Next generation quorum sensing inhibitors: Accounts on structure activity relationship studies and biological activities

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Abstract

Bacterial resistance is a growing threat which represents major scourge throughout the world. The suitable way to control the present critical situation of antimicrobial resistance would be to develop entirely novel strategies to fight antibiotic resistant pathogens such as quorum sensing (QS) inhibitors or its combination with antibiotics. Anti QS agents can eliminate the QS signals and put the barrier in bio-film formation, consequently, bacterial virulence will be reduced without causing drug-resistance to the pathogens. Among the various anti QS agents identified, especially those of natural origin, furanones or acylatedhomoserine lactones (AHLs) are most popular. Semi-synthetic and synthetic inhibitors have shown greatest potential and have inspired chemists to design synthetically modified QS inhibitors with lactone moiety. This review focuses on anti QS agents (bio-film inhibitors) of both natural and synthetic origins. Further, the synthesis, structure activity relationship and anti QS activity covering literature from 2015 till March 2020 has been discussed.

Introduction

The discovery of penicillin by Sir Alexander Fleming in 1928 has given birth to the modern era of antibiotics which culminated into modern medicine and saved millions of lives. However, antibiotics are no longer having same reputation that they had once upon a time and therefore the world is in hunt for developing alternative therapeutic strategies to fight the battle against the infectious diseases without inducing drug resistance.1 It is the fact that bacterial infection kills millions of people every year, which have prompted researchers to develop a practical alternative approaches to fight against the drug-resistant bacteria and related diseases.2 Quorum sensing (QS) is a cell–cell communication strategy that allows bacteria to act as a population by coordinating their gene expression.3 QS controls different pathogenic progressions such as bio-film formation,4 susceptibility to antibiotics,5 and bacterial cell adhesion.6 Therefore, it is not surprising that the research in field of identification of QS inhibitors has emerged as a tool to fight against drug resistant pathogens in the recent past.

Studies over the years have proved that the bacteria coordinate both bacterium-bacterium interactions and associations with higher organisms through intercellular communication systems that are often based on the expression of new genes, the process is known as quorum sensing (QS).7 The small molecules like acylhomoserine lactones (AHLs), autoinducing peptides (AIPs) and autoinducer-2 (AI-2) serves as signalling molecules in the bacterial cells and are responsible for the regulation of bacterial pathogenesis.8 These signalling molecules also participate in various physiological processes of bacteria including bio-film formation, motility, and antibiotic resistance by which bacteria adapt to and survive in the stressed environment.9 Among these processes, the bio-film formation is one of the necessary requirements for bacterial adhesion, growth and subsequently accompanied with the production of extracellular polymer and adhesion matrix as well. This further leads to fundamental changes in the bacterial growth and gene expression.10 The bio-film acts like a shield and reduces the sensitivity of bacteria to antibacterial agents as well as radiations which ultimately affects the health of the patient.11 Moreover, the production of virulence factors that helps the bacteria to evade the host's immune response is also important for the pathogenesis of infections. The disruption of QS to control the production of virulence factors is considered as an attractive therapeutic strategy.12 The use of selective QS inhibitor is considered an effective strategy to control the formation of bio-film and virulence expression by most of the pathogens, which can increase sensitivity of pathogens to drugs/antibiotics.13 However, the clinical application of anti QS agents is still in its primitive stages.14 In our previous article entitled “Next generation bio-film inhibitors for Pseudomonas aeruginosa: synthesis and rational design approaches” we have summarised the development of small molecules that inhibit and/or disperse bacterial bio-films of P. aeruginosa in particular with special emphasis on rational designs and synthetic methods to prepare the inhibitors.15 In continuation of our interest in QS inhibitors, this review article provides updates on structure activity relationship studies of various QS inhibitors covering literature from 2015 till March 2020.

Section snippets

Naturally occurring quorum sensing inhibitors

In recent times, natural sources especially plants and marine organisms have attracted more attention for their anti QS bioactive compounds. It is well known fact that researchers have been exploring the natural sources for novel QS inhibition agents due to their less toxicity, better bioavailability and therapeutic applications.16 In this section, anti QS agents derived from the natural sources have been briefly discussed. The leading phytochemical families which are responsible for

Structure activity relationships of Anti-Quorum sensing (QS) compounds

The chemical compounds obtained from nature are always a good source of new QS inhibitors. However, the bio-availability of the chemicals from a given natural source limits the exploration of biological activities.25 This problem has been overcome by chemists to some extent either by chemical synthesis of molecules or modification of the natural product-inspired molecules. In this section, we have summarized the semi-synthetic or synthetic protocols of anti QS compounds reported in literature

Summary of biological activity studies of synthesised QS inhibitors

The structures of the most active QS inhibitors are summarised (Table 1) below. The bacterial species and the mode of determination of QS inhibition activity is also given for the compounds.

Conclusions

Many researchers succeeded to identify libraries of QS inhibitors to control the pathological damage in various animal infection models till date. However, most anti-QS agents are still in the pipeline of clinical trial studies. Plant originated natural products; in particular, oxygenated derivatives which were used in ancient times as traditional medicines such as flavonoids, terpenoids, and coumarines are widely explored as QS inhibitors. Thorough understanding of the potential natural

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

One of the authors UBG is thankful to the Dnyanprassarak Mandal’s College and Research Centre, Assagao-Goa (Research Grant No. DNY/CC/2014-15/03/1198) for funding. We also acknowledge Directorate of Higher Education, Government of Goa, Porvorim-Goa (Research Grant No. 9/328/2026-17/SPSE-PP/DHE/3607) and Department of Science and Technology, Government of Goa, Porvorim-Goa (Research Grant No. 6-264-2017/STE-DIR/997) for financial support.

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