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Wo 2008/021089 A2 (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 PCT 21 February 2008 (21.02.2008) WO 2008/021089 A2 (51) International Patent Classification: (74) Agents: STAUFFER, Raymond, E . et al.; Carella, Byrne, A61K 9/22 (2006.01) Bain Gilfillan, Cecchi, Stewart & Olstein, 5 Becker Farm Road, Roseland, NJ 07068 (US). (21) International Application Number: PCT/US2007/017552 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: 7 August 2007 (07.08.2007) AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, (25) Filing Language: English ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, (26) Publication Language: English LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, (30) Priority Data: PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, 60/836,026 7 August 2006 (07.08.2006) US TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, 60/836,313 8 August 2006 (08.08.2006) US ZM, ZW (71) Applicant (for all designated States except US): MID- (84) Designated States (unless otherwise indicated, for every DLEBROOK PHARMACEUTICALS, INC. [US/US]; kind of regional protection available): ARIPO (BW, GH, 20425 Seneca Meadows Parkway, Germantown, MD GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 20878 (US). ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (72) Inventors; and FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, (75) Inventors/Applicants (for US only): FLANNER, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, Henry, H. [US/US]; 19 Dellcastle Court, Montgomery GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Village, MD 2088 (US). TREACY, Donald [US/US]; 16905 Old Saw Mill Road, Woodbine, MD 21797 (US). Declaration under Rule 4.17: TOLLE-SANDER, Sanna [DE/US]; 11 134 Rutledge — of inventorship (Rule 4.17(iv)) Drive, North Potomac, MD 20878 (US). BURNSIDE, Beth, A. [US/US]; 5404 Huntington Parkway, Bethesda, Published: MD 20814 (US). RUDNIC, Edward [US/US]; 13517 — without international search report and to be republished Maidstone Lane, Potomac, MD 20854 (US). upon receipt of that report (54) Title: ONCE-A-DAY (RNA-POLYMERASE INHIBITING OR PHENAZINE)-DIHYDROPTEROATE SYNTHASE INHIBITING-DIHYDROFOLATE REDUCTASE INHIBITING ANTIBIOTIC PHARMACEUTICAL PRODUCT, FOR- MULATION THEREOF, AND USE THEREOF IN TREATING INFECTION CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS (57) Abstract: Disclosed are once-a-day antibiotic products for treating Methicillin-Resistant Staphylococcus aureus, or "MRSA", the products comprising: a combination of at least three different antibiotics, wherein one of the at least three different antibiotics is selected from the group consisting of RNA- Polymerase Inhibiting antibiotics or Phenazine antibiotics, wherein one of the at least three different antibiotics is selected from the group consisting of Dihydropteroate Synthase Inhibiting antibiotics, and wherein one of the at least three different antibiotics is selected from the group consisting of Dihydro folate Reductase Inhibiting antibiotics (alternatively any or all of the aforementioned RNA-Polymerase Inhibiting antibiotics, Dihydropteroate Synthase Inhibiting antibi- otics, and Dihydrofolate Reductase Inhibiting antibiotics may be in the form of analogues, derivatives, polymorphs, metabolites, pro-drugs, salts, and/or hydrates of any of the foregoing); optionally in further combination with a resistance inhibitor, preferably a LexA protease cleavage inhibitor. ONCE-A-DAY (RNA-POLYMERASE INHIBITING OR PHENAZINE) - DIHYDROPTEROATE SYNTHASE INHIBITING - DIHYDROFOLATE REDUCTASE INHIBITING ANTIBIOTIC PHARMACEUTICAL PRODUCT, FORMULATION THEREOF, AND USE THEREOF IN TREATING INFECTION CAUSED BY METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS This application claims the priority of U.S. Provisional Application Serial No. 60/836,026, filed August 7, 2006; and also claims the priority of U.S. Provisional Application Serial No. 60/836,3 13, filed August 8, 2006; the disclosures of each of which are hereby incorporated by reference in their entireties. This invention relates to a once-a-day antibiotic product, and to the use and formulation thereof. More specifically this invention relates to a once-a-day antibiotic product comprising: a combination of at least three different antibiotics, wherein one of the at least three different antibiotics is selected from the group consisting of RNA-Polymerase Inhibiting antibiotics, one of the at least three different antibiotics is selected from the group consisting of Dihydropteroate Synthase Inhibiting antibiotics, and one of the at least three different antibiotics is selected from the group consisting of Dihydrofolate Reductase Inhibiting antibiotics (alternatively any or all of the aforementioned RNA-Polymerase Inhibiting antibiotics, Dihydropteroate Synthase Inhibiting antibiotics, and Dihydrofolate Reductase Inhibiting antibiotics may be in the form of analogues, derivatives, polymorphs, metabolites, pro-drugs, salts, and 7 or hydrates of any of the foregoing), and to the use and formulation of such an antibiotic product. More specifically still this invention relates to a once-a-day antibiotic product comprising the aforementioned combination of antibiotics (or analogues, etc.), to the formulation thereof, and to the use thereof in treating bacterial infection in a patient or subject. In several embodiments the invention is directed to improving upon the eradication of antibiotic-resistant bacterial pathogens and / or to reducing the emergence of any further resistant bacterial pathogens, while using the product to treat bacterial infection in a patient or subject (e.g., an infectious bacterial pathogen such as Methicillin-Resistant Staphylococcus aureus, or "MRSA"). In still other embodiments, the above-described invention is directed to a once-a-day antibiotic product comprising the aforementioned combination of antibiotics (or analogues, etc.), in further combination with a resistance inhibitor—preferably a LexA protease cleavage inhibitor; and to the similarly above-described use, and formulation of such an antibiotic product. In preferred embodiments, the above-described invention is administered orally. However, in other embodiments, the above-described invention may be delivered by a multitude of I pharmaceutically acceptable routes that are known in the art and described hereinbelow. As known in the art and as referred to herein the terms "once-a-day," "one-a-day," "once daily," and "Q.D." shall denote that the product of the hereinabove-described and hereinbelow- described invention is to be administered only once during any given twenty-four hour period, after which no further product or composition is administered during that same given twenty-four hour period. As referred to hereinabove and hereinbelow, either of the terms "patient" or "subject" shall each individually denote any host of a bacterial infection, or any organism suspected of hosting a bacterial infection, including without limitation humans and animals. As referred to hereinabove and hereinbelow, the terms "to treat," "treating," or "treatment" (of) such patient or subject shall mean that the hereinabove-described and / or hereinbelow-described products and / or processes are administered to and / or practiced upon the patient or subject, but shall neither necessarily imply nor foreclose actual treatment of such patient or subject by a physician, clinician, investigator, parent, custodian, or other caregiver; yet may include any act of prescribing or otherwise directing that any of the hereinabove-described and / or hereinbelow-described products and / or processes are administered to and / or practiced upon the patient or subject, by any such person. Similarly, "to treat," "treating," or "treatment" (of) such patient or subject may include any act whereby the hereinabove-described and / or hereinbelow-described products and / or processes are administered to and / or practiced upon the patient or subject by the patient or subject himself/ herself, or by an inanimate device or similar means. Staphylococcus aureus, sometimes referred to simply as "staph," or "staph A," is a common bacterium typically found on the skin and / or in the nasal passages of healthy people. While the presence of Staphylococcus aureus on the skin and / or in the nasal passages is usually harmless to a person at those sites, "staph" infections can occur as a result of breaks in the skin, such as through abrasions, lacerations, and wounds; or by way of surgical procedures or catheterizations. If staph gets into the body it can cause minor skin and soft tissue infections, such as boils or pimples; or it can cause more serious conditions, such as pneumonia, empyema, blood infections, bacteremia, sepsis, osteomyelitis, pyomytosis, necrotizing fascititis, purpura fulminans, infections of the bones and joints, urinary tract infections, toxic shock syndrome, and even death. Methicillin-Resistant Staphylococcus aureus is a bacteria! pathogen resistant to certain antibiotics, such as methicillin and other beta-lactams, including oxacillin, penicillin, nafcillin, amoxicillin, and the cephalosporins. (See Dellit
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