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FIG. 8B (57) Abstract: the Methods and Compositions Described Herein Relate to the Treatment of Fungal Infections, E.G

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FIG. 8B (57) Abstract: the Methods and Compositions Described Herein Relate to the Treatment of Fungal Infections, E.G (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 2014/130922 Al 28 August 2014 (28.08.2014) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/4174 (2006.01) A61K 45/06 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/7048 (2006.01) A61P 31/10 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/4412 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US20 14/0 17942 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 24 February 2014 (24.02.2014) TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 61/768,854 25 February 2013 (25.02.2013) US UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (71) Applicant: TRUSTEES OF BOSTON UNIVERSITY EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, [US/US]; One Silber Way, Boston, Massachusetts 02215 MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (US). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: COLLINS, James J.; 118 Glen Avenue, New ton, Massachusetts 02459 (US). BELENKY, Peter A.; Published: 404 Windsor Drive, Framingham, Massachusetts 01701 — with international search report (Art. 21(3)) (US). CAMACHO, Diogo M.; 72 Nixon Road, Framing- ham, Massachusetts 01701 (US). — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (74) Agents: EISENSTEIN, Ronald I. et al; Nixon Peabody amendments (Rule 48.2(h)) LLP, 100 Summer Street, Boston, Massachusetts 021 10 (US). — with sequence listing part of description (Rule 5.2(a)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (54) Title: COMPOSITIONS AND METHODS FOR TREATING FUNGAL INFECTIONS © FIG. 8B (57) Abstract: The methods and compositions described herein relate to the treatment of fungal infections, e.g. by potentiating the o sensitivity of fungi to anti-fungal agents. COMPOSITIONS AND METHODS FOR TREATING FUNGAL INFECTIONS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 61/768,854 filed February 25, 2013, the contents of which are incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0002] The field of the invention relates to treating and/or potentiating the sensitivity of fungi to antifungal compounds. GOVERNMENT SUPPORT [0003] This invention was made with Government Support under Grant No. OD003644 awarded by the National Institutes of Health. The Government has certain rights in the invention. SEQUENCE LISTING [0004] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on February 21, 2014, is named 701586-075931-PCT_SL.txt and is 296,876 bytes in size. BACKGROUND OF THE INVENTION [0005] A rapid rise in immunocompromised patients over the past five decades has led to increasing incidence of systemic fungal infections. Systemic candidiasis is the most common fo m of fungal infection in the United States, accounting for approximately 50% of cases, and is the third most common form of bloodstream infection (Ostrosky-Zeichner et al., 20 ). Despite current treatment options, the morbidity and mortality rates associated with fungal infections, specifically those of Candida species, remain high. One of the key problems associated with current antifungal treatment is toxicity. SUMMARY OF THE INVENTION [0006] As described herein, the inventors have identified a common oxidative damage cellular death pathway triggered by three representative fungicides in Candida albicans and Saccharomyces cerevisiae. This mechanism utilizes a signaling cascade involving the GTPases Rasl/2 and Protein Kinase A, and culminates in cellular death through the production of toxic hydroxyl radicals in a tricarboxylic acid cycle- and respiratory chain-dependent manner. Consistent with this, cellular mitochondrial activity is substantiaiiy elevated by fungicide treatment. In addition, it is demonstrated herein that the metabolome of C albicans is altered by antifungal drug treatment, exhibiting a . shift from fermentation to respiration, a jump in the AMP/ATP ratio, and elevated production of sugars, such as glucose, fructose and trehalose. Additionally, DNA damage is demonstrated herein to play a critical role in antifungal-induced cellular death and blocking DNA repair mechanisms potentiates antifungal activity. Finally, it was found that artificially stimulating the cAMP sensitive RAS pathway with db-cAMP elevated fungicide toxicity. [0007] Accordingly, described herein are methods and compositions relating to the modulation of these pathways to select antifungal agents and/or increase the susceptibility of fungi to antifungal agents. Through metabolic or small molecule based potentiation of currently available antifungal agents, the concentration required to achieve fungal killing can be reduced, thereby alleviating toxicity complications. The invention thereby improves the current arsenal of antifungals. [0008] In one aspect, described herein is a method for inhibiting a fungal infection, the method comprising administering to a subject having or at risk for a fungal infection an effective amount of one or more potentiator compounds and an effective amount of an antifungal agent. In one aspect, described herein is a method for inhibiting a fungal infection, the method comprising administering to a subject having or at risk for a fungal infection an effective amount of a pharmaceutical composition comprising one or more potentiator compounds and an antifungal agent. In one aspect, described herein is a method for treating a fungal infection, comprising administering to a patient having a fungal infection and undergoing treatment with an antifungal agent, an effective amount of one or more potentiator compounds. [0009] In one aspect, described herein is a method for inhibiting fungal growth, the method comprising contacting a fungal cell with an effective amount of one or more potentiator compounds and an effective amount of an antifungal agent. [0010] n one aspect, described herein is a potentiator compound for use in inhibiting or treating a fungal infection, wherein the potentiator compound is an agonist of the RAS/PKA pathway; an agonist of the TCA cycle or respiration; an inhibitor of DNA repair; cAMP or a mimetic or analog thereof; a cAMP modulator; a phosphodiesterase inhibitor; or glucose. [0011] In one aspect, described herein is a composition comprising an antifungal agent formulated in a glucose solution. [0012] In one aspect, described herein is a method comprising selecting a compound that increases ROS production in a target fungal pathogen or that increases ROS-induced cellular damage in the target fungal pathogen, and formulating the compound for treatment of a fungal pathogen, optionally with one or more additional antifungal agents. [0013] In some embodiments of any of the foregoing aspects, the potentiator compound is an agonist of the RAS/PKA pathway; an agonist of the TCA cycle or respiration; an inhibitor of DNA repair; cAMP or a mimetic or analog thereof; a cAMP modulator; a phosphodiesterase inhibitor; or glucose. In some embodiments of any of the foregoing aspects the agonist of the RAS/PKA pathway is an agonist of RAS1; RAS2; Cyrl; Cdc25; Srv2; Tpkl; Tpk2; Tpk3; and orthologs and homologs thereof; or an inhibitor of Bey1; Pdel; Pde2; or orthologs and homologs thereof. In some embodiments of any of the foregoing aspects, the inhibitor of Pdel is IC224. In some embodiments of any of the foregoing aspects, the agonist of the TCA cycle or respiration is an agonist of Hap2; Hap3; Hap4; Hap5; Citl; Cit2; Sdhl/2 or orthologs and homologs thereof. In some embodiments of any of the foregoing aspects, the potentiator compound modulates carbon source utilization or inhibits glucose utilization n some embodiments of any of the foregoing aspects, the inhibitor of DNA repair is an inhibitor of double-strand break repair; an inhibitor of single-strand repair; or an inhibitor of direct reversal. In some embodiments of any of the foregoing aspects, the inhibitor of double-strand break repair is an inhibitor of Rad54; Rad 51; Rad52; Rad55; Rad57; RPA; Xrs2; Mrel 1; Lifl; Nejl; or orthologs and homologs thereof n some embodiments of any of the foregoing aspects, the inhibitor is wortmannin; rapamycin; vorinostat; 0 -BG; NVP-BEZ235; 2-(Morpholin-4-yl)- benzo[h]chomen-4-one; l-(2-hydroxy-4-morpholin-4-yl-phenyl)-ethanone; Ku55933; NU7441; or SU1 1752. In some embodiments of any of the foregoing aspects, the cAMP mimetic or analog or modulator thereof is diburtyryl cAMP; caffeine; forskolin; 8-bromo-cAMP; phorbol ester; sclareline; cholera toxin (CTx); aminophylline; 2,4 dinitrophenol (DNP); norepinephrine; epinephrine; isoproterenol; isobutylmethylxanthine (IBMX); theophylline (dimethylxanthine); dopamine; rolipram; iloprost; prostaglandin Ei; prostaglandin E2 pituitary adenylate cyclase activating polypeptide (PACAP); vasoactive intestinal polypeptide (VIP); (S)-adenosine; cyclic 3',5'- (hydrogenphosphorothioate)triethyl ammonium; 8-bromoadenosine-3',5'-cyclic monophosphate; 8- chloroadenosine-3',5'-cyclic monophosphate; or N6,2'-0-dibutyryladenosine-3',5'-cyclic monophosphate.
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