiplasmodial activity, inhibiting both the hepatic and blood stages of Plasmodium infection., The authors thank Coimbra Chemistry Centre (CQC), supported by the Portuguese Agency for Scientific Research, “Fundação para a Ciência e a Tecnologia” (FCT) through project UIDB/00313/2020 and UIDP/00313/2020, co-funded by COMPETE2020-UE. iMed. ULisboa, Faculdade de Farmácia de Lisboa, Portugal, is supported by FCT through Projects UIDB/04138/2020 and UIDP/04138/2020, co-funded by COMPETE2020-UE. Miguel Prudêncio acknowledges FCT for grant PTDC/SAU-INF/29550/2017. Nuno Guerreiro Alves and Américo J. S. Alves thank FCT for fellowships PD/BD/135287/2017 and SFRH/BD/128910/2017, respectively.

A novel Cu(CH3CN)4PF6-catalyzed carboamination reaction of 8-aminoquinoline-oriented buteneamides with chloroform to afford 4-(2,2,2-trichloroethyl)-β-lactams is described. The reaction proceeded at 110 °C in air with di-t-butyl peroxide. Preliminary studies indicated that the reaction undergoes a free radical mechanism via a Cu(I)/Cu(II)/Cu(III) catalytic cycle.

Carbapenem resistance is a major global health problem that seriously compromises the treatment of infections caused by nosocomial pathogens. Resistance to carbapenems mainly occurs via the production of carbapenemases, such as VIM, IMP, NDM, KPC and OXA, among others. Preclinical and clinical trials are currently underway to test a new generation of promising inhibitors, together with the recently approved avibactam, relebactam and vaborbactam. This review summarizes the main, most promising carbapenemase inhibitors synthesized to date, as well as their spectrum of activity and current stage of development. We particularly focus on β-lactam/β-lactamase inhibitor combinations that could potentially be used to treat infections caused by carbapenemase-producer pathogens of critical priority. The emergence of these new combinations represents a step forward in the fight against antimicrobial resistance, especially in regard to metallo-β-lactamases and carbapenem-hydrolysing class D β-lactamases, not currently inhibited by any clinically approved inhibitor.

A cobalt-catalyzed cross-coupling of α-bromo α-fluoro β-lactams with diarylzinc or diallylzinc reagents is herein disclosed. The protocol proved to be general, chemoselective and operationally simple allowing the C4 functionalization of β-lactams. The substrate scope was expanded to α-bromo lactams and amides, α-bromo lactones and esters as well as N- and O-containing heterocycles.

Animal infection models are invaluable in optimizing antimicrobial dosage in humans. Utilization of human-simulated regimens (HSRs) in animal models helps to evaluate antimicrobial efficacy at clinically achievable drug concentrations. To that end, pharmacokinetic studies in infected animals and confirmation of the HSR pharmacokinetic profile are essential in evaluating observed versus expected drug concentrations. We present and compare two murine meropenem-vaborbactam HSR profiles, their potential impact on bacterial killing, and clinical translatability.

Methicillin‐resistant Staphylococcus aureus (MRSA) tolerates β‐lactam antibiotics by carrying out cell wall synthesis with the transpeptidase Penicillin‐binding protein 2a (PBP2a), which cannot be inhibited by β‐lactams. It has been proposed that PBP2a's active site is protected by two loops to reduce the probability of it binding with β‐lactams. Previous crystallographic studies suggested that this protected active site opens for reaction once a native substrate binds at an allosteric domain of PBP2a. This opening was proposed for the new β‐lactam ceftaroline's mechanism in successfully treating MRSA infections, i. e. by it binding to the allosteric site, thereby opening the active site to inhibition. In this work, we investigate the binding of ceftaroline at this proposed allosteric site using molecular dynamics simulations. Unstable binding was observed using the major force fields CHARMM36 and Amber ff14SB, and free energy calculations were unable to confirm a strong allosteric effect. Our study suggests that the allosteric effect induced by ceftaroline is weak at best.

NOTICE: This is the peer reviewed version of the following article: Álvarez-Pérez, A., Saá, C., Varela, J. A. (2020). Oxidation of Alkynes via Catalytic Metal-Vinylidenes. Synthesis, 52, 18, 2639-2649. [doi: 10.1055/s-0040-1707860]. This article may be used for non-commercial purposes in accordance with Thieme Terms and Conditions for self-archiving Metal-vinylidenes, generated by treatment of terminal alkynes with transition metals, are very useful intermediates in modern synthetic chemistry as shown by the high number of transformations in which they are involved. When a metal-vinylidene is generated in the presence of an oxidant, its immediate oxidation to a ketene intermediate occurred. In this short review, recent synthetic applications of the oxidation of alkynes via ketene intermediates from initially formed metal-vinylidenes are highlighted. This work has received financial support from MINECO (project CTQ2017-87939R and ORFEO-CINQA network RED2018-102387-T), the Xunta de Galicia (project ED431C 2018/04 and Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03) and the European Union (European Regional Development Fund – ERDF) SI

The degenerative xanthate addition transfer to alkenes allows the synthesis of a broad range of protected, and in some cases enantiopure, ?, ?, and ?-amino acids, including proline and pipecolic derivatives, as well as fluorinated congeners and ?-lactams. The radical addition furnishes naturally latent mercapto-?-amino acids that are ideally equipped for native chemical ligation. Most of the amino acid structures accessible rapidly by this chemistry would otherwise require tedious multi-step syntheses.

The first copper-catalyzed highly chemo-, regio-, diastereo-, and enantioselective Kinugasa/Michael domino reaction for the desymmetrization of prochiral cyclohexadienones is described. In the presence of a chiral copper catalyst, alkyne-tethered cyclohexadienones couple with nitrones to generate the chiral spirocyclic lactams with excellent stereoselectivity (up to 97 % ee, >20:1 dr). The new method provides direct access to versatile highly functionalized spirocyclic β-lactams possessing four contiguous stereocenters, including one quaternary and one tetra-substituted stereocenter.

The Staudinger reaction yielding β-lactam rings via [2 + 2] cycloaddition is a torquoselective reaction where the stereochemistry of the product can be steered by suitable substituents. Although the mechanochemical ring-opening of β-lactams has been investigated recently, the force-assisted synthesis of this important functional four-ring motif remains unexplored. As it will be computationally demonstrated, mechanochemical activation greatly reduces the barrier of the rate-limiting ring-closure step while, at the same time, preserves its torquoselectivity. This finding strongly suggests that strained four-membered rings can be readily incorporated in chain molecules using sonication techniques that greatly enhance reactivity while conserving selectivity.

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.