New amphiphilic neamine conjugates bearing a metal binding motif active against MDR E. aerogenes Gram-negative bacteria

• Published in: European journal of medicinal chemistry Vol. 127; pp. 748 - 756
• Main Authors: Allam, Anas, Maigre, Laure, Alves de Sousa, Rodolphe, Dumont, Estelle, Vergalli, Julia, Pagès, Jean-Marie, Artaud, Isabelle
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.02.2017; Elsevier
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Cell Membrane Permeability; Cephalosporins - metabolism; Chemical Sciences; Chemistry, Medicinal; DNA, Bacterial - metabolism; Drug Resistance, Multiple, Bacterial - drug effects; Enterobacter aerogenes - cytology; Enterobacter aerogenes - drug effects; Escherichia coli - drug effects; Framycetin - chemistry; Gram-negative bacteria; Hydrolysis - drug effects; Hydrophobic and Hydrophilic Interactions; Life Sciences; Life Sciences & Biomedicine; Membrane permeability; Metal-binding groups; Multidrug resistant bacteria; Neamine derivatives; Organometallic Compounds - chemistry; Organometallic Compounds - metabolism; Organometallic Compounds - pharmacology; Pharmacology & Pharmacy; Science & Technology; DIEA; Multidrug resistant bacteria; TBAF; Neamine derivatives; Membrane permeability; Antibacterial activity; Gram-negative bacteria; Metal-binding groups; HOAt; HATU; ENTEROBACTER-AEROGENES; ESCHERICHIA-COLI; ANTIMICROBIAL PEPTIDES; DRUG-RESISTANCE; ACRAB-TOLC; POLYMYXIN-B; CELL-ENVELOPE; EFFLUX PUMPS; MULTIDRUG-RESISTANCE; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.10.054

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. [Display omitted] •Synthesis of new amphiphilic neamine conjugates bearing a metal binding motif.•Evaluation of their specific metal binding ability in the Mueller Hinton medium.•Significant antibacterial activity against a multiresistant clinical isolate compared to usual antibiotic.•Membranotropic action: permeabilization of the outer membrane and action on the efflux transporter in the inner membrane.