WO 2013/038197 Al 21 March 2013 (21.03.2013) P O P C T
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(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 2013/038197 Al 21 March 2013 (21.03.2013) P O P C T (51) International Patent Classification: Geir [NO/NO]; Bj0rndalen 81, N-7072 Heimdal (NO). A01N 43/16 (2006.01) A01N 43/653 (2006.01) MYRVOLD, Rolf [NO/NO]; 0vre Gjellum vei 28, N- A61K 31/734 (2006.01) A01P 3/00 (2006.01) 1389 Heggedal (NO). A01N 43/90 (2006.01) (74) Agent: DEHNS; St Bride's House, 10 Salisbury Square, (21) International Application Number: London EC4Y 8JD (GB). PCT/GB20 12/052274 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date kind of national protection available): AE, AG, AL, AM, 14 September 2012 (14.09.2012) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (25) English Filing Language: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (26) Publication Language: English HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (30) Priority Data: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 1116010.8 15 September 201 1 (15.09.201 1) GB NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, (71) Applicant (for all designated States except US): AL- RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, GIPHARMA AS [NO/NO]; Industriveien 33, N-1337 TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, Sandvika (NO). ZM, ZW. (72) Inventors; and (84) Designated States (unless otherwise indicated, for every (75) Inventors/Applicants (for US only): ONS0YEN, Edvar kind of regional protection available): ARIPO (BW, GH, [NO/NO]; Skogbrynet 6, N-3032 Drammen (NO). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, DESSEN, Arne [NO/NO]; Alstadhaug Terrasse 20, N- UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 3440 R0yken (NO). THOMAS, David William [GB/GB]; TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Tissue Engineering and Reparative Dentistry, School of EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Dentistry, Cardiff University, Heath Park, Cardiff CF14 MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 4XY (GB). HILL, Katja Etel [GB/GB]; Tissue Engineer TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ing and Reparative Dentistry, School of Dentistry, Cardiff ML, MR, NE, SN, TD, TG). University, Heath Park, Cardiff CF14 4XY (GB). Published: SLETTA, Havard [NO/NO]; Uglavegen 19, N-7024 Trondheim (NO). T0NDERVIK, Anne [NO/NO]; — with international search report (Art. 21(3)) Lindevegen 20, N-7058 Jakobsli (NO). KLINKENBERG, 00 © (54) Title: USE OF ALGINATE OLIGOMERS TO ENHANCE THE EFFECTS OF ANTIFUNGAL AGENTS (57) Abstract: Use of alginate oligomers to enhance the effects of antifungal agents The invention provides a method to improve the o efficacy of an antifungal agent against a fungus, said method comprising using said antifungal agent together with an alginate oli - gomer. The fungus may be on an animate or inanimate surface and both medical and non-medical uses and methods are provided. In one aspect the invention provides an alginate oligomer for use together with at least one antifungal agent in treating a subject infec ted, suspected to be infected, or at risk of infection, with a fungus. In another aspect the method can be used to combat fungal con - tamination of a site e.g. for disinfection and cleaning purposes. Use of alginate oligomers to enhance the effects of antifungal agents The present invention relates to the use of alginate oligomers to potentiate, or to enhance or improve, the efficacy of an antifungal agent, e.g. an antifungal drug or a fungicide, and in particular the effectiveness (or efficacy) of an antifungal agent to inhibit the growth and/or viability of fungi. In particular, it has been found that by combining the use of antifungal agents with alginate oligomers, the amount of antifungal agent used or necessary may be reduced. Accordingly, it is proposed that alginate oligomers may reduce the tolerance or enhance the susceptibility of fungi to antifungal agents. In some circumstances at least, it is believed that synergy may be occurring between alginate oligomers and antifungal agents. The invention accordingly provides alginate oligomers for use together with (i.e. in combination or conjunction with) an antifungal agent, e.g. an antifungal drug or a fungicide, for combating fungi, for example in the context of unwanted fungal colonisation (e.g. contamination) at any site or in the context of treating or preventing a fungal infection or disease (e.g. a mycosis) , whether in an animal subject or in a plant. Thus, both medical and non-medical uses and methods are provided. Fungi are members of a kingdom of eukaryotic organisms that are considered distinct from plants and animals. Unlike plant and animal cells, they are characterised by the presence of a cell wall containing chitin. Fungi are ubiquitous in nature and although many fungi are benign, many plant and animal diseases are attributed to their activities, either through infection of a host or through their production of toxic metabolites. Thus, the means to control fungal populations provides treatments for certain animal and plant diseases and conditions, and is important for the health and well-being of humans and the plants and animals they raise. The ability to control fungal populations on plants is of particular importance in the field of agriculture where economically valuable plants may be lost to fungal disease. The human cost of losing a food crop to fungal disease can also be high if access to alternative food sources is restricted. Fungi are also responsible for the spoilage of animal foodstuffs and other materials which leads to wastage and the necessity for repair or replacement of compromised materials. Control of fungi in these areas would minimise the significant economic costs associated with spoilage. Thus, there is an ongoing need to find alternative or improved strategies to combat fungi, both in plants and animals but also in the wider environment. Alternative or improved strategies to treat fugal diseases and infections in animal subjects are especially sought because certain inherent similarities between fungal and animal cells has made the identification of chemotherapeutic molecules specific to fungi difficult. As a result, very few effective antifungal drugs are currently available and those that are cause side effects at high dose because of their lack of specificity for fungal cells, which limits their systemic use. Thus, a strategy that can improve the effectiveness (or efficacy) of an antifungal agent to inhibit the growth and/or viability of fungi will be useful because doses of the antifungal agent can be reduced and side effects minimised. Alginates are linear polymers of (1-4) linked β-D-mannuronic acid (M) and/or its C-5 epimer a-L-guluronic acid (G). The primary structure of alginates can vary greatly. The M and G residues can be organised as homopolymeric blocks of contiguous M or G residues, as blocks of alternating M and G residues and single M or G residues can be found interspacing these block structures. An alginate molecule can comprise some or all of these structures and such structures might not be uniformly distributed throughout the polymer. In the extreme, there exists a homopolymer of guluronic acid (polyguluronate) or a homopolymer of mannuronic acid (polymannuronate). Alginates have been isolated from marine brown algae (e.g. certain species of Durvillea, Lessonia and Laminaria) and bacteria such as Pseudomonas aeruginosa and Azotobacter vinelandii. Other pseudomonads (e.g. Pseudomonas fluorescens, Pseudomonas putida, and Pseudomonas mendocina) retain the genetic capacity to produce alginates but in the wild they do not produce detectable levels of alginate. By mutation these non-producing pseudomonads can be induced stably to produce large quantities of alginate. Alginate is synthesised as polymannuronate and G residues are formed by the action of epimerases (specifically C-5 epimerases) on the M residues in the polymer. In the case of alginates extracted from algae, the G residues are predominantly organised as G blocks because the enzymes involved in alginate biosynthesis in algae preferentially introduce the G neighbouring another G, thus converting stretches of M residues into G-blocks. Elucidation of these biosynthetic systems has allowed the production of alginates with specific primary structures (WO 94/09124, Gimmestad, M et al, Journal of Bacteriology, 2003, Vol 185(12) 3515-3523 and WO 2004/01 1628). Alginates are typically isolated from natural sources as large high molecular weight polymers (e.g. an average molecular weight in the range 300,000 to 500,000 Daltons). It is known, however, that such large alginate polymers may be degraded, or broken down, e.g. by chemical or enzymatic hydrolysis to produce alginate structures of lower molecular weight. Alginates that are used industrially typically have an average molecular weight in the range of 100,000 to 300,000 Daltons (such alginates are still considered to be large polymers) although alginates of an average molecular weight of approximately 35,000 Daltons have been used in pharmaceuticals. It has now been found that alginate oligomers have the ability to potentiate or to enhance or improve, the efficacy of an antifungal agent, e.g. an antifungal drug or a fungicide, and in particular the effectiveness (or efficacy) of an antifungal agent to inhibit the growth and/or viability of fungi.