Nanomaterials Regulate Bacterial Quorum Sensing: Applications, Mechanisms, and Optimization Strategies

Abstract

Anti-virulence therapy that interferes with bacterial communication, known as "quorum sensing (QS)", is a promising strategy for circumventing bacterial resistance. Using nanomaterials to regulate bacterial QS in anti-virulence therapy has attracted much attention, which is mainly attributed to unique physicochemical properties and excellent designability of nanomaterials. However, bacterial QS is a dynamic and multistep process, and there are significant differences in the specific regulatory mechanisms and related influencing factors of nanomaterials in different steps of the QS process. An in-depth understanding of the specific regulatory mechanisms and related influencing factors of nanomaterials in each step can significantly optimize QS regulatory activity and enhance the development of novel nanomaterials with better comprehensive performance. Therefore, this review focuses on the mechanisms by which nanomaterials regulate bacterial QS in the signal supply (including signal synthesis, secretion, and accumulation) and signal transduction cascade (including signal perception and response) processes. Moreover, based on the two key influencing factors (i.e., the nanomaterial itself and the environment), optimization strategies to enhance the QS regulatory activity are comprehensively summarized. Collectively, applying nanomaterials to regulate bacterial QS is a promising strategy for anti-virulence therapy. This review provides reference and inspiration for further research on the anti-virulence application of nanomaterials.

Keywords: antibacterial; anti‐virulence therapy; drug resistance; nanomaterials; optimization strategies; quorum sensing.

Figure 1

Applications of nanomaterials with QS regulatory activity.

Figure 2

Schematic illustration of the co‐assembly of Tob and QSI (1) co‐loaded SqNPs, their ultrastructure by Cryo‐TEM image, and their proposed actions at all stages of PA respiratory infections. Reproduced under the terms of the Creative Commons Attribution (CC BY) license.^{[ 40 ]} Copyright 2020, The Authors. Published by Wiley‐VCH Verlag GmbH & Co. KGaA.

Figure 3

Mechanisms of action of quorum sensing‐regulating nanomaterials. A) represents signal supply inhibition, which includes signal molecule synthesis inhibition (A1, A2, A3, A4), signal molecule secretion inhibition (A5, A6), and signal molecule accumulation inhibition (A7, A8); B) represents signal transduction cascade inhibition, which includes signal perception disruption (B1, B2) and signal response disruption (B3, B4); C) represents positive signal reinforcement, which includes amplifying QS signals (C1), delivering key QS components (C2, C3), and topologically identifying QS receptors (C4). Among them, A1, A2, and A5 are unique regulatory mechanisms of Gram‐negative bacteria, A3, A4, A6, and B3 are unique regulatory mechanisms of Gram‐positive bacteria, and the rest are common mechanisms of both.

Figure 4

PqsR inverse agonists as pathoblockers and hit‐to‐lead optimization strategy. A) Schematic representation of the mode of action. B) Bioisosteric replacement and structural simplification of hit 2 lead to 3. The discovery and exploitation of a growth vector‐enabled identification of 4. C) 3D model of compound 3 in complex with PqsR91‐319 derived from related X‐ray structure (PDB entry 6Q7W). D) Pharmacological profile of various PqsR ligands. Reproduced under the terms of the CC BY license.^{[ 26 ]} Copyright 2021, The Authors. Advanced Science published by Wiley‐VCH GmbH.

Figure 5

Engineered biological nanofactories trigger a quorum sensing response in targeted bacteria. a) Components of a conceptual biological nanofactory comprising four functional modules. b) Components of the practical demonstration of a biological nanofactory: targeting module (cell targeting antibody), and sensing, synthesis, and assembly modules (fusion protein). c) The nanofactories self‐assemble when protein G of fusion protein HGLPT binds to the Fc region of the targeting antibody. Following their addition to bacterial cultures, nanofactories bind specifically to the targeted bacteria (green circle), synthesize and deliver AI‐2 (yellow circles) at their cell surfaces and trigger the quorum sensing response. Reproduced with permission.^{[ 169 ]} Copyright 2010, Springer.

Figure 6

Flash NanoPrecipitation and drug delivery of CAI‐1. A) CAI‐1 nanoparticles decorated with a polyethylene glycol surface (PEG) can be formed by rapidly precipitating CAI‐1 in the presence of amphiphilic PEG diblock copolymers and lipophilic co‐core materials. B) Hydrophobic bulk CAI‐1 cannot penetrate the mucus that covers crypts in the small intestine where V. cholerae reside during infection. C) Delivery of CAI‐1 in small PEG covered nanoparticles can allow CAI‐1 to directly penetrate mucus layers or become rapidly solubilized into bile micelle carriers that can also penetrate intestinal barriers. Reproduced with permission.^{[ 24 ]} Copyright 2015, American Chemical Society.

Figure 7

Optimization strategies of the quorum sensing regulation activity of nanomaterials.

Figure 8

Synthesis methods of nanomaterials with QS regulatory activity A) Schematic diagram the preparation process of Ti‐M‐L@C substrate. Reproduced under the terms of the Creative Commons Non‐Commercial, No Derivatives (CC BY‐NC‐ND) license.^{[ 25 ]} Copyright 2022, The Authors. B) Pictorial representation for the biofabrication of scaffold of SeNPs and HP (SeNPs@HP). Reproduced under the terms of the CC BY license.^{[ 27 ]} Copyright 2017, The Authors. C) Schematic illustration of kaempferol encapsulated chitosan nanoparticles. Reproduced with permission.^{[ 92 ]} Copyright 2016, Elsevier. D) Schematics of the quercetin (QUE)‐chitosan (CHI) nanoplex formation. Reproduced under the terms of the CC‐BY license.^{[ 50 ]} Copyright 2021, The Authors. E) Model of formation of PC‐NPs showing the two steps of crosslinking with GNP and TPP and details of the structure and surface topology of the furnished NPs. Reproduced with permission.^{[ 192 ]} Copyright 2020, Elsevier.

Figure 9

Inhibitory effects of AgNPs and AgNRs on P. aeruginosa PAO1. A) Growth profiles in terms of OD600, B) live/dead ratio, C) the intracellular ROS level, and D) the cell membrane permeability of PAO1 under the exposure to AgNPs/AgNRs. Images of the (E) non NPs‐treated control cells and of cells in the presence of F) 20 mg L⁻¹ AgNPs and G) 300 mg L⁻¹ AgNRs by transmission electron microscopy (TEM). For E and F: bar = 200 nm, and for G: bar = 500 nm. Blue arrows indicate AgNPs/AgNRs, red arrows indicate membrane damage. H). The transcript profilesof PAO1 responses related to oxidative stress, SOS response, outer membrane porin, osmotic stress, and efflux systems under the exposure of AgNPs/AgNRs. Reproduced with permission.^{[ 56 ]} Copyright 2019, Elsevier.

Figure 10

Schematic diagram of combining PTT and quorum‐sensing‐inhibition strategy for improving osseointegration and treating biofilm‐associated bacterial infection of Ti‐based implant. Reproduced under the terms of the CC BY‐NC‐ND license.^{[ 25 ]} Copyright 2022, The Authors.

Figure 11

Schematic representation of dispersing biofilm by the bacterial enzyme‐triggered nanosystem, which could modulate QS of bacteria, potentiate antibiotic efficiency, and synergistic photodynamic treatment. Reproduced with permission.^{[ 231 ]} Copyright 2019, Wiley.

Figure 12

Molecular dynamics simulation of PSMα1 and GQDs. Schemes of a) PSMα1 and b) PSMα1 and GQD complex. β‐Turns are shown in green, α helix in red, and random coils in blue. c–e) Histogram of secondary structure amounts in PSMα1 in the GQD/PSMα1 complex. f) Histogram of the center of mass distance between two PSMα1 units showing the distance distribution with and without a GQD molecule. N: N‐terminal of PSMα1; C: C‐terminal of PSMα1. Reproduced with permission.^{[ 232 ]} Copyright 2019, American Chemical Society.

Figure 13

Environment factors cause nanomaterials aging, which affects nanomaterial QS regulatory activity and freshwater biofilm formation processes (from colonization to maturity). Reproduced with permission.^{[ 175 ]} Copyright 2020, Elsevier.