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W O 2019/074870 a L 18 April 2019 (18.04.2019) W 1P O PCT

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W O 2019/074870 a L 18 April 2019 (18.04.2019) W 1P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date W O 2019/074870 A l 18 April 2019 (18.04.2019) W 1P O PCT (51) International Patent Classification: KULESA, Anthony; c/o Massachusetts Institute of Tech¬ A61K 31/7048 (2006.01) C07D 407/04 (2006.01) nology, 77 Massachusetts Avenue, Cambridge, Massachu¬ A61K 45/00 (2006.01) C07K4/00 (2006.01) setts 02142 (US). A61K 45/06 (2006.0 1) C07K 4/04 (2006.0 1) (74) Agent: EMMONS, Richard B . et al; BURNS & LEV- (21) International Application Number: INSON, LLP, 125 Summer Street, Boston, Massachusetts PCT/US2018/0549 16 021 10 (US). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 09 October 2018 (09. 10.2018) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (25) Filing Language: English CA, CH, CL, CN, CO, CR. CU, CZ, DE, DJ, DK, DM, DO. (26) Publication Language: English DZ, EC, EE, EG, ES, FI. GB. GD, GE, GH, GM, GT, HN. HR, HU, ID, IL, IN, IR. IS. JO. JP, KE, KG, KH, KN, KP. (30) Priority Data: KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 62/570,0 4 09 October 20 7 (09. 10.2017) US MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 62/570,585 10 October 2017 (10. 10.2017) US OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 62/578,140 27 October 2017 (27. 10.2017) us SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (71) Applicants: THE BROAD INSTITUTE, INC. [US/US]; TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 415 Main Street, Cambridge, Massachusetts 02142 (US). (84) Designated States (unless otherwise indicated, for every MASSACHUSETTS INSTITUTE O F TECHNOLOGY kind of regional protection available): ARIPO (BW, GH, [US/US]; 77 Massachusetts Avenue, Cambridge, Massa¬ GM, KE, LR, LS, MW. MZ, NA, RW, SD, SL, ST, SZ, TZ. chusetts 02 142 (US). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ. (72) Inventors: BLAINEY, Paul: c/o The Broad Institute, Inc.. TM), European (AL, AT. BE. BG, CH, CY, CZ, DE, DK. 415 Main Street, Cambridge. Massachusetts 02142 (US). EE, ES, FI, FR, GB, GR. HR. HU. ΓΕ , IS, IT, LT, LU, LV. (54) Title: COMPOSITIONS AND METHODS FOR COMBINATORIAL DRUG DISCOVERY IN NANOLITER DROPLETS compound plate + RGB fluorescent dye barcodes 0 0 FIG. 1A © (57) Abstract: The present disclosure relates compositions and methods for combinatorial drug discovery in nanoliter droplets. More o particularly, the disclosure relates to novel synergistic agents that increase efficacy of antibiotic agents to treat bacterial infection. [Continued on next page] W O 2019/074870 A l Illlll II lllll lllll lllll llll III III lllll lllll lllll lllll lllll llll llll llll llll MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: COMPOSITIONS AND METHODS FOR COMBINATORIAL DRUG DISCOVERY IN NANOLITER DROPLETS CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority of U.S. Provisional Application No. 62/578,140, filed October 27, 2017; U.S. Provisional Application No. 62/570,585, filed October 10, 2017; and U.S. Provisional Application No. 62/570,014, filed October 9, 2017, the contents of each of these prior applications are hereby incorporated by reference in their entirety. FIELD OF THE DISCLOSURE The disclosure relates to compositions and methods for combinatorial drug discovery in nanoliter droplets. More particularly, the disclosure relates to the identification and characterization of novel synergistic agents that increase efficacy of antibiotic agents to treat bacterial infection. BACKGROUND OF THE DISCLOSURE Many human diseases are increasingly recognized as multifactorial in origin and therapeutic strategies increasingly leverage combination therapy or polytherapy. Combination therapy is a therapy that uses more than one therapeutic agent or medication or modality. This is in contrast to a monotherapy that uses only a single therapeutic agent or medication or modality. In general, a combination therapy refers to the use of more than one therapeutic agent or medication to treat a single disease. Combination therapies are currently used to treat a variety of indications (e.g., cancer, HIV/AIDS, tuberculosis, leprosy, and the like). Despite their utility, identification of novel drug combinations for use in combination therapy has been slowed by the complexity, cost, and high compound consumption of the combinatorics of tests required. For example, testing all pairs of drugs from a modest library of 2000 drugs (e.g., FDA approved drugs) requires 2 million pairwise combinations, and many more combinations if the compounds are titrated during the screening process. As another example, testing 2000 drugs in combination with 2000 antibiotics at four concentrations would require 32 million pairwise combinations. Experiments of this scale are restricted to specialized labs and facilities, often with prohibitive costs and complexity (e.g., total liquid handling steps, plate layout, workflow design, and the like). Additionally, since such combinatorial screens test each compound in pairwise combinations with thousands of other compounds, thousands-fold more compound is consumed relative to a typical single- compound screen. Unfortunately, this means that a combinatorial screen has the potential to deplete an entire compound inventory in a single experiment. Current methods for combinatorial drug discovery work around these issues by either leveraging computational predictions of drug synergies to reduce screening scale, or combining multiple tests in pools with subsequent deconvolution of hits from high-scoring pools. Accordingly, there is an urgent need for compositions and methods for identifying combinations of therapeutic agents or medications in a scalable, cost-efficient manner. SUMMARY OF THE DISCLOSURE In one aspect, the disclosure provides a composition comprising an antibiotic selected from the group consisting of novobiocin, erythromycin, chloramphenicol, and combinations thereof and a compound having the following formula: In embodiments, the antibiotic is novobiocin or erythromycin or chloramphenicol. In one aspect, the disclosure provides a composition comprising an antibiotic selected from the group consisting of novobiocin, erythromycin, and combinations thereof and a compound having the following formula: In embodiments, the composition has the following structure: In embodiments, the antibiotic is novobiocin or erythromycin. In one aspect, the disclosure provides a composition comprising an antibiotic selected from the group consisting of novobiocin, erythromycin, and combinations thereof and a compound having the following structure: In an embodiment, the compound has the following structure: In embodiments, the antibiotic is erythromycin or novobiocin. In one aspect, the disclosure provides a composition comprising novobiocin and a compound of formula: In embodiments, Ri to R2 are independently selected from the group consisting of H, — X-Alk, —X-Alk-X', and —X—Y—X'; wherein X is —CR7R8; X' is —CHR7R8; Alk is a C2 - CI8 substituted or unsubstituted hydrocarbon chain; Y is a C2-C8 substituted or unsubstituted alkylene chain; R6 is H or (C1-C4) alkyl; and R7 and R8 are independently selected from the group consisting of H or (C1-C4) alkyl or a salt of. In embodiments, the compound has the following structure: In one aspect, the disclosure provides a composition comprising an antibiotic selected from the group consisting of vancomycin, novobiocin, erythromycin, and combinations thereof and a compound of the following structure: wherein R is nitro or chloro. In embodiments, the compound is: In embodiments, the antibiotic is vancomycin or novobiocin or erythromycin. In one aspect, the disclosure provides a composition comprising chloramphenicol and a compound of the following structure: In one aspect, the disclosure provides a composition comprising chloramphenicol and a compound of the following structure: In one aspect, the present disclosure provides a composition comprising an H3 histamine antagonist and an antibiotic selected from the group consisting of novobiocin, erythromycin, chloramphenicol, and combinations thereof. In embodiments, the H3 histamine antagonist is selected from the group consisting of A- 349,821, ABT-239, Betahistine, Burimamide, Ciproxifan, Clobenpropit, Conessine, Failproxifan, Impentamine, lodophenpropit, Irdabisant, Pitolisant, Thioperamide (also an H4 antagonist), VUF-5681, and combinations thereof. In embodiments, the H3 histamine antagonist is lodophenpropit and the antibiotic is novobiocin. In embodiments, the H3 histamine antagonist is lodophenpropit and the antibiotic is erythromycin. In embodiments, the H3 histamine antagonist is lodophenpropit and the antibiotic is chloramphenicol. In one aspect, the present disclosure provides a composition comprising a somatostatin receptor agonist and an antibiotic selected from the group consisting of novobiocin, erythromycin, and combinations thereof. In embodiments, the somatostatin receptor agonist it selected from the group consisting of Octreotide, Lanreotide, Pasireotide, and combinations thereof. In embodiments, the somatostatin receptor agonist is Pasireotide and the antibiotic is novobiocin. In embodiments, the somatostatin receptor is Pasireotide and the antibiotic is erythromycin. In
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