This article is a commentary on:
Engineering nanoparticles to silence bacterial communication
Boris L. T. Lau
Caitlyn S. Butler- Department of Civil and Environmental Engineering, University of Massachusetts Amherst, Amherst, MA, USA
A commentary on
Engineering nanoparticles to silence bacterial communication
by Miller, K. P., Wang, L., Chen, Y.-P., Pellechia, P. J., Benicewicz, B. C., and Decho, A. W. (2015). Front. Microbiol. 6:189. doi: 10.3389/fmicb.2015.00189
As soon as researchers uncovered microorganisms' abilities to communicate, efforts began to control the conversation. Among other cellular functions, quorum-sensing is implicated in biofilm formation, a problematic phenomena in a variety of settings such as persistence of infections (Costerton et al., 1999; Rutherford and Bassler, 2012) and biofouling of water- and wastewater-treatment membranes (Flemming, 1997; Ramesh et al., 2007; Yeon et al., 2008; Shrout and Nerenberg, 2012). Cell-to-cell communication has also been documented in biofilm dispersal leading to further propagation of biofilms within these systems (Solano et al., 2014).
Many efforts to interrupt and quench quorum-sensing have exploited the knowledge of signaling systems using specific model organisms, most notably Pseudomona aeruginosa, Staphylococcus aureus, and Vibrio fischeri (Stevens and Greenberg, 1997; Miller and Bassler, 2001; Schuster and Greenberg, 2006; Novick and Geisinger, 2008). However, specific approaches have been developed to target and block gene-regulation or to inactivate receptor proteins, however, these approaches may have limited effects in mixed-community biofilms. Non-specific quenching of quorum-sensing molecules may have broader impact. Microbially-generated enzymes such as lactonases and acylases can hydrolyse N-acyl-L-homoserine lactones (HSLs), and interfere with communication (Park et al., 2006; Uroz et al., 2008; Romero et al., 2011). Both naturally-derived-, such as rosamaric acid and vanillin (Walker et al., 2004; Choo et al., 2006; Ponnusamy et al., 2009), and synthetic-chemicals, including brominated furanones, have been shown to effectively inhibit biofilm formation. The delivery of effective and non-toxic quorum-sensing inhibitors however, remains a challenge in managing biofilms. In a recent Frontiers in Microbiology article, Miller et al. (2015) introduce a different and unique approach that exploited the slightly-hydrophobic core of a beta-cyclodextrin (β-CD) to non-specifically bind HSLs, and quench the signaling between V. fischeri cells. What makes Miller et al.'s approach stand apart is they immobilized the β-CD on the surface of silicon dioxide nanoparticles1 (Si-NPs).
Like quorum-inhibition and quenching approaches, NPs, on their own, offer opportunities for biofilm control. NPs are being explored to inhibit or prevent biofilm formation on surfaces (Kalishwaralal et al., 2010; Tran and Webster, 2011) as well as increase biofilm vulnerability to antibiotics (Applerot et al., 2012; Radzig et al., 2013). Miller et al. have demonstrated a proof-of-concept approach, using NPs for quorum-quenching. However, NP penetration into biofilms should be carefully considered. Diffusion is reported as a function of NP size, surface charge, biofilm density and thickness. Self-diffusion of NPs is reported to decrease exponentially with square of the NP radius and negatively-charged NPs is reduced further (Peulen and Wilkinson, 2011).
One of the interesting findings by Miller et al. is that the state of β-CD (i.e., unbound vs. immobilized on 15 or 50 nm Si-NPs) greatly affects its ability to impact QS. It is important to recognize that surface-immobilized organics possess very different properties than unbound ligands. For example, the apparent acid dissociation constant (pKa) of 11-mercaptoundecanoic acid (MUA) lies between ~4.8 (when the free molecules are in solution) to ~10 (when immobilized on a flat surface). When MUA is immobilized on a relatively small NP (surface with a high curvature), a mere change of NP diameter from 4 to 7 nm could result in a change of pKa by as much as one pH unit.(Wang et al., 2011) On a non-spherical NP surface (e.g., nanorod or nano-dumbbell), organic molecules tethered onto regions of different geometric curvature would experience different degrees of confinement, which ultimately translate into location-specific chemical properties (Walker et al., 2013).
NP ligand properties (e.g., size, density, type, and orientation) have been shown to greatly impact drug delivery (Bandyopadhyay et al., 2011; Wang et al., 2014; Amin et al., 2015). Depending on the sizes and shapes of NPs, ligand density could affect in-vitro cellular internalization and/or in-vivo biodistribution (Reuter et al., 2015). β-CD, being used as a scaffold for ligands, is capable of regulating ligand properties. The primary hydroxyl group located on the narrower ring of β-CD can be selectively modified by various biomolecules (e.g., peptides, ssDNA). For example, the average and localized lysine density on β-CD can be tuned to regulate the adsorption of proteins (Shi et al., 2015).
Distinct control of ligand density is an important design parameter for NPs to be a more effective sponge of QS signaling molecules. An optimal non-saturating ligand density has been found to exist (across different sizes of NPs and targeted receptors) and that identifying this density is crucial for various applications of nanomedicines (Poon et al., 2010; Elias et al., 2013). Increasing the average number of ligands per NP will greatly reduce the inter-ligand spacing. An overcrowding of ligands on NP surface could potentially (1) create a competitive sorption environment for multiple ligands to bind to a single receptor and (2) prevent ligands from obtaining the necessary conformation for binding (Elias et al., 2013).
Overall, future improvements in NP design to facilitate quorum quenching lies in: (1) the careful selection of NPs with appropriate sizes and shapes and (2) the development of novel bioconjugation strategies (e.g., click chemistry) to maintain the functional properties of ligands. These advances should propel NPs into a prominent position in the toolbox for stopping the microbial chatter.
Author Contributions
CB provided an overview of quorum sensing and the different approaches of its interruption. BL discussed some of the important nanoparticle design considerations for effective quorum quenching.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Footnotes
1 ^Generally speaking, nanomaterials are often defined as a material that consists of particles with one or more dimensions in the size range 1–100 nm. It is important to note that a ‘one size fits all’ definition may fail to capture what is important. The change in reactivity at the nanoscale depends critically on the particular material and the context.
References
Amin, M. L., Joo, J. Y., Yi, D. K., and An, S. S. A. (2015). Surface modification and local orientations of surface molecules in nanotherapeutics. J. Control. Rel. 207, 131–142. doi: 10.1016/j.jconrel.2015.04.017
Applerot, G., Lellouche, J., Perkas, N., Nitzan, Y., Gedanken, A., and Banin, E. (2012). ZnO nanoparticle-coated surfaces inhibit bacterial biofilm formation and increase antibiotic susceptibility. RSC Adv. 2, 2314–2321. doi: 10.1039/c2ra00602b
Bandyopadhyay, A., Fine, R. L., Demento, S., Bockenstedt, L. K., and Fahmy, T. M. (2011). The impact of nanoparticle ligand density on dendritic-cell targeted vaccines. Biomaterials 32, 3094–3105. doi: 10.1016/j.biomaterials.2010.12.054
Choo, J., Rukayadi, Y., and Hwang, J. K. (2006). Inhibition of bacterial quorum sensing by vanilla extract. Lett. Appl. Microbiol. 42, 637–641. doi: 10.1111/j.1472-765x.2006.01928.x
Costerton, J. W., Stewart, P. S., and Greenberg, E. (1999). Bacterial biofilms: a common cause of persistent infections. Science 284, 1318–1322. doi: 10.1126/science.284.5418.1318
Elias, D. R., Poloukhtine, A., Popik, V., and Tsourkas, A. (2013). Effect of ligand density, receptor density, and nanoparticle size on cell targeting. Nanomed. Nanotechnol. Biol. Med. 9, 194–201. doi: 10.1016/j.nano.2012.05.015
Flemming, H.-C. (1997). Reverse osmosis membrane biofouling. Exp. Therm. Fluid Sci. 14, 382–391. doi: 10.1016/S0894-1777(96)00140-9
Kalishwaralal, K., Barathmanikanth, S., Pandian, S. R. K., Deepak, V., and Gurunathan, S. (2010). Silver nanoparticles impede the biofilm formation by Pseudomonas aeruginosa and Staphylococcus epidermidis. Colloids Surf. B Biointerf. 79, 340–344. doi: 10.1016/j.colsurfb.2010.04.014
Miller, K. P., Wang, L., Chen, Y.-P., Pellechia, P. J., Benicewicz, B. C., and Decho, A. W. (2015). Engineering nanoparticles to silence bacterial communication. Front. Microbiol. 6:189. doi: 10.3389/fmicb.2015.00189
Miller, M. B., and Bassler, B. L. (2001). Quorum sensing in bacteria. Ann. Rev. Microbiol. 55, 165–199. doi: 10.1146/annurev.micro.55.1.165
Novick, R. P., and Geisinger, E. (2008). Quorum sensing in staphylococci. Annu. Rev. Genet. 42, 541–564. doi: 10.1146/annurev.genet.42.110807.091640
Park, S.-Y., Hwang, B.-J., Shin, M.-H., Kim, J.-A., Kim, H.-K., and Lee, J.-K. (2006). N-acylhomoserine lactonase producing Rhodococcus spp. with different AHL-degrading activities. FEMS Microbiol. Lett. 261, 102–108. doi: 10.1111/j.1574-6968.2006.00336.x
Peulen, T.-O., and Wilkinson, K. J. (2011). Diffusion of nanoparticles in a biofilm. Environ. Sci. Technol. 45, 3367–3373. doi: 10.1021/es103450g
Ponnusamy, K., Paul, D., and Kweon, J. H. (2009). Inhibition of quorum sensing mechanism and Aeromonas hydrophila biofilm formation by vanillin. Environ. Eng. Sci. 26, 1359–1363. doi: 10.1089/ees.2008.0415
Poon, Z., Chen, S., Engler, A. C., Lee, H.-I., Atas, E., Von Maltzahn, G., et al. (2010). Ligand-clustered “patchy” nanoparticles for modulated cellular uptake and in vivo tumor targeting. Angew. Chem. Int. Ed. 49, 7266–7270. doi: 10.1002/anie.201003445
Radzig, M. A., Nadtochenko, V. A., Koksharova, O. A., Kiwi, J., Lipasova, V. A., and Khmel, I. A. (2013). Antibacterial effects of silver nanoparticles on gram-negative bacteria: influence on the growth and biofilms formation, mechanisms of action. Colloids Surf. B Biointerf. 102, 300–306. doi: 10.1016/j.colsurfb.2012.07.039
Ramesh, A., Lee, D., and Lai, J. (2007). Membrane biofouling by extracellular polymeric substances or soluble microbial products from membrane bioreactor sludge. Appl. Microbiol. Biotechnol. 74, 699–707. doi: 10.1007/s00253-006-0706-x
Reuter, K. G., Perry, J. L., Kim, D., Luft, J. C., Liu, R., and Desimone, J. M. (2015). Targeted PRINT hydrogels: the role of nanoparticle size and ligand density on cell association, biodistribution, and tumor accumulation. Nano Lett. 15, 6371–6378. doi: 10.1021/acs.nanolett.5b01362
Romero, M., Martin-Cuadrado, A.-B., Roca-Rivada, A., Cabello, A. M., and Otero, A. (2011). Quorum quenching in cultivable bacteria from dense marine coastal microbial communities. FEMS Microbiol. Ecol. 75, 205–217. doi: 10.1111/j.1574-6941.2010.01011.x
Rutherford, S. T., and Bassler, B. L. (2012). Bacterial quorum sensing: its role in virulence and possibilities for its control. Cold Spring Harb. Perspect. Med. 2:a012427. doi: 10.1101/cshperspect.a012427
Schuster, M., and Greenberg, E. P. (2006). A network of networks: quorum-sensing gene regulation in Pseudomonas aeruginosa. Int. J. Med. Microbiol. 296, 73–81. doi: 10.1016/j.ijmm.2006.01.036
Shi, X., Zhan, W., Chen, G., Yu, Q., Liu, Q., Du, H., et al. (2015). Regulation of protein binding capability of surfaces via host-guest interactions: effects of localized and average ligand density. Langmuir 31, 6172–6178. doi: 10.1021/acs.langmuir.5b01380
Shrout, J. D., and Nerenberg, R. (2012). Monitoring bacterial twitter: does quorum sensing determine the behavior of water and wastewater treatment biofilms? Environ. Sci. Technol. 46, 1995–2005. doi: 10.1021/es203933h
Solano, C., Echeverz, M., and Lasa, I. (2014). Biofilm dispersion and quorum sensing. Curr. Opin. Microbiol. 18, 96–104. doi: 10.1016/j.mib.2014.02.008
Stevens, A. M., and Greenberg, E. (1997). Quorum sensing in Vibrio fischeri: essential elements for activation of the luminescence genes. J. Bacteriol. 179, 557–562.
Tran, P. A., and Webster, T. J. (2011). Selenium nanoparticles inhibit Staphylococcus aureus growth. Int. J. Nanomed. 6, 1553–1558. doi: 10.2147/IJN.S21729
Uroz, S., Oger, P. M., Chapelle, E., Adeline, M.-T., Faure, D., and Dessaux, Y. (2008). A Rhodococcus qsdA-encoded enzyme defines a novel class of large-spectrum quorum-quenching lactonases. Appl. Environ. Microbiol. 74, 1357–1366. doi: 10.1128/AEM.02014-07
Walker, D. A., Leitsch, E. K., Nap, R. J., Szleifer, I., and Grzybowski, B. A. (2013). Geometric curvature controls the chemical patchiness and self-assembly of nanoparticles. Nat. Nanotechnol. 8, 676–681. doi: 10.1038/nnano.2013.158
Walker, T. S., Bais, H. P., Déziel, E., Schweizer, H. P., Rahme, L. G., Fall, R., et al. (2004). Pseudomonas aeruginosa-plant root interactions. Pathogenicity, biofilm formation, and root exudation. Plant Physiol. 134, 320–331. doi: 10.1104/pp.103.027888
Wang, B., Galliford, C. V., and Low, P. S. (2014). Guiding principles in the design of ligand-targeted nanomedicines. Nanomedicine 9, 313–330. doi: 10.2217/nnm.13.175
Wang, D., Nap, R. J., Lagzi, I., Kowalczyk, B., Han, S., Grzybowski, B. A., et al. (2011). How and Why Nanoparticle's Curvature Regulates the Apparent pK(a) of the Coating Ligands. J. Am. Chem. Soc. 133, 2192–2197. doi: 10.1021/ja108154a
Keywords: nanomedicine, nanoparticles, quorumsensing, quorumquenching, acylhomoserine lactone, cyclodextrins, biofilms
Citation: Lau BLT and Butler CS (2016) Censored at the Nanoscale. Front. Microbiol. 7:253. doi: 10.3389/fmicb.2016.00253
Received: 22 December 2015; Accepted: 15 February 2016;
Published: 26 February 2016.
Edited by:
Bradley M. Tebo, Oregon Health and Science University, USAReviewed by:
Matthew J. Marshall, Pacific Northwest National Laboratory, USAWilliam Thomas Self, University of Central Florida, USA
Copyright © 2016 Lau and Butler. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Boris L. T. Lau, Ym9yaXNsYXVAZW5naW4udW1hc3MuZWR1