Development of a nebramine-cyclam conjugate as an antibacterial adjuvant to potentiate β-lactam antibiotics against multidrug-resistant P. aeruginosa

• Published in: Journal of antibiotics Vol. 72; no. 11; pp. 816 - 826
• Main Authors: Ammeter, Derek, Idowu, Temilolu, Zhanel, George G., Schweizer, Frank
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2019; Springer Nature; Nature Publishing Group
• Subjects: 631/92/72/1199; 692/699/255/1318; Adjuvants, Pharmaceutic - chemistry; Adjuvants, Pharmaceutic - pharmacology; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics; Bacteria; Bacteriology; Biomedical and Life Sciences; Bioorganic Chemistry; Biotechnology & Applied Microbiology; Cell Survival - drug effects; Disaccharides - chemistry; Disaccharides - pharmacology; Drug Resistance, Multiple, Bacterial; Drug Synergism; HEK293 Cells; Hep G2 Cells; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Humans; Immunology; Life Sciences; Life Sciences & Biomedicine; Medicinal Chemistry; Microbiology; Molecular Structure; Multidrug resistant organisms; Organic Chemistry; Pathogens; Pharmacology & Pharmacy; Pseudomonas aeruginosa - drug effects; Pyrans - chemistry; Pyrans - pharmacology; Science & Technology; STRAINS; COMBINATIONS; TOBRAMYCIN; THERAPY; PSEUDOMONAS-AERUGINOSA; SYNERGY; INHIBITORS; GENTAMICIN; CARBAPENEM RESISTANCE; PATHOGENS
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/s41429-019-0221-9

The β-lactams are the most widely used class of antibiotics due to their safety, effectiveness, and spectrum of activity. As a result of their ubiquitous usage, there has been a steady rise in β-lactam resistant Gram-negative bacteria, especially Pseudomonas aeruginosa , resulting in limited treatment options. P. aeruginosa can develop multidrug-resistant phenotypes using a multifaceted approach of β-lactamase expression, decreased porin production and increased efflux. Current β-lactamase inhibitors address drug hydrolyzing enzymes but may not be as effective in phenotypes with reduced permeability and/or overexpressed efflux pumps. Herein, we present the synthesis and biological evaluation of a nebramine-cyclam conjugate molecule that is able to potentiate β-lactam antibiotics, as well as other legacy antibiotics, against P. aeruginosa in vitro. Combination studies show that this adjuvant is able to synergize with β-lactams such as aztreonam and ceftazidime against multidrug-resistant and extremely drug-resistant clinical isolates through a hypothesized mechanism of outer membrane permeabilization. Importantly, the addition of low concentrations (8 µM) of the nontoxic nebramine-cyclam conjugate is able to further potentiate existing β-lactam/β-lactamase inhibitor combinations in β-lactamase-harboring P. aeruginosa strains. These data support a potential application of the nebramine-cyclam conjugate as an adjuvant for treating infections caused by P. aeruginosa strains that utilize multiple mechanisms of resistance.