New amphiphilic neamine conjugates bearing a metal binding motif active against MDR E. aerogenes Gram-negative bacteria.
Structure of bacterial envelope is one of the major factors contributing to Gram negative bacterial resistance. To develop new agents that target the bacterial membranes, we synthesized, by analogy with our previous peptide conjugates, new amphiphilic 3',4',6-trinaphthylmethylene neamines functionalized at position 5 through a short spacer by a chelating group, tris(2-pyridylmethyl)amine (TPA) and di-(picolyl)amine (DPA) and tetraazacyclotetradecane (Cyclam). ESI+mass spectrometry analyses showed that neither Zn(II)(NeaDPA) nor Cu(II)(NeaCyclam) were stable in the Mueller Hinton (MH) medium used for antibacterial assays. In contrast Zn(NeaTPA) was stable in the MH medium. Interestingly, in MH, the free ligand NeaTPA was found bound to zinc, the zinc salt being the most abundant salt in this medium. Thus, the antibacterial activities of all compounds were evaluated as free ligands against E. coli strains, wild type AG100 and E. aerogenes EA289 (a clinical MDR strain that overexpresses AcrAB-TolC efflux pump), as well as AG100A an AcrAB- E. coli strain and EA298 a TolC- derivative. NeaCyclam and Zn(NeaTPA) were by far the most efficient compounds active against resistant isolate EA289 with MICs in the range 16-4 and 4 μM, respectively, while usual antibiotics such as β-lactams and phenicols were inactive (MICs > 128) and ciprofloxacin was at 64 μM. Zn(NeaTPA) and NeaCyclam were shown to target and permeabilize the outer membrane of EA289 by promoting the cleavage of nitrocefin by periplasmic β-lactamase. Moreover, all the neamine conjugates were able to block the efflux of 1,2'-dinaphthylamine in EA289, by acting on the efflux transporter located in the inner membrane. These membranotropic properties contribute to explain the activities of these neamine conjugates toward the MDR EA289 strain.
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR8601, CNRS Université Paris Descartes, PRES Paris Cité, 45 Rue des St Pères, 75270 Paris Cedex 06, France.
Anas
A
Allam
UMR_MD1 Aix Marseille Univ, IRBA, Transporteurs Membranaires, Chimiorésistance et Drug-Design, Facultés de Médecine et de Pharmacie, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 05, France.
Laure
L
Maigre
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR8601, CNRS Université Paris Descartes, PRES Paris Cité, 45 Rue des St Pères, 75270 Paris Cedex 06, France.
Rodolphe
R
Alves de Sousa
UMR_MD1 Aix Marseille Univ, IRBA, Transporteurs Membranaires, Chimiorésistance et Drug-Design, Facultés de Médecine et de Pharmacie, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 05, France.
Estelle
E
Dumont
UMR_MD1 Aix Marseille Univ, IRBA, Transporteurs Membranaires, Chimiorésistance et Drug-Design, Facultés de Médecine et de Pharmacie, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 05, France.
Julia
J
Vergalli
UMR_MD1 Aix Marseille Univ, IRBA, Transporteurs Membranaires, Chimiorésistance et Drug-Design, Facultés de Médecine et de Pharmacie, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 05, France. Electronic address: jean-marie.pages@univ-amu.fr.
Jean-Marie
JM
Pagès
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR8601, CNRS Université Paris Descartes, PRES Paris Cité, 45 Rue des St Pères, 75270 Paris Cedex 06, France. Electronic address: isabelle.artaud@parisdescartes.fr.
Isabelle
I
Artaud
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D002511:Cephalosporins / Q000378:metabolism; D004269:DNA, Bacterial / Q000378:metabolism; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D021902:Enterobacter aerogenes / Q000166:cytology / Q000187:drug effects*; D004926:Escherichia coli / Q000187:drug effects; D005601:Framycetin / Q000737:chemistry*; D006868:Hydrolysis / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D004269:DNA, Bacterial; D009942:Organometallic Compounds; D005601:Framycetin; C488396:neamine; C021720:nitrocefin
Antibacterial activity; Gram-negative bacteria; Membrane permeability; Metal-binding groups; Multidrug resistant bacteria; Neamine derivatives