Overcoming β-Lactam resistance in Pseudomonas aeruginosa using non-canonical tobramycin-based antibiotic adjuvants

Abstract

β-Lactam antibiotics have for long been a mainstay in antimicrobial chemotherapy. However, due to its ubiquitous usage, bacteria have evolved multiple concerted pathways to evade its actions, underscoring the complexity of resistance to this class of drug. Current strategies to mitigate this problem are geared towards developing inhibitors that can shield the β-lactam core from enzymatic hydrolysis. In reality, a combination of factors including porin loss, overexpressed efflux pumps, expression of β-lactamases, reduced outer membrane permeability, and target modifications are characteristics of phenotypes that are microbiologically resistant to β-lactam antibiotics, especially Pseudomonas aeruginosa. Herein, we describe a strategy that may simultaneously address multiple mechanisms of resistance to β-lactams. A triple combination with β-lactam/β-lactamase inhibitors offers better microbiological response against carbapenem-resistant P. aeruginosa than the current standard of care. The observed interactions are also unaffected by efflux pumps. We conclude that a multicomponent combination therapy may be the way forward in addressing the myriads of emerging therapy failure associated with β-lactam resistance.

Keywords: Adjuvant; Aminoglycoside; Amphiphile; Antimicrobial resistance; Outer membrane; Permeability; Pseudomonas aeruginosa; Tobramycin; β-Lactam.