High-Throughput Approaches for the Identification of Pseudomonas aeruginosa Antivirulents

Abstract

Antimicrobial resistance is a serious medical threat, particularly given the decreasing rate of discovery of new treatments. Although attempts to find new treatments continue, it has become clear that merely discovering new antimicrobials, even if they are new classes, will be insufficient. It is essential that new strategies be aggressively pursued. Toward that end, the search for treatments that can mitigate bacterial virulence and tilt the balance of host-pathogen interactions in favor of the host has become increasingly popular. In this review, we will discuss recent progress in this field, with a special focus on synthetic small molecule antivirulents that have been identified from high-throughput screens and on treatments that are effective against the opportunistic human pathogen Pseudomonas aeruginosa.

Keywords: Caenorhabditis elegans; Pseudomonas aeruginosa; antimicrobial resistance; antivirulence; biofilm; biofilms; drug discovery; drug screens; high-throughput screen; pyoverdine; quorum sensing; secretion systems; type II secretion; type III secretion.

FIG 1

P. aeruginosa virulence factors for therapeutic intervention. Antivirulents identified from high-throughput screens inhibit quorum-sensing (QS), biofilm formation, toxin secretion (via T2SS or T3SS), or pyoverdine production or function. QS antivirulents inhibit autoinducers (e.g., acylhomoserine lactones and 2-alkyl-4-quinolones), their synthases (e.g., LasI, RhlI, and PqsABCDH), or their receptors (e.g., LasR, RhlR, and PqsR). Biofilm inhibitors often target regulators of formation, such as QS or c-di-GMP production, as well as components of the extracellular matrix. T2SS- and T3SS-dependent virulence targets have included effectors (e.g., LasB, PlcH, ExoS, or ExoU) and delivery systems like the twin arginine translocase (Tat) and the T3SS needle complex. Pyoverdine inhibitors have been found to hamper the production of pyoverdine and its function by binding to the siderophore directly.