Alternative approaches to treat bacterial infections: targeting quorum-sensing

Abstract

Introduction: The emergence of multi- and pan-drug-resistant bacteria represents a global crisis that calls for the development of alternative anti-infective strategies. These comprise anti-virulence approaches, which target pathogenicity without exerting a bacteriostatic or bactericidal effect and are claimed to reduce the development of resistance. Because in many pathogens, quorum-sensing (QS) systems control the expression of virulence factors, interference with QS, or quorum-quenching, is often proposed as a strategy with a broad anti-virulence effect.Areas covered: We discuss the role and regulatory targets of QS control in selected Gram-positive and Gram-negative bacteria, focusing on those with clinical importance and QS control of virulence. We present the components of QS systems that form possible targets for the development of anti-virulence drugs and discuss recent research on quorum-quenching approaches to control bacterial infection.Expert opinion: While there has been extensive research on QS systems and quorum-quenching approaches, there is a paucity of in-vivo research using adequate animal models to substantiate applicability. In-vivo research on QS blockers needs to be intensified and optimized to use clinically relevant setups, in order to underscore that such drugs can be used effectively to overcome problems associated with the treatment of severe infections by antibiotic-resistant pathogens.

Keywords: Pseudomonas aeruginosa; Quorum-sensing; Staphylococcus aureus; anti-virulence; biofilm; quorum-quenching.

Fig. 1.. Principles of QS in Gram-positive and Gram-negative bacteria.

In Gram-positive bacteria, usually QS genes encode pre-peptides that are exported and sometimes post-translationally modified. Upon reaching a cell density-determined threshold, they activate a membrane-located receptor (histidine kinase), which via a phosphorylation cascade activates a cytoplasmic DNA-binding protein (response regulator). The response regulator activates target genes directly or indirectly via further regulatory components such as regulatory RNAs and/or proteins, in addition to positively regulating the QS system genes, resulting in an autofeedback loop. In Gram-negative bacteria, QS systems usually have membrane-diffusible signals that upon reaching a threshold directly activate DNA-binding proteins. Most Gram-negative bacteria use homologs of the LuxI/LuxR system and AHLs, but there are a variety of other systems.

Fig. 2.. QQ approaches in Gram-negative bacteria.

Many QQ approaches in Gram-negative bacteria are based on three mechanisms targeting LuxR/I homologs, (i) AHL-degrading enzymes (AHL acylase, AHL lactonase), (ii) AHL analogs that inhibit AHL binding to and activation of the DNA-binding LuxR homolog, or (iii) inhibitors of AHL biosynthesis.

Fig. 3.. QQ approaches in Gram-positive bacteria.

QQ approaches in Gram-positive bacteria comprise first and foremost (i) AIP analogs that inhibit AIP binding to the histidine kinase receptor, (ii) compounds that inhibit the DNA-binding response regulator, or (iii) biosynthesis of the AIP. Note several targets of Gram-positive QS systems can be reached by drugs from the extracellular space, allowing greater drug hydrophilicity.