The development of resistance against most of the available antibiotics has made Acinetobacter baumannii(A.baumannii)a pathogen of high risk.In this study,thirty novel berberine derivatives are rationally designed,syn...The development of resistance against most of the available antibiotics has made Acinetobacter baumannii(A.baumannii)a pathogen of high risk.In this study,thirty novel berberine derivatives are rationally designed,synthesized,and evaluated for their synergistic antibacterial activities against A.baumannii.Among them,compound 2d shows the most potent synergetic effect to aztreonam against A.baumannii,including carbapenem-resistant and extended-spectrumβ-lactamases-producing strains.Moreover,synergistic effects were observed for the combinations of 2d and different antibacterial used in clinical practices,indicating its potent broad-spectrum antibiotic-sensitizing effects against A.baumannii.The combination of 2d and aztreonam significantly improves the survival rates of G.mellonella larvae compared with aztreonam treatment alone.Mechanism studies indicate that 2d inhibits the drug efflux and iron acquisition of the bacteria by targeting the AdeB transporter protein,thus achieving a synergistic antimicrobial efficacy with different antibacterial agents.Therefore,berberine derivatives represent a new family of antimicrobial adjuvants against A.baumannii,with the advantage of dual-function antibacterial effect,and are worthy of further investigation.展开更多
Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxidation on the 10-α-C-H induced by sulfonyl and a nucleophilic substitution with the stereoselectivity and scalab...Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxidation on the 10-α-C-H induced by sulfonyl and a nucleophilic substitution with the stereoselectivity and scalability.Of them,compound 6b displayed a moderate anti-human coronavirus OC43(HCoV-OC43)potency and blocked the viral entry stage through a host mechanism of action.Using chemoproteomic techniques,both transmembrane serine protease 2(TMPRSS2)and scavenger receptor class B type 1(SR-B1)proteins,which act as host cofactors of viral entry,were identified to be the direct targets of 6b against HCoV-OC43.Furthermore,6b may deactivate the TMPRSS2 by inducing a change in protein conformation,rather than binding to its catalytic center,thus suppressing the viral membrane fusion.Accordingly,our study provided key scientific data for the development of aloperine derivatives into a new class of antiviral candidates against humanβ-coronavirus,including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).展开更多
Helicobacter pylori(H.pylori)is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis,and its high prevalence and resistance make it difficult to tackle.A graph neural network...Helicobacter pylori(H.pylori)is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis,and its high prevalence and resistance make it difficult to tackle.A graph neural network-based deep learning model,employing different training sets of 13,638 molecules for pre-training and fine-tuning,was aided in predicting and exploring novel molecules against H.pylori.A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H.pylori strains with minimum inhibitory concentrations(MICs)of 0.25-0.5μg/mL.Pharmacokinetic studies demonstrated an ideal gastric retention of 8,with the stomach concentration significantly higher than its MIC at 24 h post dose.Oral administration of 8 and omeprazole(OPZ)showed a comparable gastric bacterial reduction(2.2-log reduction)to the triple-therapy,namely OPZ+amoxicillin(AMX)+clarithromycin(CLA)without obvious disturbance on the intestinal flora.A combination of OPZ,AMX,CLA,and 8 could further decrease the bacteria load(2.8-log reduction).More importantly,the mono-therapy of 8 exhibited comparable eradication to both triple-therapy(OPZ+AMX+CLA)and quadrupletherapy(OPZ+AMX+CLA+bismuth citrate)groups.SecA and BamD,playing a major role in outer membrane protein(OMP)transport and assembling,were identified and verified as the direct targets of 8 by employing the chemoproteomics technique.n summary,by targeting the relatively conserved OMPs transport and assembling system,8 has the potential to be developed as a novel anti-H.pylori candidate,especially for the eradication of drug-resistant strains.展开更多
基金supported by grants from National Natural Science Foundation of China(Nos.32141003,82104013)CAMS Initiative for Innovative Medicine(Nos.2021-1-I2M-070,2021-1-I2M-039,China)。
文摘The development of resistance against most of the available antibiotics has made Acinetobacter baumannii(A.baumannii)a pathogen of high risk.In this study,thirty novel berberine derivatives are rationally designed,synthesized,and evaluated for their synergistic antibacterial activities against A.baumannii.Among them,compound 2d shows the most potent synergetic effect to aztreonam against A.baumannii,including carbapenem-resistant and extended-spectrumβ-lactamases-producing strains.Moreover,synergistic effects were observed for the combinations of 2d and different antibacterial used in clinical practices,indicating its potent broad-spectrum antibiotic-sensitizing effects against A.baumannii.The combination of 2d and aztreonam significantly improves the survival rates of G.mellonella larvae compared with aztreonam treatment alone.Mechanism studies indicate that 2d inhibits the drug efflux and iron acquisition of the bacteria by targeting the AdeB transporter protein,thus achieving a synergistic antimicrobial efficacy with different antibacterial agents.Therefore,berberine derivatives represent a new family of antimicrobial adjuvants against A.baumannii,with the advantage of dual-function antibacterial effect,and are worthy of further investigation.
基金supported by the National Natural Science Foundation of China(No.81974494)CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-070).
文摘Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxidation on the 10-α-C-H induced by sulfonyl and a nucleophilic substitution with the stereoselectivity and scalability.Of them,compound 6b displayed a moderate anti-human coronavirus OC43(HCoV-OC43)potency and blocked the viral entry stage through a host mechanism of action.Using chemoproteomic techniques,both transmembrane serine protease 2(TMPRSS2)and scavenger receptor class B type 1(SR-B1)proteins,which act as host cofactors of viral entry,were identified to be the direct targets of 6b against HCoV-OC43.Furthermore,6b may deactivate the TMPRSS2 by inducing a change in protein conformation,rather than binding to its catalytic center,thus suppressing the viral membrane fusion.Accordingly,our study provided key scientific data for the development of aloperine derivatives into a new class of antiviral candidates against humanβ-coronavirus,including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).
基金This research project was supported by grants from National Natural Science Foundationof China(32141003,82330110,61976050,61972384,and 82003575)CAMS Initiative for Innovative Medicine(2021-1-12M-030).
文摘Helicobacter pylori(H.pylori)is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis,and its high prevalence and resistance make it difficult to tackle.A graph neural network-based deep learning model,employing different training sets of 13,638 molecules for pre-training and fine-tuning,was aided in predicting and exploring novel molecules against H.pylori.A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H.pylori strains with minimum inhibitory concentrations(MICs)of 0.25-0.5μg/mL.Pharmacokinetic studies demonstrated an ideal gastric retention of 8,with the stomach concentration significantly higher than its MIC at 24 h post dose.Oral administration of 8 and omeprazole(OPZ)showed a comparable gastric bacterial reduction(2.2-log reduction)to the triple-therapy,namely OPZ+amoxicillin(AMX)+clarithromycin(CLA)without obvious disturbance on the intestinal flora.A combination of OPZ,AMX,CLA,and 8 could further decrease the bacteria load(2.8-log reduction).More importantly,the mono-therapy of 8 exhibited comparable eradication to both triple-therapy(OPZ+AMX+CLA)and quadrupletherapy(OPZ+AMX+CLA+bismuth citrate)groups.SecA and BamD,playing a major role in outer membrane protein(OMP)transport and assembling,were identified and verified as the direct targets of 8 by employing the chemoproteomics technique.n summary,by targeting the relatively conserved OMPs transport and assembling system,8 has the potential to be developed as a novel anti-H.pylori candidate,especially for the eradication of drug-resistant strains.
