TEM and SHV are among the most prevalentβ-lactamases contributing toβ-lactam antibiotic resistance in clinical settings,leading to treatment challenges and increased mortality rates.Except for penicillin and early c...TEM and SHV are among the most prevalentβ-lactamases contributing toβ-lactam antibiotic resistance in clinical settings,leading to treatment challenges and increased mortality rates.Except for penicillin and early cephalosporins,TEM and SHV variants have evolved with the ability to hydrolyze the second-and third-generation cephalosporins,monobactams,and evenβ-lactamase inhibitors.Accurate detection of β-lactamases is of paramount importance for optimizing antibiotic use and combating antimicrobial resistance(AMR).While genetic detection methods,such as polymerase chain reaction(PCR),are widely employed,their positive results may lack phenotypic correlation due to the low or absent expression of blaSHV and blaTEM in many strains[1].Therefore,a direct protein-level detection method such as targeted proteomics is more precise and clinically relevant.This study highlights the development of a rapid detection method using targeted proteomics with high-resolution accurate mass(HRAM)Orbitrap MS for the direct detection of TEM and SHV in Enterobacteriaceae strains,which offers greater clinical relevance compared to conventional genetic approaches.展开更多
Objectives:The Sorbin and SH3 domain containing 1(SORBS1),a protein linked to insulin signaling CBL interaction,was investigated for its role in pancreatic cancer apoptosis.This study explored polyphyllin H(PPH)’s ab...Objectives:The Sorbin and SH3 domain containing 1(SORBS1),a protein linked to insulin signaling CBL interaction,was investigated for its role in pancreatic cancer apoptosis.This study explored polyphyllin H(PPH)’s ability to restore SORBS1-knockdown-mediated repair functions.Methods:PANC-1 cells were divided into Blank,overexpression(OE),and knockdown groups.CCK-8 assays assessed proliferation and drug toxicity.Western blot and flow cytometry analyzed SORBS1 levels and PPH effects.Comet assays quantified DNA damage.Subcutaneous xenograft tumors in nude mice(Blank vs.knockdown)were treated with PPH to evaluate in vivo efficacy.SORBS1-H2AX gene correlation was analyzed Spearman rank clustering(p<0.05).Results:PPH suppressed pancreatic cancer growth in vitro/vivo,but its efficacy was attenuated by SORBS1 downregulation.Clinically,low SORBS1 correlated with poor prognosis.SORBS1 knockdown promoted tumor proliferation and reduced PPH-induced apoptosis.While PPH decreased tumor volume in both Blank and knockdown groups compared to controls,SORBS1 knockdown diminished PPH’s inhibitory effects.Mechanistically,SORBS1 depletion mitigated PPH-triggered DNA damage,circumventing G2/M arrest by modulating WEE1,Cyclin A2,CDK1,and Cyclin B1,thereby impairing apoptosis.Conclusion:SORBS1 knockdown counteracts PPH-mediated S/G2 arrest and apoptosis by alleviating DNA damage in pancreatic cancer.These findings highlight SORBS1 as a critical modulator of PPH’s therapeutic potential,linking its expression to chemoresistance mechanisms.展开更多
Three hundred and twenty endophytic actinobacterial strains were isolated from psammophytes collected from Taklamakan Desert and identified. Among them, three strains already had been identified as new species of two ...Three hundred and twenty endophytic actinobacterial strains were isolated from psammophytes collected from Taklamakan Desert and identified. Among them, three strains already had been identified as new species of two genera and sixteen isolates showed relatively low 16 S rRNA similarities < 98.6% to validly described species. Seventy-five of the isolates were selected as representative strains to screen antibacterial activity and mechanism. Forty-seven strains showed antagonistic activity against at least one of the indicator bacteria. Two Streptomyces strains produced bioactive compounds inducing DNA damage, and two Streptomyces strains produced bioactive compounds with inhibitory activity on protein biosynthesis. Notably, the strain Streptomyces sp. 8P21H-1 that demonstrated both strong antibacterial activity and inhibitory activity on protein biosynthesis was prioritized for exploring new antibiotics.Under the strategy of integrating genetics-based discovery program and MS/MS-based molecular networking, two new streptogramin-type antibiotics, i.e., acetyl-griseoviridin and desulphurizing griseoviridin, along with known griseoviridin, were isolated from the culture broth of strain 8P21H-1. Their chemical structures were determined by HR-MS, and 1D and 2D NMR. Desulphurizing griseoviridin and griseoviridin exhibited antibacterial activities by inhibiting translation.展开更多
We propose and experimentally demonstrate a long-range chaotic Brillouin optical correlation domain analysis by employing an optimized time-gated scheme and differential denoising configuration,where the number of eff...We propose and experimentally demonstrate a long-range chaotic Brillouin optical correlation domain analysis by employing an optimized time-gated scheme and differential denoising configuration,where the number of effective resolving points largely increases to more than one million.The deterioration of the chaotic Brillouin gain spectrum(BGS)and limitation of sensing range owing to the intrinsic noise structure,resulting from the time delay signature(TDS)and nonzero background of chaotic laser,is theoretically analyzed.The optimized time-gated scheme with a higher extinction ratio is used to eliminate the TDS-induced impact.The signal-to-background ratio of the measured BGS is enhanced by the differential denoising scheme to furthest remove the accumulated nonzero noise floor along the fiber,and the pure chaotic BGS is ulteriorly obtained by the Lorentz fit.Ultimately,distributed strain sensing along a 27.54-km fiber with a 2.69-cm spatial resolution is experimentally demonstrated,and the number of effective resolving points is more than 1,020,000.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
The objective of this study was to investigate the genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii clinical isolates from Beijing,China.173 A.baumannii clinical isolates from hospitals...The objective of this study was to investigate the genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii clinical isolates from Beijing,China.173 A.baumannii clinical isolates from hospitals in Beijing from 2006 to 2009 were first subjected to high level aminoglycoside resistance(HLAR,MIC to gentamicin and amikacin>512 mg/mL)phenotype selection by broth microdilution method.The strains were then subjected to genetic basis analysis by PCR detection of the aminoglycoside modifying enzyme genes(aac(3)-Ⅰ,aac(3)-Ⅱc,aac(60)-Ⅰb,aac(60)-Ⅱ,aph(4)-Ⅰa,aph(30)-Ⅰ,aph(30)-Ⅱb,aph(30)-Ⅲa,aph(30)-Ⅵa,aph(2″)-Ⅰb,aph(2″)-Ⅰc,aph(2″)-Ⅰd,ant(2″)-Ⅰa,ant(3″)-Ⅰand ant(40)-Ⅰa)and the 16S rRNA methylase genes(armA,rmtB and rmtC).Correlation analysis between the presence of aminoglycoside resistance gene and HLAR phenotype were performed by SPSS.Totally 102(58.96%)HLAR isolates were selected.The HLAR rates for year 2006,2007,2008 and 2009 were 52.63%,65.22%,51.11%and 70.83%,respectively.Five modifying enzyme genes(aac(3)-Ⅰ,detection rate of 65.69%;aac(60)-Ⅰb,detection rate of 45.10%;aph(30)-Ⅰ,detection rate of 47.06%;aph(30)-Ⅱb,detection rate of 0.98%;ant(3″)-Ⅰ,detection rate of 95.10%)and one methylase gene(armA,detection rate of 98.04%)were detected in the 102 A.baumannii with aac(3)-Ⅰ+aac(60)-Ⅰ+þant(3″)-Ⅰ+armA(detection rate of 25.49%),aac(3)-Ⅰ+aph(30)-Ⅰ+ant(3″)-Ⅰ+armA(detection rate of 21.57%)and ant(3″)-Ⅰ+armA(detection rate of 12.75%)being the most prevalent gene profiles.The values of chi-square tests showed correlation of armA,ant(3″)-Ⅰ,aac(3)-Ⅰ,aph(30)-Ⅰand aac(60)-Ⅰb with HLAR.armA had significant correlation(contingency coefficient 0.685)and good contingency with HLAR(kappa 0.940).The high rates of HLAR may cause a serious problem for combination therapy of aminoglycoside with β-lactams against A.baumannii infections.As armA was reported to be able to cause high level aminoglycoside resistance to most of the clinical important aminoglycosides(gentamicin,amikacin,tobramycin,etc),the function of aminoglycoside modifying enzyme gene(s)in A.baumannii carrying armA deserves further investigation.展开更多
A new cyclic thiopeptide,berninamycin F(3),three new linear thiopeptides,berninamycins G—I(4-6),and two known berninamycin derivatives,berninamycins C and D(1 and 2)were isolated from Streptomyces sp.CPCC 203702.Thei...A new cyclic thiopeptide,berninamycin F(3),three new linear thiopeptides,berninamycins G—I(4-6),and two known berninamycin derivatives,berninamycins C and D(1 and 2)were isolated from Streptomyces sp.CPCC 203702.Their structures were elucidated through HRESIMS and one-and two-dimensional NMR data,and the absolute configurations were assigned using Marfey's method.Compounds 4-6 are the first examples of linear berninamycin analogs.Notably,compound 4 is the first example of linear thiopeptide with a 1-(oxazol-2-yl)ethan-1-one group,compound 6 is the first linear thiopeptide derivative with methylated oxoacetate moiety.Compounds 1-6 exhibited excellent anti-Zika virus activities with IC_(50) values in the range of 4.4-10.5μmol/L,which were superior to that of the positive control ribavirin(IC_(50)=49.2μmol/L).Compounds 1 and 3 showed strong anti-influenza A virus activities with the IC_(50) values of 15.6 and 3.2μmol/L,respectively.Compound 1 exhibited good antibacterial activities against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp.pathogens.展开更多
Polymyxin B and polymyxin E(colistin)are presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer Enterobacterales,Aci...Polymyxin B and polymyxin E(colistin)are presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer Enterobacterales,Acinetobacter baumannii,and Klebsiella pneumoniae.Yet resistance to this last-line drugs is a major public health threat and is rapidly increasing.Polymyxin S2(S2)is a polymyxin B analogue previously synthesized in our institute with obviously high antibacterial activity and lower toxicity than polymyxin B and colistin.To predict the possible resistant mechanism of S2for wide clinical application,we experimentally induced bacterial resistant mutants and studied the preliminary resistance mechanisms.Mut-S,a resistant mutant of K.pneumoniae ATCC BAA-2146(Kpn2146)induced by S2,was analyzed by whole genome sequencing,transcriptomics,mass spectrometry and complementation experiment.Surprisingly,large-scale genomic inversion(LSGI)of approximately 1.1 Mbp in the chromosome caused by IS26mediated intramolecular transposition was found in Mut-S,which led to mgrB truncation,lipid A modification and hence S2resistance.The resistance can be complemented by plasmid carrying intact mgrB.The same mechanism was also found in polymyxin B and colistin induced drug-resistant mutants of Kpn2146(Mut-B and Mut-E,respectively).This is the first report of polymyxin resistance caused by IS26 intramolecular transposition mediated mgrB truncation in chromosome in K.pneumoniae.The findings broaden our scope of knowledge for polymyxin resistance and enriched our understanding of how bacteria can manage to survive in the presence of antibiotics.展开更多
A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria.Compound 33a(IMBZ18G)is highly effective in vitro and in vivo against c...A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria.Compound 33a(IMBZ18G)is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant(MDR)Gram-negative strains,with a highly druglike nature.The checkerboard assay reveals its significant synergistic effect withβ-lactamase inhibitor avibactam,and the MIC values against MDR enterobacteria were reduced up to 4—512folds.X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and Cβ-lactamases.Accordingly,preclinical studies of 33a alone and 33a-avibactam combination as potential innovative candidates are actively going on,in the treatment ofβ-lactamase-producing MDR Gram-negative bacterial infections.展开更多
Background and objectives:High-pressure processing(HPP)is a promising assistive method to extract pectic polysaccharides with high rhamnogalacturonan I(RG-I)domain and berries are sources of such pectic polysaccharide...Background and objectives:High-pressure processing(HPP)is a promising assistive method to extract pectic polysaccharides with high rhamnogalacturonan I(RG-I)domain and berries are sources of such pectic polysaccharides.This study extracts pectic polysaccharides from goji berry,raspberry,and cranberry,examines how HPP influences the pectic polysaccharide structure of three berries,and provides a basis for the extraction and modification of pectic polysaccharides with specific structure and bioactivity.Materials and methods:An orthogonal test was performed to optimize the HPP-assisted alkali method to extract the high yield and high RG-I content pectic polysaccharides from three berries.Structural information of pectic polysaccharides extracted by the HPP method and conventional methods were compared from the perspectives of monosaccharide composition,molecular weight,Fourier transform infrared spectroscopy,andnuclearmagneticresonancespectroscopy.Results:For raspberry,the optimal conditions consisted of a pressure of 50o MPa,a pH of 13,and a pressure-holding time of 12 min,while the optimal conditions for goji berry and cranberry were both 40o MPa,pH 13,and 15 min.Under the optimal conditions,the yields for goji berry,raspberry,and cranberry were 10.49%,16.63%,and 17.52%,respectively,and RG-l contents were 81.85%,83.30%,and 63.22%,respectively.HPP showed an effect to degrade homogalacturonan backbones and side chains and increase the RG-I content to some extent.Conclusion:HPP-assisted alkali method was revealed to be an efficient method to extract high RG-I content pectic polysaccharides,especially for cranberry,and was a potential method to modify pectic polysaccharide structure in a certain way.展开更多
This study was designed to establish a strategy for the extraction,purification,and structure analysis of chondroitin sulfate(cs)in milligram amounts.Crude acidic polysaccharides were extracted from six kinds of marin...This study was designed to establish a strategy for the extraction,purification,and structure analysis of chondroitin sulfate(cs)in milligram amounts.Crude acidic polysaccharides were extracted from six kinds of marine animals by enzymatic hydrolysis and hexadecylpyridinium chloride precipitation and purified by Q Sepharose Fast Flow strong anion exchange column.The purification of each crude polysaccharide was completed within 1 h.The structure of the polysaccharides,i.e.their chemical characterization,functional group,molecular weight and monosaccharide composition,were analyzed by colorimetry,nuclear magnetic resonace and high-performance liquid chromatogrpahy,respectively.All polysaccharides were identified as Cs.The oligosaccharide profile produced by enzyme hydrolysis of polysaccharides was determined by strong anion-exchange high-performance liquid chromatorgraphy.This method can be widely applied to the extraction and characterization of chondroitin sulfate from unknown raw materials,screening high-quality sources of functional polysaccharides,and laying a good foundation for thefollowing studyof the structure-function relationshipof polysaccharides.展开更多
Wetlands are critical nature-based solutions advancing climate mitigation,water security,and biodiversity conservation targets.Their ongoing degradation undermines climate resilience,ecosystem integrity,economic stabi...Wetlands are critical nature-based solutions advancing climate mitigation,water security,and biodiversity conservation targets.Their ongoing degradation undermines climate resilience,ecosystem integrity,economic stability,and hu-man health at multiple scales.Against this urgent backdrop,the 15th Confer-ence of the Contracting Parties(COP15)to the Ramsar Convention on Wetlands convened 1,284 delegates from 172 parties in Victoria Falls,Zimbabwe,from July 23rd to 31st,2025,under the theme“Wetlands Action for People and Na-ture”to reinforce global commitment to wetland conservation,restoration,and wise use(Figure 1).展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:32141003,82330110,and 81803593)the CAMS Innovation Fund for Medical Sciences(CIFMS),China(Grant Nos.:2021-I2M-1-030,and 2021-I2M-1-039)+1 种基金the Fundamental Research Funds for the Central Universities,China(Grant No.:3332018094)the National Science and Technology Infrastructure of China(Project No.:National Pathogen Resource Center-NPRC-32).
文摘TEM and SHV are among the most prevalentβ-lactamases contributing toβ-lactam antibiotic resistance in clinical settings,leading to treatment challenges and increased mortality rates.Except for penicillin and early cephalosporins,TEM and SHV variants have evolved with the ability to hydrolyze the second-and third-generation cephalosporins,monobactams,and evenβ-lactamase inhibitors.Accurate detection of β-lactamases is of paramount importance for optimizing antibiotic use and combating antimicrobial resistance(AMR).While genetic detection methods,such as polymerase chain reaction(PCR),are widely employed,their positive results may lack phenotypic correlation due to the low or absent expression of blaSHV and blaTEM in many strains[1].Therefore,a direct protein-level detection method such as targeted proteomics is more precise and clinically relevant.This study highlights the development of a rapid detection method using targeted proteomics with high-resolution accurate mass(HRAM)Orbitrap MS for the direct detection of TEM and SHV in Enterobacteriaceae strains,which offers greater clinical relevance compared to conventional genetic approaches.
基金funded by the National Natural Science Foundation of China(No.81973192 and 82304782)the Key Research and Development Program of Shaanxi Province(No.2024SF-ZDCYL-03-17)+1 种基金the Social R&D Program of Shaanxi Province(No.2023-YBSF-514,2023-YBSF-170 and 2025SF-YBXM-477)the Project of Shaanxi Administration of Traditional Chinese Medicine(No.SZY-KJCYC-2023-001).
文摘Objectives:The Sorbin and SH3 domain containing 1(SORBS1),a protein linked to insulin signaling CBL interaction,was investigated for its role in pancreatic cancer apoptosis.This study explored polyphyllin H(PPH)’s ability to restore SORBS1-knockdown-mediated repair functions.Methods:PANC-1 cells were divided into Blank,overexpression(OE),and knockdown groups.CCK-8 assays assessed proliferation and drug toxicity.Western blot and flow cytometry analyzed SORBS1 levels and PPH effects.Comet assays quantified DNA damage.Subcutaneous xenograft tumors in nude mice(Blank vs.knockdown)were treated with PPH to evaluate in vivo efficacy.SORBS1-H2AX gene correlation was analyzed Spearman rank clustering(p<0.05).Results:PPH suppressed pancreatic cancer growth in vitro/vivo,but its efficacy was attenuated by SORBS1 downregulation.Clinically,low SORBS1 correlated with poor prognosis.SORBS1 knockdown promoted tumor proliferation and reduced PPH-induced apoptosis.While PPH decreased tumor volume in both Blank and knockdown groups compared to controls,SORBS1 knockdown diminished PPH’s inhibitory effects.Mechanistically,SORBS1 depletion mitigated PPH-triggered DNA damage,circumventing G2/M arrest by modulating WEE1,Cyclin A2,CDK1,and Cyclin B1,thereby impairing apoptosis.Conclusion:SORBS1 knockdown counteracts PPH-mediated S/G2 arrest and apoptosis by alleviating DNA damage in pancreatic cancer.These findings highlight SORBS1 as a critical modulator of PPH’s therapeutic potential,linking its expression to chemoresistance mechanisms.
基金supported by CAMS Innovation Fund for Medical Sciences (Grant Nos. CAMS 2017-I2M-B&R-08 and 2017I2M-1-012)the PUMC Doctoral Innovation Fund Project (Grant No. 2018-1007-16)+2 种基金the Drug Innovation Major Project of China (Grant No. 2018ZX09711001-007-002)the Russian Foundation for Basic Research (Grant No. 20-54-53014)the National Natural Science Foundation of China (Grant No. 82011530051)。
文摘Three hundred and twenty endophytic actinobacterial strains were isolated from psammophytes collected from Taklamakan Desert and identified. Among them, three strains already had been identified as new species of two genera and sixteen isolates showed relatively low 16 S rRNA similarities < 98.6% to validly described species. Seventy-five of the isolates were selected as representative strains to screen antibacterial activity and mechanism. Forty-seven strains showed antagonistic activity against at least one of the indicator bacteria. Two Streptomyces strains produced bioactive compounds inducing DNA damage, and two Streptomyces strains produced bioactive compounds with inhibitory activity on protein biosynthesis. Notably, the strain Streptomyces sp. 8P21H-1 that demonstrated both strong antibacterial activity and inhibitory activity on protein biosynthesis was prioritized for exploring new antibiotics.Under the strategy of integrating genetics-based discovery program and MS/MS-based molecular networking, two new streptogramin-type antibiotics, i.e., acetyl-griseoviridin and desulphurizing griseoviridin, along with known griseoviridin, were isolated from the culture broth of strain 8P21H-1. Their chemical structures were determined by HR-MS, and 1D and 2D NMR. Desulphurizing griseoviridin and griseoviridin exhibited antibacterial activities by inhibiting translation.
基金supported by the National Natural Science Foundation of China(Grant Nos.62205233,62075151,and 62105234)the Fundamental Research Program of Shanxi Province(Grant No.202103021223041)Shanxi-Zheda Institute of Advanced Materials and Chemical Engineering.
文摘We propose and experimentally demonstrate a long-range chaotic Brillouin optical correlation domain analysis by employing an optimized time-gated scheme and differential denoising configuration,where the number of effective resolving points largely increases to more than one million.The deterioration of the chaotic Brillouin gain spectrum(BGS)and limitation of sensing range owing to the intrinsic noise structure,resulting from the time delay signature(TDS)and nonzero background of chaotic laser,is theoretically analyzed.The optimized time-gated scheme with a higher extinction ratio is used to eliminate the TDS-induced impact.The signal-to-background ratio of the measured BGS is enhanced by the differential denoising scheme to furthest remove the accumulated nonzero noise floor along the fiber,and the pure chaotic BGS is ulteriorly obtained by the Lorentz fit.Ultimately,distributed strain sensing along a 27.54-km fiber with a 2.69-cm spatial resolution is experimentally demonstrated,and the number of effective resolving points is more than 1,020,000.
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This study was supported by the National Natural Science Foundation of China(Nos.81321004 and 81361138020)the National Mega-project for Innovative Drugs(Nos.2012ZX09301002-001,2012ZX09301002-005 and 2014ZX09507009).
文摘The objective of this study was to investigate the genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii clinical isolates from Beijing,China.173 A.baumannii clinical isolates from hospitals in Beijing from 2006 to 2009 were first subjected to high level aminoglycoside resistance(HLAR,MIC to gentamicin and amikacin>512 mg/mL)phenotype selection by broth microdilution method.The strains were then subjected to genetic basis analysis by PCR detection of the aminoglycoside modifying enzyme genes(aac(3)-Ⅰ,aac(3)-Ⅱc,aac(60)-Ⅰb,aac(60)-Ⅱ,aph(4)-Ⅰa,aph(30)-Ⅰ,aph(30)-Ⅱb,aph(30)-Ⅲa,aph(30)-Ⅵa,aph(2″)-Ⅰb,aph(2″)-Ⅰc,aph(2″)-Ⅰd,ant(2″)-Ⅰa,ant(3″)-Ⅰand ant(40)-Ⅰa)and the 16S rRNA methylase genes(armA,rmtB and rmtC).Correlation analysis between the presence of aminoglycoside resistance gene and HLAR phenotype were performed by SPSS.Totally 102(58.96%)HLAR isolates were selected.The HLAR rates for year 2006,2007,2008 and 2009 were 52.63%,65.22%,51.11%and 70.83%,respectively.Five modifying enzyme genes(aac(3)-Ⅰ,detection rate of 65.69%;aac(60)-Ⅰb,detection rate of 45.10%;aph(30)-Ⅰ,detection rate of 47.06%;aph(30)-Ⅱb,detection rate of 0.98%;ant(3″)-Ⅰ,detection rate of 95.10%)and one methylase gene(armA,detection rate of 98.04%)were detected in the 102 A.baumannii with aac(3)-Ⅰ+aac(60)-Ⅰ+þant(3″)-Ⅰ+armA(detection rate of 25.49%),aac(3)-Ⅰ+aph(30)-Ⅰ+ant(3″)-Ⅰ+armA(detection rate of 21.57%)and ant(3″)-Ⅰ+armA(detection rate of 12.75%)being the most prevalent gene profiles.The values of chi-square tests showed correlation of armA,ant(3″)-Ⅰ,aac(3)-Ⅰ,aph(30)-Ⅰand aac(60)-Ⅰb with HLAR.armA had significant correlation(contingency coefficient 0.685)and good contingency with HLAR(kappa 0.940).The high rates of HLAR may cause a serious problem for combination therapy of aminoglycoside with β-lactams against A.baumannii infections.As armA was reported to be able to cause high level aminoglycoside resistance to most of the clinical important aminoglycosides(gentamicin,amikacin,tobramycin,etc),the function of aminoglycoside modifying enzyme gene(s)in A.baumannii carrying armA deserves further investigation.
基金This work was financially supported by the National Natural Science Foundation of China(Nos.82073744 and 81402835)CAMS Initiative for Innovative Medicine(Nos.2020-I2M-2-010 and CAMS-I2M-3-014)+1 种基金the National Mega-project for Innovative Drugs(Nos.2019ZX09721001-004-006 and 2018ZX09711001-007-001)the National Microbial Resource Center(No.NMRC-2020-3).
文摘A new cyclic thiopeptide,berninamycin F(3),three new linear thiopeptides,berninamycins G—I(4-6),and two known berninamycin derivatives,berninamycins C and D(1 and 2)were isolated from Streptomyces sp.CPCC 203702.Their structures were elucidated through HRESIMS and one-and two-dimensional NMR data,and the absolute configurations were assigned using Marfey's method.Compounds 4-6 are the first examples of linear berninamycin analogs.Notably,compound 4 is the first example of linear thiopeptide with a 1-(oxazol-2-yl)ethan-1-one group,compound 6 is the first linear thiopeptide derivative with methylated oxoacetate moiety.Compounds 1-6 exhibited excellent anti-Zika virus activities with IC_(50) values in the range of 4.4-10.5μmol/L,which were superior to that of the positive control ribavirin(IC_(50)=49.2μmol/L).Compounds 1 and 3 showed strong anti-influenza A virus activities with the IC_(50) values of 15.6 and 3.2μmol/L,respectively.Compound 1 exhibited good antibacterial activities against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp.pathogens.
基金supported by the National Natural Science Foundation of China(32141003)the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-030,2021-I2M-1-039,China)+1 种基金the Fundamental Research Funds for the Central Universities(2021-PT350-001,China)the National Science and Technology Infrastructure of China(NPRC-32)。
文摘Polymyxin B and polymyxin E(colistin)are presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer Enterobacterales,Acinetobacter baumannii,and Klebsiella pneumoniae.Yet resistance to this last-line drugs is a major public health threat and is rapidly increasing.Polymyxin S2(S2)is a polymyxin B analogue previously synthesized in our institute with obviously high antibacterial activity and lower toxicity than polymyxin B and colistin.To predict the possible resistant mechanism of S2for wide clinical application,we experimentally induced bacterial resistant mutants and studied the preliminary resistance mechanisms.Mut-S,a resistant mutant of K.pneumoniae ATCC BAA-2146(Kpn2146)induced by S2,was analyzed by whole genome sequencing,transcriptomics,mass spectrometry and complementation experiment.Surprisingly,large-scale genomic inversion(LSGI)of approximately 1.1 Mbp in the chromosome caused by IS26mediated intramolecular transposition was found in Mut-S,which led to mgrB truncation,lipid A modification and hence S2resistance.The resistance can be complemented by plasmid carrying intact mgrB.The same mechanism was also found in polymyxin B and colistin induced drug-resistant mutants of Kpn2146(Mut-B and Mut-E,respectively).This is the first report of polymyxin resistance caused by IS26 intramolecular transposition mediated mgrB truncation in chromosome in K.pneumoniae.The findings broaden our scope of knowledge for polymyxin resistance and enriched our understanding of how bacteria can manage to survive in the presence of antibiotics.
基金supported by CAMS Innovation Fund for Medical Sciences(2021-12M-1-070)National Natural Science Foundation of China(32141003)。
文摘A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria.Compound 33a(IMBZ18G)is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant(MDR)Gram-negative strains,with a highly druglike nature.The checkerboard assay reveals its significant synergistic effect withβ-lactamase inhibitor avibactam,and the MIC values against MDR enterobacteria were reduced up to 4—512folds.X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and Cβ-lactamases.Accordingly,preclinical studies of 33a alone and 33a-avibactam combination as potential innovative candidates are actively going on,in the treatment ofβ-lactamase-producing MDR Gram-negative bacterial infections.
基金the Project of National Natural Science Foundation of China(32202071)Zhejiang Basic Public Welfare Research Project(LQ22C200003)+1 种基金Zhejiang Province Key R&D Project(2021C02001)the Key Research and Development Program of Ningxia Province(2022BBF02006),China.
文摘Background and objectives:High-pressure processing(HPP)is a promising assistive method to extract pectic polysaccharides with high rhamnogalacturonan I(RG-I)domain and berries are sources of such pectic polysaccharides.This study extracts pectic polysaccharides from goji berry,raspberry,and cranberry,examines how HPP influences the pectic polysaccharide structure of three berries,and provides a basis for the extraction and modification of pectic polysaccharides with specific structure and bioactivity.Materials and methods:An orthogonal test was performed to optimize the HPP-assisted alkali method to extract the high yield and high RG-I content pectic polysaccharides from three berries.Structural information of pectic polysaccharides extracted by the HPP method and conventional methods were compared from the perspectives of monosaccharide composition,molecular weight,Fourier transform infrared spectroscopy,andnuclearmagneticresonancespectroscopy.Results:For raspberry,the optimal conditions consisted of a pressure of 50o MPa,a pH of 13,and a pressure-holding time of 12 min,while the optimal conditions for goji berry and cranberry were both 40o MPa,pH 13,and 15 min.Under the optimal conditions,the yields for goji berry,raspberry,and cranberry were 10.49%,16.63%,and 17.52%,respectively,and RG-l contents were 81.85%,83.30%,and 63.22%,respectively.HPP showed an effect to degrade homogalacturonan backbones and side chains and increase the RG-I content to some extent.Conclusion:HPP-assisted alkali method was revealed to be an efficient method to extract high RG-I content pectic polysaccharides,especially for cranberry,and was a potential method to modify pectic polysaccharide structure in a certain way.
基金the National Key Research and Development Program of China(No.2018YFD0901101).
文摘This study was designed to establish a strategy for the extraction,purification,and structure analysis of chondroitin sulfate(cs)in milligram amounts.Crude acidic polysaccharides were extracted from six kinds of marine animals by enzymatic hydrolysis and hexadecylpyridinium chloride precipitation and purified by Q Sepharose Fast Flow strong anion exchange column.The purification of each crude polysaccharide was completed within 1 h.The structure of the polysaccharides,i.e.their chemical characterization,functional group,molecular weight and monosaccharide composition,were analyzed by colorimetry,nuclear magnetic resonace and high-performance liquid chromatogrpahy,respectively.All polysaccharides were identified as Cs.The oligosaccharide profile produced by enzyme hydrolysis of polysaccharides was determined by strong anion-exchange high-performance liquid chromatorgraphy.This method can be widely applied to the extraction and characterization of chondroitin sulfate from unknown raw materials,screening high-quality sources of functional polysaccharides,and laying a good foundation for thefollowing studyof the structure-function relationshipof polysaccharides.
基金supported by the National Key Research and Development Program of China(2022YFF1300900)the National Natural Science Foundation of China(42430511)the Science and Technology Development Program of Jilin Province,China(20230101348JC).
文摘Wetlands are critical nature-based solutions advancing climate mitigation,water security,and biodiversity conservation targets.Their ongoing degradation undermines climate resilience,ecosystem integrity,economic stability,and hu-man health at multiple scales.Against this urgent backdrop,the 15th Confer-ence of the Contracting Parties(COP15)to the Ramsar Convention on Wetlands convened 1,284 delegates from 172 parties in Victoria Falls,Zimbabwe,from July 23rd to 31st,2025,under the theme“Wetlands Action for People and Na-ture”to reinforce global commitment to wetland conservation,restoration,and wise use(Figure 1).
