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US 2014.0128399A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0128399 A1 Abraham et al. (43) Pub. Date: May 8, 2014 (54) METHODS AND COMPOSITIONS FOR Publication Classification TREATING URINARY TRACT INFECTIONS USINGAGENTS THAT MIMIC OR ELEVATE (51) Int. Cl. CYCLICAMP A613 L/53 (2006.01) A6II 45/06 (2006.01) (71) Applicant: DUKE UNIVERSITY, DURHAM, NC A613 L/4985 (2006.01) (US) A 6LX3/59 (2006.01) (52) U.S. Cl. (72) Inventors: Soman N. Abraham, Chapel Hill, NC CPC ............... A61 K3I/53 (2013.01); A61 K3I/519 (US); Brian L. Bishop. Durham, NC (2013.01); A61K 45/06 (2013.01); A61 K (US); Matthew J. Duncan, Duncan, SC 31/4985 (2013.01) (US); K. Ranga Rama Krishnan, USPC 514/243; 514/261.1: 514/252.16; 514/262.1; Chapel Hill, NC (US); Jeongmin Song, 514/250 Chapel Hill, NC (US); Guojie Li, (57) ABSTRACT Charlotte, NC (US); David W. Zaas, Methods and compositions are provided for treating a urinary Chapel Hill, NC (US) tract infection (UTI). The methods involve administering to a subject in need thereof a cAMP elevator or agent that mimics cAMP particularly a labdane diterpene such as forskolin or a (73) Assignee: DUKE UNIVERSITY, DURHAM, NC derivative or analog thereof in a therapeutically effective (US) amount to treat a UTI. The methods may further include administration of at least one cAMP elevator in combination (21) Appl. No.: 14/098,839 with one or more additional active compounds from other classes of therapeutic agents, such as antimicrobial agents or cholesterol lowering drugs. Compositions of the invention (22) Filed: Dec. 6, 2013 include pharmaceutical compositions and kits for treating a UTI in a subject in need thereof that include therapeutically Related U.S. Application Data effective amounts of at least two cAMP elevators, particularly where one of the cAMP elevators is a labdane diterpene such (63) Continuation of application No. 12/663,959, filed on as forskolin or a derivative oranalog thereof. In particular, the Sep. 21, 2010, now abandoned, filed as application No. compositions and kits may also include at least one cAMP PCT/US2008/066647 on Jun. 12, 2008. elevator in combination with one or more additional active (60) Provisional application No. 60/944,182, filed on Jun. compounds from other classes of therapeutic agents. Such as 15, 2007. antimicrobial agents or cholesterol lowering drugs. Patent Application Publication May 8, 2014 Sheet 1 of 19 US 2014/O128399 A1 Patent Application Publication May 8, 2014 Sheet 2 of 19 US 2014/O128399 A1 Figure 2 After alterest e 120% 8 3 100% e 80% 60% & 40% is 20% 0% Patent Application Publication May 8, 2014 Sheet 3 of 19 US 2014/O128399 A1 Figure 3 c 100% : 40% as 80% as O 3O% 3 60% 38 5 g a g 20% 3 40% E3 (s ; its c & 20% a: Ys 10% O% S O% Forskoln dibutyryl ionophore E. Col E. coli E. coli (100M) cAMP (1 M) - NC - H89 (1 mM) Patent Application Publication May 8, 2014 Sheet 4 of 19 US 2014/O128399 A1 Figure 4 the '9e anti-EE A1 merge transferrin-A483 merge's Patent Application Publication May 8, 2014 Sheet 5 of 19 US 2014/0128399 A1 Figure 5 a g 14.0% b. 3,500 3 120% as 3,000 s 100% s 2,500 is 80% is 2,000 60% 1,500 $ 40% 1,000 20% soo 0%. H v 0 24 48 72 96 i20 s'sNS s SSY S&SS Time after invasion (h) s s so MS S C 6% d ar 3g a 2.4% 3 is 10% & 1 R sis 8% gA. 6%4% S. ig 2% gs O%, S. &Sis S a es S S gy ca CS&S oSS8 Patent Application Publication May 8, 2014 Sheet 6 of 19 US 2014/O128399 A1 Figure 6 SO9. 12596 OO96 S. 25 Control Bafilomycin NHC NH4Cl (M) (OmM) (SOmM) Patent Application Publication May 8, 2014 Sheet 7 of 19 US 2014/0128399 A1 Figure 7 frner unon lufter C S 150% d 1509. t 8 i25% 125% s 8 g is 100% 100% s is 8 75% 75 60% Egg 50% g f is 25% 25% t O% -- O control Forskoir- Contro Forskoin- Salie Forskolin E. cf treated S.&retica treated Ecci S. enterica e 150% f 140% 25% g 23% i. re 100% to 85 OO%o is 80% 2 3. 739. 3: g s 3 60% S 50% & S. 40% 25% &. 2O's r O% O% Saline Forskoln S&tine Foskolin Salle ForSkoli Before treatment 8 after treatment Patent Application Publication May 8, 2014 Sheet 8 of 19 US 2014/O128399 A1 Patent Application Publication May 8, 2014 Sheet 9 of 19 US 2014/O128399 A1 OOOOOO OOOOO 1DOD) OOO OO O Bis gii; 1 3. : s ES: PFsk f Catheter FS AO2OOO 1653 Patent Application Publication May 8, 2014 Sheet 10 of 19 US 2014/O128399 A1 Figure 10 20 O 18O 16O. 40 1 2 O 100 Untreated TLR4 ligand (LPS) Patent Application Publication May 8, 2014 Sheet 11 of 19 US 2014/0128399 A1 Figure 11 Forskoi W Caffeine s e s s Untreated OOM forsko in 1 nM Caffeine O ty f) Skoli nM Caffeine Patent Application Publication May 8, 2014 Sheet 12 of 19 US 2014/O128399 A1 Figure 12 Forskolin wi Papa verine se 5 C o s m s se Se: s te & g 5 o V. o war Ve Patent Application Publication May 8, 2014 Sheet 13 of 19 US 2014/0128399 A1 Figure 13 Forsko in W. B. VX Untreated 10DuM forskolin 500 unt BMX forskors) LM BMX Patent Application Publication May 8, 2014 Sheet 14 of 19 US 2014/0128399 A1 Figure 14 Forskolin W. ENA Untreated 1 OOM forskoir 2 UM EHNA ftorsko in 200 M E-NA, Patent Application Publication May 8, 2014 Sheet 15 of 19 US 2014/0128399 A1 Figure 15 Forskolin wi Rolipram Untreated 1 OOM forskolin 40Ould rolipram Ouwford 400u M rol Patent Application Publication May 8, 2014 Sheet 16 of 19 US 2014/O128399 A1 Figure 16 Forskolin w Zaprina st s ads s s Untreated y forsko Zapirast firsgirlf?0 M Zaprinast Patent Application Publication May 8, 2014 Sheet 17 of 19 US 2014/0128399 A1 Figure 17 Ciliostamide-POE3 inhibitor s 3. - - - - - - - - - - - - - - - --------------------------------- - Patent Application Publication May 8, 2014 Sheet 18 of 19 US 2014/0128399 A1 Figure 18 PMA-PKC activator 2 Untreated Patent Application Publication May 8, 2014 Sheet 19 of 19 US 2014/O128399 A1 Figure 19 hs wu O 9 O 9. (vs. w 9 g SS le () O wVCoy 8 X O) s () US 2014/O128399 A1 May 8, 2014 METHODS AND COMPOSITIONS FOR activators, including, for example, labdane diterpenes (par TREATING URINARY TRACT INFECTIONS ticularly labdane, forskolin, and forskolin derivatives and USINGAGENTS THAT MIMIC OR ELEVATE analogs); agents that inhibit or block the activity of phos CYCLICAMP phodiesterases (PDE inhibitors); Toll-like receptor ligands; calcium channel activators or calcium activators; protein CROSS-REFERENCE TO RELATED kinase C (PKC) activators; and adenylate cyclase toxin. APPLICATIONS Exemplary agents that mimic cAMP include protein kinase A (PKA) activators. The methods may further include adminis 0001. This application is a continuation of U.S. patent tration of at least one cAMP elevator or agent that mimics application Ser. No. 12/663,959, filed Sep. 21, 2010, which is cAMP in combination with one or more additional active a national stage application of PCT/US2008/066647, filed compounds from other classes of therapeutic agents. In one Jun. 12, 2008, which claims the benefit of U.S. Provisional Such embodiment, the other class of therapeutic agents Patent Application Ser. No. 60/944,182, filed Jun. 15, 2007: includes any agent in use or in development to treat a UTI. the disclosures of which are incorporated herein by reference including antimicrobial agents such as, for example, antibi in their entirety. otics, and drugs that block bacterial adherence to the bladder wall. In another embodiment, the other class of therapeutic FEDERALLY SPONSORED RESEARCHOR agents includes cholesterol lowering drugs. DEVELOPMENT 0008 Compositions of the invention include pharmaceu 0002 This invention was made with government support tical compositions and kits for treating a UTI in a subject in under grant number R37 DK50814 awarded by the National need thereof. In some embodiments, the pharmaceutical com Institutes of Health. The United States government has cer positions and kits include therapeutically effective amounts tain rights in the invention. of at least two cAMP elevators or agents that mimic cAMP. and optionally one or more additional active compounds from FIELD OF THE INVENTION other classes of therapeutic agents. In other embodiments, the 0003. The presently disclosed subject matter relates to pharmaceutical compositions and kits include one or more methods and compositions to treat urinary tract infections cAMP elevator or agent that mimics cAMP in combination using agents that mimic or elevate intracellular levels of with at least one additional active compound from other cAMP. classes of therapeutic agents. BACKGROUND BRIEF DESCRIPTION OF THE DRAWINGS 0004 Urinary tract infections (UTIs) represent one of the 0009 FIG. 1 shows transmission electron micrographs of most common bacterial infections in humans. Each year at uropathogenic E. coli (UPEC) invading superficial bladder least 4 million patients (mostly women) seek treatment for epithelial cells (BECs) through fusiform canals. (A) Unin UTIs, and approximately $1.6 billion will be spent in the fected bladder epithelium showing scalloped plaques in the diagnosis and treatment of UTIS. Frequent recurrences in lumenal surface as well as in intracellular fusiform vesicles healthy adult females after an initial bout of UTI continue to (scale bars-2 um).
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