Small Molecule Inhibitors of the Response Regulator ArsR Exhibit Bactericidal Activity against Helicobacter pylori.

Andrés González,Javier Sancho,Eduardo Chueca,Ángel Lanas,Sandra Salillas,Javier Casado,Adrián Velázquez-Campoy

doi:10.3390/microorganisms8040503

Abstract

Helicobacter pylori is considered the most prevalent bacterial pathogen in humans. The increasing antibiotic resistance evolved by this microorganism has raised alarm bells worldwide due to the significant reduction in the eradication rates of traditional standard therapies. A major challenge in this antibiotic resistance crisis is the identification of novel microbial targets whose inhibitors can overcome the currently circulating resistome. In the present study, we have validated the use of the essential response regulator ArsR as a novel and promising therapeutic target against H. pylori infections. A high-throughput screening of a repurposing chemical library using a fluorescence-based thermal shift assay identified several ArsR binders. At least four of these low-molecular weight compounds noticeably inhibited the DNA binding activity of ArsR and showed bactericidal effects against antibiotic-resistant strains of H. pylori. Among the ArsR inhibitors, a human secondary bile acid, lithocholic acid, quickly destroyed H. pylori cells and exhibited partial synergistic action in combination with clarithromycin or levofloxacin, while the antimicrobial effect of this compound against representative members of the normal human microbiota such as Escherichia coli and Staphylococcus epidermidis appeared irrelevant. Our results enhance the battery of novel therapeutic tools against refractory infections caused by multidrug-resistant H. pylori strains.

Highlights

Multidrug resistance in most clinically relevant bacterial pathogens is a major global public health concern [1,2]
Focusing on new molecular targets could lead to the development of novel classes of antibacterial drugs that avoid the resistance strategies evolved by microorganisms to existing antibiotics
A major challenge in the current antibiotic resistance crisis is the identification of novel microbial targets, essential for in vivo growth or pathogenicity, whose inhibitors can overcome the currently circulating resistome of human pathogens

Summary

Introduction

Multidrug resistance in most clinically relevant bacterial pathogens is a major global public health concern [1,2]. Focusing on new molecular targets could lead to the development of novel classes of antibacterial drugs that avoid the resistance strategies evolved by microorganisms to existing antibiotics. In vivo essential genes represent a powerful source of promising targets for antibacterial drug development [3]. Anti-TR drugs will inhibit the activity of TRs, but will potentially affect the expression of the downstream genes into the regulatory network. Anti-TRs drugs could function both as bactericidal/bacteriostatic chemotherapy and as antivirulence strategies, avoiding the expression of toxins, adhesins, invasins, capsule, quorum-sensing mechanisms and efflux pumps and thereby disarming the pathogen, and enhancing its susceptibility to the host immune response or to the action of conventional antibiotics [4]

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