Regulatory Mechanisms and Promising Applications of Quorum Sensing-Inhibiting Agents in Control of Bacterial Biofilm Formation

Abstract

A biofilm is an assemblage of microbial cells attached to a surface and encapsulated in an extracellular polymeric substance (EPS) matrix. The formation of a biofilm is one of the important mechanisms of bacterial resistance, which not only leads to hard-to-control bacterial infections in humans and animals but also enables bacteria to be a major problem in various fields, such as food processing, wastewater treatment and metalworking. Quorum sensing (QS) is a bacterial cell-to-cell communication process that depends on the bacterial population density and is mediated by small diffusible signaling molecules called autoinducers (AIs). Bacteria use QS to regulate diverse arrays of functions, including virulence and biofilm formation. Therefore, the interference with QS by using QS inhibiting agents, including QS inhibitors (QSIs) and quorum quenching (QQ) enzymes, to reduce or even completely repress the biofilm formation of pathogenic bacteria appears to be a promising approach to control bacterial infections. In this review, we summarize the mechanisms of QS-regulating biofilm formation and QS-inhibiting agents that control bacterial biofilm formation, strategies for the discovery of new QS inhibiting agents, and the current applications of QS-inhibiting agents in several fields to provide insight into the development of effective drugs to control pathogenic bacteria.

Impacts of Ser/Thr Protein Kinase Stk1 on the Proteome, Twitching Motility, and Competitive Advantage in Pseudomonas aeruginosa

“…Notably, those differentially expressed proteins associated with the quorum sensing (QS) system, including the downregulated proteins of RhlR, PqsH, LecA, LasB, and PhnB, and the upregulated proteins of LasI and RhlA were found, as shown in the pae02024 quorum sensing map ( Supplementary Figure S8 ). The QS network of P. aeruginosa is a multi-layered hierarchy composed of at least four interconnected signal mechanisms, including Las, Rhl, Pqs, and Iqs systems ( Lee and Zhang, 2015 ; Turkina and Vikström, 2019 ; Zhou et al, 2020 ). These differentially expressed QS proteins are mainly involved in regulating the production of rhamnolipid and lectin A ( Diggle et al, 2006 ; Soto-Aceves et al, 2021 ) and play a role in promoting the formation and maintenance of the mature structure of biofilm ( Fila et al, 2018 ).…”

Multidrug Resistant Acinetobacter baumannii Biofilms: Evaluation of Phenotypic–Genotypic Association and Susceptibility to Cinnamic and Gallic Acids

“…Former studies demonstrated that gallic acid inhibited biofilm formation in Staphylococcus aureus (Luís et al, 2014), P. aeruginosa (Zhang et al, 2020), E. coli, and Streptococcus mutans (Shao et al, 2015). Likewise, the antibiofilm effect of cinnamic acid derivatives was recognized in recent studies (Zhou et al, 2020). Various mechanisms have been proposed to justify the antibiofilm activities of phenolic compounds including gallic and cinnamic acid derivatives.…”

Bacterial virulence factors: a target for heterocyclic compounds to combat bacterial resistance

“…; (3) interfere with the signal receptors using AI antagonists; (4) interfere with the response regulators thus disturbing signaling cascade; (5) reduce the extracellular AIs accumulation by inhibiting AIs efflux hence inhibited cell-to-cell signaling. 82,90 Fig. 12 Some reported substituents as head group replacements in AHL to obtain QSI.…”

“…The ideal cellular effect of QSI targeting LasR and/or RhlR would be the reduction in the production of virulence factors (such as elastase, hydrogen cyanide, pyocyanin, pyoverdin, rhamnolipid or alkaline protease) as well as the attenuation of biolm formation. [82][83][84][85][86][87][88][89][90] The following section provides a detailed but not exhaustive overview of the structures covered by the synthetic QSI that interferes with AHL signals. Generally, compounds targeting LasR and Rh1R can be divided into two categories: structural mimics of AHL and structurally unrelated substances.…”