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

Abstract

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.

• Authors: Derek Ammeter, Temilolu Idowu, George G Zhanel, Frank Schweizer
• Journal: The Journal of antibiotics (J Antibiot (Tokyo)) Vol. 72 Issue 11 Pg. 816-826 (11 2019) ISSN: 1881-1469 [Electronic] England
• PMID: 31420586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Pharmaceutic
• Anti-Bacterial Agents
• Disaccharides
• Heterocyclic Compounds
• Pyrans
• nebramine
• cyclam

Topics

• Adjuvants, Pharmaceutic (chemistry, pharmacology)
• Anti-Bacterial Agents (chemical synthesis, chemistry, pharmacology)
• Cell Survival (drug effects)
• Disaccharides (chemistry, pharmacology)
• Drug Resistance, Multiple, Bacterial
• Drug Synergism
• HEK293 Cells
• Hep G2 Cells
• Heterocyclic Compounds (chemistry, pharmacology)
• Humans
• Molecular Structure
• Pseudomonas aeruginosa (drug effects)
• Pyrans (chemistry, pharmacology)