New Class of Adjuvants Enables Lower Dosing of Colistin Against Acinetobacter baumannii

Abstract

Antibiotic resistance has become increasingly prevalent over the past few decades, and this combined with a dearth in the development of new classes of antibiotics to treat multidrug resistant Gram-negative infections has led to a significant global health problem and the increased usage of colistin as the last resort antibiotic. Colistin, however, presents dose dependent toxicity in the clinic. One potential approach to combatting this problem is the use of an antibiotic adjuvant, a compound that is nontoxic to the bacteria that enhances the potency of colistin and ultimately allows for reducing dosing. Herein, we present a new urea-containing class of 2-aminoimidazole-based adjuvants that potentiates colistin activity against colistin-sensitive Acinetobacter baumannii. Lead compounds enabled 1000-fold reduction in the minimum inhibitory concentration of colistin in vitro and showed efficacy in a Galleria mellonella infection model, representing the first step toward validating the potential of employing these adjuvants to lower colistin dosage.

A Whole-Cell Screen Identifies Small Bioactives That Synergize with Polymyxin and Exhibit Antimicrobial Activities against Multidrug-Resistant Bacteria

“…Recent repurposed pharmaceuticals have been experimentally used with varying success to potentiate the activity of polymyxins; however, none of these has been demonstrated to be effective against all of the ESKAPE pathogens (28,46,47,49,71,73,(75)(76)(77)(78)(79)(80)(81). New antimicrobials have also been identified and shown to be effective against polymyxin-resistant bacterial strains, which raises the hope that new FDA-approved antibiotics may emerge in the future (30)(31)(32)(33)(34)(35)(82)(83)(84)(85)(86)(87)(88). In the interim, other groups have pursued developing polymyxin-sparing regimes, such as pentamidine, in order to avoid the clinical use of polymyxins and circumvent their inherent toxicity (29).…”

“…Large-scale robotic screens have been employed by others to identify repurposed compounds that can potentiate the activity of nonpolymyxin antibiotics in order to produce polymyxin-sparing regimes for treating multidrug-resistant Gram-negative bacteria (28,29). Other groups have focused on identifying analogues or constructing derivatives of novel compounds that can potentiate the activity of polymyxin (30)(31)(32)(33)(34)(35). In this study, we merged these approaches with the goal of identifying existing compounds (either new bioactives or repurposed pharmaceuticals) that could act synergistically with PMB to yield new last-resort therapeutic options for polymyxinresistant bacterial infections that fail to respond to either polymyxin-sparing approaches or polymyxins themselves.…”

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

“…Minrovic et al, carried out a toxicity and antibacterial assay using the G. mellonella model to test, in vivo, five colistin adjuvants based on a new urea-containing class of 2-aminoimidazole compounds against a highly virulent isolate of Acinetobacter baumannii AB5075. During the 24h observation period, an increase in the survival of infected larvae treated with five different combinations of colistin and adjuvant compounds was observed [82].…”

Imidazole Type Antifungal Drugs Are Effective Colistin Adjuvants That Resensitize Colistin‐Resistant Enterobacteriaceae

“…To combat colistin resistance in bacterial pathogens, several colistin adjuvants have been discovered including antimicrobial compounds, FDA approved drugs, Eukaryotic kinase inhibitors, cationic block beta‐peptide, and small molecular compounds. [ 33–39 ] These compounds exhibited different level of synergistic effect with colistin and potentate its activity against colistin‐resistant Enterobacteriaceae. However, for most of these published compounds, they either lack in vivo efficacy data or knowledge regarding mechanism of action, hence further development of these compounds for clinical use is prohibited.…”