Dual-Activity Polymers DOI: 10.1002/anie.201103130 Synthetic Polymers for Simultaneous Bacterial Sequestration and Quorum Sense Interference** Xuan Xue, George Pasparakis, Nigel Halliday, Klaus Winzer, StevenM. Howdle, Christopher J. Cramphorn, Neil R. Cameron, Paul M. Gardner, Benjamin G. Davis,* Francisco Fernµndez-Trillo,* and Cameron Alexander* Materials that interfere with bacteria–host interactions are an attractive approach for controlling infectious diseases (Fig- ure 1 a, route 1). [1] Synthetic polymers are especially useful in this context, because their affinity with cell surface receptors can be tailored through multivalent ligand display, while at the same time avoiding selection pressure and resistance invoked in bacteria by antibiotics. However, many bacterial species employ additional strategies for environmental adap- tation and host invasion, thus confounding therapies that depend on cell sequestration alone. Amongst these mecha- nisms are communication systems such as quorum sensing (QS), which allows bacteria to synchronize transcriptional changes at the population level (Figure 1 a, route 2). [2–5] Inhibition of QS is itself a potential further method of controlling bacterial infection, [6] but targeting QS signals in isolation can still allow bacterial infection by alternative pathways. Materials that could interfere with both communi- cation mechanisms and cell adhesion/aggregation at the same time would allow greater flexibility in anti-infective strategies. Herein, we report polymers that combine potent activity in binding QS autoinducers with effective adhesion at bacterial surfaces (Figure 1). We designed polymers to attach to Vibrio species (such as the human pathogen V. cholerae), while at the same time binding specific autoinducers for QS. For this, we used the marine bacterium V. harveyi, as QS in this species not only controls virulence but also bioluminescence, thereby facilitat- ing readout of the effects of polymers on the QS network. V. harveyi uses two types of autoinducers (AIs), acyl homo- serine lactones (AI-1) and the AI-2 network, a “universal” pathway that functions in both Gram-positive and Gram- negative bacteria. [7] The key compound in the AI-2-mediated QS pathway is 4,5-dihydroxy-2,3-pentanedione (DPD), which can exist in several forms. In V. harveyi and other marine species, DPD reacts with boric acid to yield the active furanosyl borate ester (1), one of the few known biomolecules incorporating boron (Figure 1 b). [8, 9] We reasoned that if Figure 1. a) Polymer-mediated interference in bacterial aggregation and signaling. b) Structures of the key components in the autoinducer AI-2 network. c) Structures of polymers. DPD = 4,5-dihydroxy-2,3-penta- nedione, DMAm = N-dopamine methacrylamide, DMAPMAm = N-[3- (dimethylamino)propyl]methacrylamide, p(GlcEMA) = poly(b-d-gluco- syloxyethyl methacrylate). [*] X. Xue, Dr. G. Pasparakis, Dr. F. Fernµndez-Trillo, Prof. C. Alexander School of Pharmacy, The University of Nottingham University Park, Nottingham NG7 2RD (UK) E-mail: francisco.fernandez-trillo@nottingham.ac.uk cameron.alexander@nottingham.ac.uk Dr. P. M. Gardner, Prof. B. G. Davis Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA (UK) E-mail: ben.davis@chem.ox.ac.uk Dr. N. Halliday, Dr. K. Winzer School of Molecular Medical Sciences, Centre for Biomolecular Sciences, The University of Nottingham, University Park, Notting- ham NG7 2RD (UK) Prof. S. M. Howdle School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD (UK) Dr. C. J. Cramphorn, Prof. N. R. Cameron Biophysical Sciences Institute and Department of Chemistry, Durham University, University Science Laboratories, South Road, Durham DH1 3LE (UK) [**] We thank the UK EPSRC and BBSRC (Grants EP/G042462/1, EP/ D022347/1, D021847/1, and BB/F01855X/1) and the University of Nottingham, UK, for funding. We thank Bonnie Bassler (Depart- ment of Molecular Biology, Princeton University) for the gift of V. harveyi strain MM32, Adrienne Davis and Shazhad Aslam (School of Chemistry, University of Nottingham) and Istvan Pelczer (Department of Chemistry, Princeton University) for help and useful discussions regarding 11 B NMR spectroscopy, and Natalio Krasno- gor, Leung Lui (School of Computer Sciences, University of Nottingham), and Chunjuan Liu (Department of Chemistry, Uni- versity of Oxford) for helpful discussions. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201103130. Communications 9852  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2011, 50, 9852 –9856