Evaluation of Heterocyclic Carboxamides as Potential Efflux Pump Inhibitors in Pseudomonas aeruginosa.

Yi Yuan,Yongzheng Zhang,Yanlu Cao,Jesus D Rosado-Lugo,Pratik Datta,Yangsheng Sun,Ajit K Parhi,Anamika Banerjee

doi:10.3390/antibiotics11010030

Abstract

The ability to rescue the activity of antimicrobials that are no longer effective against bacterial pathogens such as Pseudomonas aeruginosa is an attractive strategy to combat antimicrobial drug resistance. Herein, novel efflux pump inhibitors (EPIs) demonstrating strong potentiation in combination with levofloxacin against wild-type P. aeruginosa ATCC 27853 are presented. A structure activity relationship of aryl substituted heterocyclic carboxamides containing a pentane diamine side chain is described. Out of several classes of fused heterocyclic carboxamides, aryl indole carboxamide compound 6j (TXA01182) at 6.25 µg/mL showed 8-fold potentiation of levofloxacin. TXA01182 was found to have equally synergistic activities with other antimicrobial classes (monobactam, fluoroquinolones, sulfonamide and tetracyclines) against P. aeruginosa. Several biophysical and genetic studies rule out membrane disruption and support efflux inhibition as the mechanism of action (MOA) of TXA01182. TXA01182 was determined to lower the frequency of resistance (FoR) of the partner antimicrobials and enhance the killing kinetics of levofloxacin. Furthermore, TXA01182 demonstrated a synergistic effect with levofloxacin against several multidrug resistant P. aeruginosa clinical isolates.

Highlights

IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
A promising strategy for combating efflux-mediated resistance is the combination of antimicrobials with indirect antimicrobial agents such as efflux pump inhibitors (EPIs)
There is an urgent need for effective efflux inhibitors that can restore the activity of conventional antibiotics

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Efflux is one of the major resistance mechanisms in Gram-negative bacteria [1,2]. Efflux pumps are transporter proteins involved in the extrusion of a wide range of antimicrobials from the bacterial cell [3]. Many of these efflux pumps in Gram-negative bacteria belong to the resistance-nodulation-cell division (RND) family of tripartite efflux pumps [4,5].

Methods

Discussion

Conclusion