Phenazine Antibiotic‐Inspired Discovery of Bacterial Biofilm‐Eradicating Agents

Abstract

Bacterial biofilms are surface‐attached communities of slow‐growing and non‐replicating persister cells that demonstrate high levels of antibiotic tolerance. Biofilms occur in nearly 80 % of infections and present unique challenges to our current arsenal of antibiotic therapies, all of which were initially discovered for their abilities to target rapidly dividing, free‐floating planktonic bacteria. Bacterial biofilms are credited as the underlying cause of chronic and recurring bacterial infections. Innovative approaches are required to identify new small molecules that operate through bacterial growth‐independent mechanisms to effectively eradicate biofilms. One source of inspiration comes from within the lungs of young cystic fibrosis (CF) patients, who often endure persistent Staphylococcus aureus infections. As these CF patients age, Pseudomonas aeruginosa co‐infects the lungs and utilizes phenazine antibiotics to eradicate the established S. aureus infection. Our group has taken a special interest in this microbial competition strategy and we are investigating the potential of phenazine antibiotic‐inspired compounds and synthetic analogues thereof to eradicate persistent bacterial biofilms. To discover new biofilm‐eradicating agents, we have established an interdisciplinary research program involving synthetic medicinal chemistry, microbiology and molecular biology. From these efforts, we have identified a series of halogenated phenazines (HPs) that potently eradicate bacterial biofilms, and future work aims to translate these preliminary findings into ground‐breaking clinical advances for the treatment of persistent biofilm infections.

Bacterial Biofilm Eradication Agents: A Current Review

“…Of those, halogenated quinoline-3 (Figure 12) completely eradicated S. epidermidis biofilms at only 3.0 μM, while halogenated quinoline-4 eradicated (Figure 12) E. faecium biofilm at just 1.0 μM (Basak et al, 2015, 2016). The potential of phenazines as biofilm eradication agents was comprehensively reviewed by the same authors recently (Huigens et al, 2019).…”

Nucleoside-Lipid-Based Nanoparticles for Phenazine Delivery: A New Therapeutic Strategy to Disrupt Hsp27-eIF4E Interaction in Castration Resistant Prostate Cancer

“…In our previous work, we have shown that phenazine derivative phenazine #14 specifically disrupted the Hsp27/eIF4E interaction, increased apoptosis, and decreased tumor growth [ 15 ]. The family of heterocyclic nitrogenous phenazine molecules have been originally extracted [ 32 ] and used as antibiotic [ 33 ], antimalarial [ 34 ], and anticancer agents [ 35 ] with limited side effects on healthy tissues [ 36 ]. 2,3-Dialkoxyphenazine lipidic derivatives have shown anticancer activities on pancreatic cancer cell lines [ 37 ].…”

Efficacy data of halogenated phenazine and quinoline agents and an NH125 analogue to veterinary mycoplasmas

“…The collection of halogenated phenazine and quinoline compounds tested in this study originated by probing pyocyanin, a compound produced within the natural setting through bacterial competition. Pyocyanin, a phenazine compound produced by Pseudomonas aeruginosa and the presumed compound credited with outcompeting Staphylococcus aureus in the context of cystic fibrosis lung infections, served as the base structure used to initiate this exploration [40]. Halogenated phenazine analogue [42].…”