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1.
Angew Chem Int Ed Engl ; 61(51): e202210747, 2022 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-36197755

RESUMO

Herein, we describe the myxobacterial natural product Corramycin isolated from Corallococcus coralloides. The linear peptide structure contains an unprecedented (2R,3S)-γ-N-methyl-ß-hydroxy-histidine moiety. Corramycin exhibits anti-Gram-negative activity against Escherichia coli (E. coli) and is taken up via two transporter systems, SbmA and YejABEF. Furthermore, the Corramycin biosynthetic gene cluster (BGC) was identified and a biosynthesis model was proposed involving a 12-modular non-ribosomal peptide synthetase/polyketide synthase. Bioinformatic analysis of the BGC combined with the development of a total synthesis route allowed for the elucidation of the molecule's absolute configuration. Importantly, intravenous administration of 20 mg kg-1 of Corramycin in an E. coli mouse infection model resulted in 100 % survival of animals without toxic side effects. Corramycin is thus a promising starting point to develop a potent antibacterial drug against hospital-acquired infections.


Assuntos
Antibacterianos , Escherichia coli , Camundongos , Animais , Antibacterianos/química , Policetídeo Sintases , Família Multigênica
2.
J Med Chem ; 66(24): 16869-16887, 2023 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-38088830

RESUMO

Corramycin 1 is a novel zwitterionic antibacterial peptide isolated from a culture of the myxobacterium Corallococcus coralloides. Though Corramycin displayed a narrow spectrum and modest MICs against sensitive bacteria, its ADMET and physchem profile as well as its high tolerability in mice along with an outstanding in vivo efficacy in an Escherichia coli septicemia mouse model were promising and prompted us to embark on an optimization program aiming at enlarging the spectrum and at increasing the antibacterial activities by modulating membrane permeability. Scanning the peptidic moiety by the Ala-scan strategy followed by key stabilization and introduction of groups such as a primary amine or siderophore allowed us to enlarge the spectrum and increase the overall developability profile. The optimized Corramycin 28 showed an improved mouse IV PK and a broader spectrum with high potency against key Gram-negative bacteria that translated into excellent efficacy in several in vivo mouse infection models.


Assuntos
Antibacterianos , Infecções por Escherichia coli , Camundongos , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/química , Bactérias Gram-Negativas , Bactérias , Testes de Sensibilidade Microbiana
3.
J Med Chem ; 61(8): 3565-3581, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29596745

RESUMO

In our quest for new antibiotics able to address the growing threat of multidrug resistant infections caused by Gram-negative bacteria, we have investigated an unprecedented series of non-quinolone bacterial topoisomerase inhibitors from the Sanofi patrimony, named IPYs for imidazopyrazinones, as part of the Innovative Medicines Initiative (IMI) European Gram Negative Antibacterial Engine (ENABLE) organization. Hybridization of these historical compounds with the quinazolinediones, a known series of topoisomerase inhibitors, led us to a novel series of tricyclic IPYs that demonstrated potential for broad spectrum activity, in vivo efficacy, and a good developability profile, although later profiling revealed a genotoxicity risk. Resistance studies revealed partial cross-resistance with fluoroquinolones (FQs) suggesting that IPYs bind to the same region of bacterial topoisomerases as FQs and interact with at least some of the keys residues involved in FQ binding.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Imidazóis/farmacologia , Pirazinas/farmacologia , Quinazolinonas/farmacologia , Inibidores da Topoisomerase/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/farmacocinética , Antibacterianos/toxicidade , Farmacorresistência Bacteriana/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Células Hep G2 , Humanos , Imidazóis/síntese química , Imidazóis/farmacocinética , Imidazóis/toxicidade , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Pirazinas/síntese química , Pirazinas/farmacocinética , Pirazinas/toxicidade , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Quinazolinonas/toxicidade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/farmacocinética , Inibidores da Topoisomerase/toxicidade
4.
Org Lett ; 5(23): 4253-6, 2003 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-14601973

RESUMO

[reaction: see text] Enantiomerically pure 5-acetyl-3-amino-3,4-dihydro-2H-1-benzopyran and methyl 3-amino-3,4-dihydro-2H-1-benzopyran-5-carboxylate were successfully synthesized starting from d- or l-serine. The formation of the benzopyran ring involved a radical cyclization step. The enantiomeric purities of the final aminochroman derivatives were determined by capillary electrophoresis using beta-cyclodextrins as a chiral selector.

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