Organosulfur scaffolds as quorum sensing and biofilm modulators in Gram-negative bacteria

Disrupting Bacterial Quorum Sensing: A Review of Protein Families and Natural Inhibitors for Combating Resistance.

The Quorum Sensing (QS) system plays a central role in regulating several processes that influence bacterial physiology, communication, and pathogenesis. It governs the production of virulence factors, facilitates biofilm formation, and contributes to the development of antibiotic resistance, all of which are critical to bacterial survival and pathogenicity. QS enables both intraspecies and inter-species bacterial communication, operating through distinct pathways in Gram-positive and Gram-negative bacteria. This review provides a comprehensive overview of the major families of quorum-sensing proteins involved in the working of the signalling molecules. It examines the structural features, functional roles, and mechanisms of action of these proteins, highlighting their significance in bacterial behaviour. Furthermore, the study explores the potential of plant-derived secondary metabolites as natural inhibitors targeting QS systems to disrupt bacterial pathogenicity. Finally, it discusses the implications of exploiting these inhibitors as promising strategies to address the growing challenge of antibiotic resistance in bacterial infections.

Bioorganic strategies for quorum sensing inhibition: disrupting biofilms and virulence in drug-resistant pathogens.

The escalating global crisis of antimicrobial resistance (AMR) poses a severe threat to public health, with bacterial biofilms and virulence factors exacerbating treatment failures in drug-resistant pathogens. Quorum sensing (QS), a density-dependent communication system, orchestrates biofilm formation, virulence expression, and resistance mechanisms in clinically relevant bacteria, including Pseudomonas aeruginosa, Staphylococcus aureus, and other pathogenic bacteria. Unlike conventional antibiotics, which exert selective pressure that can lead to resistance, QS inhibition offers a promising anti-virulence strategy by attenuating pathogenicity without directly killing bacteria. This review focuses on bioorganic approaches to QS disruption, encompassing natural products, synthetic analogues, hybrid phytocompound-nanoparticle conjugates, and metal-organic frameworks (MOFs). Key sections explore QS systems in Gram-negative and Gram-positive pathogens; molecular mechanisms of inhibition, including autoinducer synthesis blockade, receptor antagonism, and enzymatic degradation; structure-activity relationships (SAR), with emphasis on pharmacophores such as hydroxyl groups and α,β-unsaturated carbonyls; and evidence of biofilm and virulence attenuation in drug-resistant strains from in vitro, ex vivo, and in vivo studies. Synergistic effects with sub-MIC antibiotics are also highlighted, alongside challenges related to bioavailability, toxicity, and regulatory hurdles. Prospects include bioorthogonal probes for QS tracking, machine learning-aided design of next-generation inhibitors, nanoparticle-mediated targeted delivery, and emerging preclinical candidates. By leveraging advances in bioorganic chemistry, QS inhibition holds substantial translational potential for the management of AMR-driven infections and may redefine future therapeutic paradigms in infectious disease control.

Quorum-quenching enzymes as next-generation antibiofilm therapeutics: mechanisms, applications, and future perspectives

Disruption of quorum sensing and biofilm formation by lawsone in gram-negative bacteria

ABSTRACT Antimicrobial resistance is a major global health threat, exacerbated by bacterial virulence mechanisms such as quorum sensing (QS) and biofilm formation, which enhance pathogenicity and reduce antibiotic susceptibility. Targeting QS offers a promising antivirulence strategy that may attenuate pathogenic traits without imposing selective pressure. In this study, lawsone was evaluated for anti-QS and antibiofilm activity against Chromobacterium violaceum, Pseudomonas aeruginosa, and Serratia marcescens. Lawsone significantly inhibited QS-regulated virulence factors, with reductions in violacein production in C. violaceum (90.62%) at 250 µg/mL (1.43 mM). There was also a reduction in pyocyanin and pyoverdin in P. aeruginosa (87.90% and 81.97%, respectively) and prodigiosin in S. marcescens (~83%) at 500 µg/mL (2.87 mM) lawsone. Additionally, lawsone suppressed protease and elastase activities, as well as rhamnolipid production in P. aeruginosa. Biofilm formation was inhibited in a dose-dependent manner, reaching 84.28% in C. violaceum, 76.22% in P. aeruginosa, and 56.27% in S. marcescens at respective sub-MICs. Computational analyses supported these findings; docking showed stable binding of lawsone to QS regulators, including CviR (−7.8 kcal/mol), LasR (−8.5 kcal/mol), and SmaR (−7.7 kcal/mol). Molecular dynamics simulations confirmed the stability of these complexes, with root mean square deviation values of 0.200 ± 0.016 nm (CviR-lawsone), 0.238 ± 0.036 nm (LasR-lawsone), and 0.632 ± 0.061 nm (SmaR-lawsone). Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculations further demonstrated favorable binding. To my knowledge, this is the first study to systematically demonstrate the anti-QS and antibiofilm potential of lawsone across multiple clinically relevant gram-negative pathogens using an integrated experimental and computational approach. This work provides possible mechanistic insights into lawsone-QS regulator interactions, highlighting its potential as a broad-spectrum antivirulence agent targeting conserved QS systems. IMPORTANCE Antimicrobial resistance is a growing global threat, driven in part by bacterial virulence mechanisms such as quorum sensing (QS) and biofilm formation. Targeting QS offers an alternative strategy to reduce pathogenicity without promoting resistance. This study shows that lawsone effectively inhibits QS-regulated virulence factors and biofilm formation in gram-negative pathogens, like Pseudomonas aeruginosa, Serratia marcescens, and Chromobacterium violaceum. These findings highlight lawsone as a promising antivirulence agent that could complement existing therapies for managing biofilm-associated and drug-resistant infections. Antimicrobial resistance is a growing global threat, driven in part by bacterial virulence mechanisms such as quorum sensing (QS) and biofilm formation. Targeting QS offers an alternative strategy to reduce pathogenicity without promoting resistance. This study shows that lawsone effectively inhibits QS-regulated virulence factors and biofilm formation in gram-negative pathogens, like Pseudomonas aeruginosa, Serratia marcescens, and Chromobacterium violaceum. These findings highlight lawsone as a promising antivirulence agent that could complement existing therapies for managing biofilm-associated and drug-resistant infections.

Quorum Sensing as an Antivirulence Strategy in Control of Bacterial Infections

Quorum sensing (QS) is a bacterial cell-to-cell communication system that plays a central role in regulating virulence, biofilm formation, pathogen adaptation, and infection persistence. The global rise in antimicrobial resistance, driven by conventional antibiotic use, has spurred the development of alternative, non-lethal strategies, including antivirulence approaches. This review aims to examine quorum sensing as an antivirulence target and to evaluate the potential of quorum-sensing inhibition (QSI) to control bacterial infection. A narrative literature review was conducted using scientific publications from 2016 to 2026 retrieved from reputable databases. The review highlights that QS regulates multiple pathogenic determinants, including virulence factor production, secretion system control, biofilm development, colonization processes, and bacterial survival within host environments. QSI-based interventions can be achieved through inhibition of signal molecule synthesis, enzymatic degradation of autoinducers, and receptor competition. This strategy potentially reduces selective pressure that causes resistance since it does not directly affect bacterial viability. Beyond clinical applications in chronic and biofilm-associated infections, QSI also has promising prospects in food safety, environmental management, and medical technologies. However, challenges related to compound stability, in vivo effectiveness, and potential bacterial adaptation require further investigation before broader clinical implementation can be achieved.

A quorum sensing antagonist with dual bacterium- and host-directed anti-pathogenic activity against Pseudomonas aeruginosa

ABSTRACT Pseudomonas aeruginosa is a major opportunistic pathogen whose clinical management is increasingly compromised by antibiotic resistance and biofilm-associated persistence. Anti-pathogenic strategies that attenuate virulence without inhibiting bacterial growth offer a promising alternative to conventional antibiotics. Here, we identify the Spongosorites sp-derived bisindole alkaloid (R)-6’-debromohamacanthin B (RDB) as a potent dual bacterium- and host-directed anti-pathogenic agent against P. aeruginosa. RDB suppressed quorum sensing (QS) activity and markedly inhibited biofilm formation at growth-independent concentrations starting at 100 pM. Mechanistically, RDB functionally interfered with several central QS regulators, including LasR, RhlR, PqsR, and QscR, consistent with network-level attenuation of QS signaling, and reduced intracellular c-di-GMP levels associated with biofilm regulation. Beyond its bacterium-directed activity, RDB enhanced macrophage-mediated phagocytosis and intracellular bacterial clearance while limiting excessive production of pro-inflammatory mediators. In a murine wound infection model, RDB significantly reduced infection severity, restricted systemic dissemination, and promoted wound healing without detectable toxicity. Collectively, these findings demonstrate that RDB exerts dual bacterium-directed and host-directed activities, simultaneously attenuating virulence and biofilm formation while reinforcing host defense and controlling pathological inflammation. This multifaceted mode of action positions RDB as a promising anti-pathogenic therapeutic candidate for the management of P. aeruginosa infections without promoting antimicrobial resistance.