A novel method for the enantioselective synthesis of β-lactams is described in this study. 2,3-Dihydrobenzooxazin-4-one derived from salicylamide and L-menthone was used as the chiral auxiliary, which reacted with a-...A novel method for the enantioselective synthesis of β-lactams is described in this study. 2,3-Dihydrobenzooxazin-4-one derived from salicylamide and L-menthone was used as the chiral auxiliary, which reacted with a-bromo-acyl bromides in the presence of pyridine to give carboximides 2. The stereo-controlled Reformatsky-type reactions of carboximides with imines yielded the corresponding trans β-lactams with high enantioselectivities（e.e. 75%-86%） and high chemical yields（63%-85%）, meanwhile, the chiral auxiliary dihydrobenzooxazin-4-one was released and recovered.展开更多
A copper-catalyzed enantioconvergent radical C-(sp^(3))-N cross-coupling of racemic tertiaryα-bromo-β-lactams with aromatic amines is developed under mild thermal reaction conditions.The use of a sterically demanded...A copper-catalyzed enantioconvergent radical C-(sp^(3))-N cross-coupling of racemic tertiaryα-bromo-β-lactams with aromatic amines is developed under mild thermal reaction conditions.The use of a sterically demanded oxazoline-derived sulfonamide N,N,N-ligand is crucial for the reaction initiation and effective enantio-discrimination of the azetidinone-derived cyclic alkyl radicals.The strategy provides an attractive approach to access chiralα-amino-β-lactams,an important structural motif in many biologically active molecules.Preliminary mechanistic studies support the formation of azetidinone-derived alkyl radicals from the L*Cu(I)-amido complex andα-bromo-β-lactams.展开更多
Background:Carbapenems are effective against severe Pseudomonas aeruginosa nosocomial infections.Therefore,carbapenem-resistant Pseudomonas aeruginosa is a serious public health threat.An understanding of the risk of ...Background:Carbapenems are effective against severe Pseudomonas aeruginosa nosocomial infections.Therefore,carbapenem-resistant Pseudomonas aeruginosa is a serious public health threat.An understanding of the risk of inappropriate exposure to different antimicrobials in resistant Pseudomonas aeruginosa infection could help in elucidating the effective approach towards using antimicrobials in vulnerable patients with CRPA infection.Object:To investigate the association between exposure ofβ-lactam antimicrobials and CRPA infection relative to control patients.Methods:The MEDLINE/PubMed and OVID/Embase databases were used to search case-control and cohort studies in English language which reported antimicrobial exposure as risk factors for CRPA infection.The pooled odds ratios(OR)were calculated using a random-effect and fixed-effect model,and forest plots from a cumulative meta-analysis method were used to better show how pooled OR changed as updated evidence accumulated.Results:A total of 24 studies comprising 7039 participants were included for cumulative meta-analysis.A positive correlation was found between development of CRPA infection and exposure of beta-lactam antimicrobials:carbapenems(OR=7.60,95%CI:3.95 to 14.62,P<0.0001),imipenem(OR=9.81,95%CI:5.56 to 17.33),ampicillin(OR=1.86,95%CI:1.14 to 2.41),piperacillin(OR=2.82,95%CI:1.46 to 2.43),penicillins(OR=1.42,95%CI:0.90 to 2.24),cephalosporins(OR=1.88,95%CI:1.46 to 2.43)andβlactamase inhibitors(OR=1.96,95%CI:1.44 to 2.67).Further,exposure of other antimicrobial agents like quinolone(OR=2.35,95%CI:1.78 to 3.10),ciprofloxacin(OR=2.35,95%CI:1.66 to 3.95),aminoglycoside(OR=2.17,95%CI:1.60 to 2.95),amikacin(OR=3.11,95%CI:2.10 to 4.61),glycopeptides(OR=3.02,95%CI:1.92 to 4.75)and vancomycin(OR=3.26,95%CI:1.48 to 7.18),were also found to be positively associated with development of CRPA infection.Conclusions:Exposure of all kinds ofβ-lactams is significantly associated with development of carbapenemresistant Pseudomonas aeruginosa infection.These findings provide an impetus to take a more active approach while usingβ-lactam antimicrobials in patients with resistant Pseudomonas aeruginosa infections.展开更多
Typhoid fever caused by the bacterium Salmonella enterica serovar Typhi (S. Typhi) causes an estimated 25 million illnesses and approximately 200,000 deaths annually mostly in developing countries. Although the manage...Typhoid fever caused by the bacterium Salmonella enterica serovar Typhi (S. Typhi) causes an estimated 25 million illnesses and approximately 200,000 deaths annually mostly in developing countries. Although the management of typhoid fever has been effectively through antibiotic treatment, S. Typhi is increasingly becoming resistant to the currently recommended drugs. This study utilized a quasi-experimental design focusing on archived samples to describe antimicrobial susceptibility patterns of S. Typhi and determine the genetic basis of resistance to the two most commonly used classes of antimicrobials. A total sample size of 287 isolates of S. Typhi isolates stored in -80°C freezer at the Centre for Microbiology Research was utilized. Isolates were subjected to anti-microbial susceptibility testing to commonly available antimicrobials using disk diffusion method, then analyzed for trends in resistance to fluoroquinolones and extended spectrum beta lactams. Among the 287 isolates 158 (55.5%) were found to be Multi Drug Resistant (MDR). This implied that these isolates were resistant to all first line classes of treatment such as ampicillin, chloramphenicol and sulfamethoxazole-trimethroprim. In addition to this, these isolates were also resistant to at least one of the currently recommended drugs of choice, either a β-lactam or a fluoroquinolone. This study observed resistances at 18.2% and 15.4% to fluoroquinolones and cephalosporins respectively. PCR results revealed presence of blaTEM, blaINT and blaCTX-M genes coding for resistance to β-lactams in 80% of the isolates that had combined resistance to β-lactams and fluoroquinolones. It is likely that recent heavy use of these classes of antimicrobials is driving resistances to these antimicrobials.展开更多
Bacteremia is a life-threating syndrome often caused by methicillin-resistant Staphylococcus aureus(MRSA).Thus,there is an urgent need to develop novel approaches to successfully treat this infection.Staphylococcal ac...Bacteremia is a life-threating syndrome often caused by methicillin-resistant Staphylococcus aureus(MRSA).Thus,there is an urgent need to develop novel approaches to successfully treat this infection.Staphylococcal accessory regulator A(SarA),a global virulence regulator,plays a critical role in pathogenesis andβ-lactam antibiotic resistance in Staphylococcus aureus.Hypericin is believed to act as an antibiotic,antidepressant,antiviral and non-specific kinase inhibitor.In the current study,we investigated the impact of hypericin onβ-lactam antibiotics susceptibility and mechanism(s)of its activity.We demonstrated that hypericin significantly decreased the minimum inhibitory concentrations ofβ-lactam antibiotics(e.g.,oxacillin,cefazolin and nafcillin),biofilm formation and fibronectin binding in MRSA strain JE2.In addition,hypericin significantly reduced sarA expression,and subsequently decreased mecAy and virulence-related regulators(e.g.,agr RNAIII)and genes(e.g.,fnbA and hla)expression in the studied MRSA strain.Importantly,the in vitro synergistic effect of hypericin withβ-lactam antibiotic(e.g.,oxacillin)translated into in vivo therapeutic outcome in a murine MRSA bacteremia model.These findings suggest that hypericin plays an important role in abrogation ofβ-lactam resistance againstMRSA through sarA inhibition,and may allow us to repurpose the use ofβ-lactam antibiotics,which are normally ineffective in the treatment of MRSA infections(e.g.,oxacillin).展开更多
As D-amino acids play important roles in the physiological metabolism of bacteria,combination of D-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate in v...As D-amino acids play important roles in the physiological metabolism of bacteria,combination of D-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate in vitro and in vivo activity of D-serine alone and in combination withβ-lactams against methicillin-resistant Staphylococcus aureus(MRSA) strains, and to explore the possible sensitization mechanisms. The activity of D-serine, β-lactams alone and in combinations was evaluated both in vitro by standard MICs, time–kill curves and checkerboard assays, and in vivo by murine systemic infection model as well as neutropenic thigh infection model. An in vitro synergistic effect was demonstrated with the combination of D-serine and β-lactams against MRSA standard and clinical strains.Importantly, the combinations enhanced the therapeutic efficacy in the animal models as compared toβ-lactam alone groups. Initial mechanism study suggested possible revision of D-alanine-D-alanine residue to D-alanine-D-serine in peptidoglycan by adding of D-alanine in the medium, which may cause decreased affinity to PBPs during transpeptidation. In conclusion, D-serine had synergistic activity in combination with β-lactams against MRSA strains both in vitro and in vivo. Considering the relatively good safety of D-serine alone or in combination with β-lactams, D-serine is worth following up as new anti-MRSA infection strategies.展开更多
A manganese-catalyzed bicyclic annulation of imines with α,β-unsaturated esters via C–H activation is described, which provides an expedient access to fused β-lactams in one-step operation with high efficiency and...A manganese-catalyzed bicyclic annulation of imines with α,β-unsaturated esters via C–H activation is described, which provides an expedient access to fused β-lactams in one-step operation with high efficiency and good functional group tolerance. Of note, both ketimines and aldimines are amenable to this transformation. Mechanistic studies have identified a five-membered azamanganacycle as the key reaction intermediate.展开更多
基金National Natural Science Foundation of China(No. 20272051)Natural Science Foundation of Zhejiang Province, China(No. R404109)
文摘A novel method for the enantioselective synthesis of β-lactams is described in this study. 2,3-Dihydrobenzooxazin-4-one derived from salicylamide and L-menthone was used as the chiral auxiliary, which reacted with a-bromo-acyl bromides in the presence of pyridine to give carboximides 2. The stereo-controlled Reformatsky-type reactions of carboximides with imines yielded the corresponding trans β-lactams with high enantioselectivities（e.e. 75%-86%） and high chemical yields（63%-85%）, meanwhile, the chiral auxiliary dihydrobenzooxazin-4-one was released and recovered.
基金support from the National Key R&D Program of China(Nos.2021YFF0701604 and 2021YFF0701704)National Natural Science Foundation of China(Nos.22025103,92256301,21831002,and 22271133)+1 种基金Shenzhen Key Labor atory of Cross-Coupling Reactions(ZDSYS20220328104200001)Shenzhen Science and Technology Program(Nos.KQTD20210811090112004,JCYJ20200109141001789,JCYJ20220818100600001,and JCYJ202205300115409020).
文摘A copper-catalyzed enantioconvergent radical C-(sp^(3))-N cross-coupling of racemic tertiaryα-bromo-β-lactams with aromatic amines is developed under mild thermal reaction conditions.The use of a sterically demanded oxazoline-derived sulfonamide N,N,N-ligand is crucial for the reaction initiation and effective enantio-discrimination of the azetidinone-derived cyclic alkyl radicals.The strategy provides an attractive approach to access chiralα-amino-β-lactams,an important structural motif in many biologically active molecules.Preliminary mechanistic studies support the formation of azetidinone-derived alkyl radicals from the L*Cu(I)-amido complex andα-bromo-β-lactams.
文摘Background:Carbapenems are effective against severe Pseudomonas aeruginosa nosocomial infections.Therefore,carbapenem-resistant Pseudomonas aeruginosa is a serious public health threat.An understanding of the risk of inappropriate exposure to different antimicrobials in resistant Pseudomonas aeruginosa infection could help in elucidating the effective approach towards using antimicrobials in vulnerable patients with CRPA infection.Object:To investigate the association between exposure ofβ-lactam antimicrobials and CRPA infection relative to control patients.Methods:The MEDLINE/PubMed and OVID/Embase databases were used to search case-control and cohort studies in English language which reported antimicrobial exposure as risk factors for CRPA infection.The pooled odds ratios(OR)were calculated using a random-effect and fixed-effect model,and forest plots from a cumulative meta-analysis method were used to better show how pooled OR changed as updated evidence accumulated.Results:A total of 24 studies comprising 7039 participants were included for cumulative meta-analysis.A positive correlation was found between development of CRPA infection and exposure of beta-lactam antimicrobials:carbapenems(OR=7.60,95%CI:3.95 to 14.62,P<0.0001),imipenem(OR=9.81,95%CI:5.56 to 17.33),ampicillin(OR=1.86,95%CI:1.14 to 2.41),piperacillin(OR=2.82,95%CI:1.46 to 2.43),penicillins(OR=1.42,95%CI:0.90 to 2.24),cephalosporins(OR=1.88,95%CI:1.46 to 2.43)andβlactamase inhibitors(OR=1.96,95%CI:1.44 to 2.67).Further,exposure of other antimicrobial agents like quinolone(OR=2.35,95%CI:1.78 to 3.10),ciprofloxacin(OR=2.35,95%CI:1.66 to 3.95),aminoglycoside(OR=2.17,95%CI:1.60 to 2.95),amikacin(OR=3.11,95%CI:2.10 to 4.61),glycopeptides(OR=3.02,95%CI:1.92 to 4.75)and vancomycin(OR=3.26,95%CI:1.48 to 7.18),were also found to be positively associated with development of CRPA infection.Conclusions:Exposure of all kinds ofβ-lactams is significantly associated with development of carbapenemresistant Pseudomonas aeruginosa infection.These findings provide an impetus to take a more active approach while usingβ-lactam antimicrobials in patients with resistant Pseudomonas aeruginosa infections.
文摘Typhoid fever caused by the bacterium Salmonella enterica serovar Typhi (S. Typhi) causes an estimated 25 million illnesses and approximately 200,000 deaths annually mostly in developing countries. Although the management of typhoid fever has been effectively through antibiotic treatment, S. Typhi is increasingly becoming resistant to the currently recommended drugs. This study utilized a quasi-experimental design focusing on archived samples to describe antimicrobial susceptibility patterns of S. Typhi and determine the genetic basis of resistance to the two most commonly used classes of antimicrobials. A total sample size of 287 isolates of S. Typhi isolates stored in -80°C freezer at the Centre for Microbiology Research was utilized. Isolates were subjected to anti-microbial susceptibility testing to commonly available antimicrobials using disk diffusion method, then analyzed for trends in resistance to fluoroquinolones and extended spectrum beta lactams. Among the 287 isolates 158 (55.5%) were found to be Multi Drug Resistant (MDR). This implied that these isolates were resistant to all first line classes of treatment such as ampicillin, chloramphenicol and sulfamethoxazole-trimethroprim. In addition to this, these isolates were also resistant to at least one of the currently recommended drugs of choice, either a β-lactam or a fluoroquinolone. This study observed resistances at 18.2% and 15.4% to fluoroquinolones and cephalosporins respectively. PCR results revealed presence of blaTEM, blaINT and blaCTX-M genes coding for resistance to β-lactams in 80% of the isolates that had combined resistance to β-lactams and fluoroquinolones. It is likely that recent heavy use of these classes of antimicrobials is driving resistances to these antimicrobials.
基金supported in part by CAMS Initiative for Innovative Medicine(grant numbers 2016-I2M-2-002 and 2016-I2M3-014,China)National Mega-project for Innovative Drugs(grant number 2018ZX09721001,China)the National Science Foundation of China(grant number 81621064,China).
文摘Bacteremia is a life-threating syndrome often caused by methicillin-resistant Staphylococcus aureus(MRSA).Thus,there is an urgent need to develop novel approaches to successfully treat this infection.Staphylococcal accessory regulator A(SarA),a global virulence regulator,plays a critical role in pathogenesis andβ-lactam antibiotic resistance in Staphylococcus aureus.Hypericin is believed to act as an antibiotic,antidepressant,antiviral and non-specific kinase inhibitor.In the current study,we investigated the impact of hypericin onβ-lactam antibiotics susceptibility and mechanism(s)of its activity.We demonstrated that hypericin significantly decreased the minimum inhibitory concentrations ofβ-lactam antibiotics(e.g.,oxacillin,cefazolin and nafcillin),biofilm formation and fibronectin binding in MRSA strain JE2.In addition,hypericin significantly reduced sarA expression,and subsequently decreased mecAy and virulence-related regulators(e.g.,agr RNAIII)and genes(e.g.,fnbA and hla)expression in the studied MRSA strain.Importantly,the in vitro synergistic effect of hypericin withβ-lactam antibiotic(e.g.,oxacillin)translated into in vivo therapeutic outcome in a murine MRSA bacteremia model.These findings suggest that hypericin plays an important role in abrogation ofβ-lactam resistance againstMRSA through sarA inhibition,and may allow us to repurpose the use ofβ-lactam antibiotics,which are normally ineffective in the treatment of MRSA infections(e.g.,oxacillin).
基金supported by the National Natural Science Foundation of China (Grant Nos. 81621064 and 81361138020)CAMS Initiative for Innovative Medicine (Grant No. 2016-I2M-3-014, China)+1 种基金PUMC Youth Fund (Grant No. 3332013145, China)National Mega-project for Innovative Drugs (Grant No. 2018ZX09721001, China)
文摘As D-amino acids play important roles in the physiological metabolism of bacteria,combination of D-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate in vitro and in vivo activity of D-serine alone and in combination withβ-lactams against methicillin-resistant Staphylococcus aureus(MRSA) strains, and to explore the possible sensitization mechanisms. The activity of D-serine, β-lactams alone and in combinations was evaluated both in vitro by standard MICs, time–kill curves and checkerboard assays, and in vivo by murine systemic infection model as well as neutropenic thigh infection model. An in vitro synergistic effect was demonstrated with the combination of D-serine and β-lactams against MRSA standard and clinical strains.Importantly, the combinations enhanced the therapeutic efficacy in the animal models as compared toβ-lactam alone groups. Initial mechanism study suggested possible revision of D-alanine-D-alanine residue to D-alanine-D-serine in peptidoglycan by adding of D-alanine in the medium, which may cause decreased affinity to PBPs during transpeptidation. In conclusion, D-serine had synergistic activity in combination with β-lactams against MRSA strains both in vitro and in vivo. Considering the relatively good safety of D-serine alone or in combination with β-lactams, D-serine is worth following up as new anti-MRSA infection strategies.
基金supported by the National Basic Research Program of China (2012CB821600)the National Natural Science Foundation of China (21322203, 21272238, 21521002)
文摘A manganese-catalyzed bicyclic annulation of imines with α,β-unsaturated esters via C–H activation is described, which provides an expedient access to fused β-lactams in one-step operation with high efficiency and good functional group tolerance. Of note, both ketimines and aldimines are amenable to this transformation. Mechanistic studies have identified a five-membered azamanganacycle as the key reaction intermediate.
