François Moreau, Dmytro Atamanyuk, Markus Blaukopf, Marek Barath, Mihály Herczeg, Nuno M. Xavier, Jérôme Monbrun, Etienne Airiau, Vivien Henryon, Frédéric Leroy, Stéphanie Floquet, Damien Bonnard, Robert Szabla, Chris Brown, Murray S. Junop, Paul Kosma* and Vincent Gerusz*,
{"title":"GmhA 抑制剂对革兰氏阴性细菌的增效作用","authors":"François Moreau, Dmytro Atamanyuk, Markus Blaukopf, Marek Barath, Mihály Herczeg, Nuno M. Xavier, Jérôme Monbrun, Etienne Airiau, Vivien Henryon, Frédéric Leroy, Stéphanie Floquet, Damien Bonnard, Robert Szabla, Chris Brown, Murray S. Junop, Paul Kosma* and Vincent Gerusz*, ","doi":"10.1021/acs.jmedchem.4c00037","DOIUrl":null,"url":null,"abstract":"<p >Inhibition of the biosynthesis of bacterial heptoses opens novel perspectives for antimicrobial therapies. The enzyme GmhA responsible for the first committed biosynthetic step catalyzes the conversion of sedoheptulose 7-phosphate into <span>d</span>-<i>glycero</i>-<span>d</span>-<i>manno</i>-heptose 7-phosphate and harbors a Zn<sup>2+</sup> ion in the active site. A series of phosphoryl- and phosphonyl-substituted derivatives featuring a hydroxamate moiety were designed and prepared from suitably protected ribose or hexose derivatives. High-resolution crystal structures of GmhA complexed to two <i>N</i>-formyl hydroxamate inhibitors confirmed the binding interactions to a central Zn<sup>2+</sup> ion coordination site. Some of these compounds were found to be nanomolar inhibitors of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity of their own, they demonstrated in vitro lipopolysaccharide heptosylation inhibition in <i>Enterobacteriaceae</i> as well as the potentiation of erythromycin and rifampicin in a wild-type <i>Escherichia coli</i> strain. These inhibitors pave the way for a novel treatment of Gram-negative infections.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 8","pages":"6610–6623"},"PeriodicalIF":6.8000,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jmedchem.4c00037","citationCount":"0","resultStr":"{\"title\":\"Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria\",\"authors\":\"François Moreau, Dmytro Atamanyuk, Markus Blaukopf, Marek Barath, Mihály Herczeg, Nuno M. Xavier, Jérôme Monbrun, Etienne Airiau, Vivien Henryon, Frédéric Leroy, Stéphanie Floquet, Damien Bonnard, Robert Szabla, Chris Brown, Murray S. Junop, Paul Kosma* and Vincent Gerusz*, \",\"doi\":\"10.1021/acs.jmedchem.4c00037\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Inhibition of the biosynthesis of bacterial heptoses opens novel perspectives for antimicrobial therapies. The enzyme GmhA responsible for the first committed biosynthetic step catalyzes the conversion of sedoheptulose 7-phosphate into <span>d</span>-<i>glycero</i>-<span>d</span>-<i>manno</i>-heptose 7-phosphate and harbors a Zn<sup>2+</sup> ion in the active site. A series of phosphoryl- and phosphonyl-substituted derivatives featuring a hydroxamate moiety were designed and prepared from suitably protected ribose or hexose derivatives. High-resolution crystal structures of GmhA complexed to two <i>N</i>-formyl hydroxamate inhibitors confirmed the binding interactions to a central Zn<sup>2+</sup> ion coordination site. Some of these compounds were found to be nanomolar inhibitors of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity of their own, they demonstrated in vitro lipopolysaccharide heptosylation inhibition in <i>Enterobacteriaceae</i> as well as the potentiation of erythromycin and rifampicin in a wild-type <i>Escherichia coli</i> strain. These inhibitors pave the way for a novel treatment of Gram-negative infections.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"67 8\",\"pages\":\"6610–6623\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-04-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.acs.org/doi/epdf/10.1021/acs.jmedchem.4c00037\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00037\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00037","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria
Inhibition of the biosynthesis of bacterial heptoses opens novel perspectives for antimicrobial therapies. The enzyme GmhA responsible for the first committed biosynthetic step catalyzes the conversion of sedoheptulose 7-phosphate into d-glycero-d-manno-heptose 7-phosphate and harbors a Zn2+ ion in the active site. A series of phosphoryl- and phosphonyl-substituted derivatives featuring a hydroxamate moiety were designed and prepared from suitably protected ribose or hexose derivatives. High-resolution crystal structures of GmhA complexed to two N-formyl hydroxamate inhibitors confirmed the binding interactions to a central Zn2+ ion coordination site. Some of these compounds were found to be nanomolar inhibitors of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity of their own, they demonstrated in vitro lipopolysaccharide heptosylation inhibition in Enterobacteriaceae as well as the potentiation of erythromycin and rifampicin in a wild-type Escherichia coli strain. These inhibitors pave the way for a novel treatment of Gram-negative infections.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.