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WO 2016/176146 Al 3 November 2016 (03.11.2016) P O P C T

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WO 2016/176146 Al 3 November 2016 (03.11.2016) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/176146 Al 3 November 2016 (03.11.2016) P O P C T (51) International Patent Classification: (74) Agent: WALES, Michele M. 118 16 Centurion Way, Po- A01N 25/08 (2006.01) A01N 43/647 (2006.01) tomac, Maryland 20854 (US). A 25/10 (2006.01) A01P 1/00 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US20 16/0292 13 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) International Filing Date: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 25 April 2016 (25.04.2016) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (26) Publication Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (30) Priority Data: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/152,896 26 April 2015 (26.04.2015) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: THE TRUSTEES OF PRINCETON UNI¬ (84) Designated States (unless otherwise indicated, for every VERSITY [US/US]; 87 Prospect Avenue, 3rd Floor, Prin kind of regional protection available): ARIPO (BW, GH, ceton, New Jersey 08544 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (72) Inventors: BASSLER, Bonnie L.; 39 Pine Street, Prin TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, ceton, New Jersey 08540 (US). STONE, Howard A.; 94 DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, McCosh Circle, Princeton, New Jersey 08540 (US). KIM, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Min Young; 15 1 Taylor Court, Room 212, Princeton, New SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Jersey 08540 (US). MUIR, Thomas William; 35 Lit- GW, KM, ML, MR, NE, SN, TD, TG). tlebrook Road, N, Princeton, New Jersey 08540 (US). Published: ZHAO, Aishan; 2 Lawrence Drive, Apt. 104, Princeton, New Jersey 08540 (US). — with international search report (Art. 21(3)) (54) Title: SURFACES COMPRISING ATTACHED QUORUM SENSING MODULATORS (57) Abstract: The invention relates to compositions comprising QS modulating molecules attached to a surface via a linker. This QS modulator attached surface can then be used to modulate QS, biofilm production, biofilm streamer production and/or virulence factor production. These QS modulator attached surfaces can be used to treat areas known to contain human pathogens notorious for causing hospital-acquired infections as well as fatal infections that occur outside of health care settings. Other surfaces that can be coated according to embodiments of the invention include abiotic materials, such as intravenous catheters, implants, medical devices, and cooling towers. Preferred microorganisms that can be treated with the compositions of the invention include, but are not limited to S. aureus and/or P. aeruginosa. SURFACES COMPRISING ATTACHED QUORUM SENSING MODULATORS STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0001] This invention was made with government support under Grant No MCB-1 119232, Grant No. MCB-1344191 and Grant No. MCB-09481 12 awarded by the National Science Foundation and Grant No. GM- 065859 awarded by the National Institutes of Health. The government may have certain rights in the invention. BACKGROUND [0002] In a process referred to as quorum sensing, microorganisms, such as bacteria, communicate using chemical signaling molecules called autoinducers. By monitoring increases and decreases in autoinducer concentration, quorum-sensing bacteria track changes in cell-population density and synchronously switch into and out of group behaviors. Quorum sensing allows bacteria to collectively carry out tasks that would be unsuccessful if carried out by an individual bacterium acting alone. [0003] Both Gram-positive and Gram-negative infectious bacteria, which include human, animal, plant, and marine pathogens, use quorum-sensing strategies to control virulence. Quorum sensing also controls biofilm and streamer formation. Biofilms are communities of bacterial cells adhered to surfaces and encased in a self-excreted matrix of extracellular polymeric substances. In most environments, bacteria are found predominantly in biofilms. These biofilms are also widespread in industrial systems and are associated with increased risk of infection when found in clinical environments and in indwelling medical devices. These bacterial biofilm communities can cause chronic infections in humans by colonizing, for example, in medical implants, heart valves, or lungs. [0004] In settings involving fluid flow across the biofilm, as in rivers or in industrial and medical systems that are subject to flow, filamentous biofilms, called streamers, can be formed. These streamers can have a dramatic effect on the biofilm environment. In rivers, for example, the biofilm streamers can increase transient storage and cycling of nutrients and can enhance the retention of suspended particles. In industrial and medical settings, the biofilm streamers have been associated with increased issues associated with clogging and pressure drops. [0005] Bacterial infections are treated with bactericidal or bacteriostatic molecules that impede at least five major processes: cell wall formation, DNA replication, transcription, translation or tetrahydrofolic acid synthesis. Existing methods for treating bacterial infection unfortunately exacerbate the growing antibiotic resistance problem because they inherently select for growth of bacteria that can resist the drug. [0006] For example, Staphylococcus aureus is a human pathogen notorious for causing hospital-acquired infections as well as fatal infections that occur outside of health care settings. S. aureus infections that are associated with abiotic materials, such as intravenous catheters and implants, are of primary concern as S. aureus readily colonizes such medical devices, forming biofilms, biofilm streamers and initiates virulence factor production under these conditions. [0007] In fact, methicillin-resistant S. aureus (MRSA) is a major concern due to its potent virulence coupled with resistance to many antibiotics. MRSA is the most widespread cause of hospital-associated infections in the United States and Europe with a high mortality rate. S. aureus and MRSA cause a variety of infections ranging from minor skin infections to serious illnesses such as infections of indwelling medical devices, osteomyelitis, endocarditis, sepsis, and toxic shock syndrome. S. aureus is just one example of a microorganism that uses quorum-sensing-mediated communication to control virulence factor production and to regulate biofilm formation. [0008] Thus, what is needed are new methods of modulating quorum sensing, biofilm formation, biofilm streamer formation, and/or virulence factor production from microorganisms. SUMMARY [0009] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject. [0010] The present invention targets the quorum sensing ("QS") systems utilized by microorganisms, which are crucial in microorganism infection and pathogenicity. This technology is the first to describe and successfully conjugate QS modulating molecules (either QS antagonists or agonists) to a surface and show alterations in QS-controlled phenotypes. Preferred examples of altered QS phenotypes (also referred to as traits) include, but are not limited to, significant reductions in biofilm formation, biofilm streamer formation and virulence factor production. This technology can be immediately applied to many current and urgent issues in healthcare settings, such as the accidental introduction of pathogens into patients during medical procedures and the entry of bacteria at wound sites. This technology can be used to modify existing (e.g., medical, food processing, agricultural, etc.) devices, create new devices, and it could also be applied as a direct treatment for patients. Beyond medicine, this technology can also be applied to fields including, but not limited to, industrial and engineering processes, food processing, cooling towers, and mining. [0011] Thus, the present invention relates to a method of modulating QS, biofilm production, biofilm streamer production, and/or virulence factor production by a microorganism using: (1) an antagonist to decrease QS, or (2) an agonist to increase QS, wherein the QS modulator is attached to a surface through a linker. A microorganism that is exposed to the surface will exhibit altered biofilm production, biofilm streamer production, and/or virulence factor production. In some embodiments, inhibiting QS will lead to a decrease in biofilm production, biofilm streamer production, and/or virulence factor production. In other embodiments, agonizing QS will lead to a decrease in biofilm production, biofilm streamer production, and/or virulence factor production. [0012] For example, a QS modulator molecule attached to a surface can be used
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