Using Small-Molecule Adjuvants to Repurpose Azithromycin for Use against Pseudomonas aeruginosa

Abstract

A major contributor to fatalities in cystic fibrosis (CF) patients stems from infection with opportunistic bacterium Pseudomonas aeruginosa. As a result of the CF patient's vulnerability to bacterial infections, one of the main treatment focuses is antibiotic therapy. However, the highly adaptive nature of P. aeruginosa, in addition to the intrinsic resistance to many antibiotics exhibited by most Gram-negative bacteria, means that multi-drug-resistant (MDR) strains are increasingly prevalent. This makes the eradication of pseudomonal lung infections nearly impossible once the infection becomes chronic. New methods to treat pseudomonal infections are greatly needed in order to eradicate MDR bacteria found within the respiratory tract, and ultimately better the quality of life for CF patients. Herein, we describe a novel approach to combatting pseudomonal infections through the use of bis-2-aminoimidazole adjuvants that can potentiate the activity of a macrolide antibiotic commonly prescribed to CF patients as an anti-inflammatory agent. Our lead bis-2-AI exhibits a 1024-fold reduction in the minimum inhibitory concentration of azithromycin in vitro and displays activity in a Galleria mellonella model of infection.

Galleria mellonella as a consolidated in vivo model hosts: New developments in antibacterial strategies and novel drug testing

“…Authors performed both toxicity and infection studies, demonstrating that the adjuvant is not toxic at the tested concentration and that it increased the survival of larvae when administered in a single dose in combination with azithromycin. This is equivalent to the treatment of infected worms with clavulanic acid/penicillin, one of the few clinically approved antibiotic/adjuvant combinations [88].…”

PEGylation of Polyethylenimine Lowers Acute Toxicity while Retaining Anti-Biofilm and β-Lactam Potentiation Properties against Antibiotic-Resistant Pathogens

“… 1 − 3 In contrast, multipurpose potentiators offer therapeutic advantages by counteracting resistance and biofilms. 1 , 3 − 8 Low-molecular-weight (600 Da) branched polyethylenimine (600 Da BPEI) has the ability to overcome AMR in staphylococci and Pseudomonas aeruginosa , potentiating penicillins, carbapenems, cephalosporins, and macrolides. 4 , 9 − 14 Nevertheless, the presence of primary amines creates toxicity issues that are paramount.…”

Antimicrobial Activity of Naturally Occurring Phenols and Derivatives Against Biofilm and Planktonic Bacteria

“…Pseudomonas aeruginosa is a Gram-negative, rod shaped bacterium with a pronounced tendency to form biofilms. It is also an opportunistic pathogen that exhibits multidrug resistance (Hubble et al, 2018). Its ubiquity in hospital-acquired infection has provided impetus for advancements in treating infections and diminishing the number of associated illnesses.…”