Mark S.Butler and David J.Newman vancomycin (35),is being evaluated in Phase IlI trials for treatment of patients whose infections are due to MRSA in both Gram-positive cSSSI and CAP by Theravance and Astellas.Oritavancin(NuvocidTM,LY-333328) (32)is a semi-synthetic derivative of the vancomycin analogue chloroer emomycin(36)[48],which Targanta Therapeutics acquired the rights to in December 2005 from InterMune,who had licensed it originally from Eli Lilly.Phase IlI clinical trials of oritavancin(32)for the treatment of cSSSI have been completed and an NDA is planned for 2007.Targanta also has Phase II clinical trials for the treatment of catheter-related bacteremia and nosocomial pneumonia in progress. There are two semi-synthetic derivatives of the macrolide erythromycin (17),the ketolides cethromycin (ABT-773)(37)and EP-420 (EP-013420. S-013420)(38),in active clinical development [28,49].Advanced Life Sciences have been evaluating cethromycin(37)[50,51]in Phase III trials for the treatment of CAP.Advanced Life Sciences licensed the worldwide rights to cethromycin (37)from Abbott Laboratories,except in Japan where it had been licensed previously by Taisho.EP-420(38)[52,53]is a novel,bridged bicyclic derivative developed by Enanta Pharmaceuticals, which is being evaluated in Phase II trials for treatment of CAP by both Enanta and Shionogi. The only rifamycin derivative under late stage evaluation is rifalazil (ABI-1648,KRM-1648)(39),a semi-synthetic of rifamycin B(40)[54]devel- oped by Kaneda Corporation [55]and licensed to ActivBiotics [56].Rifalazil (39)and related compounds are bactericidal and can effectively penetrate target tissues and cells,which may enable them to be used to eliminate intracellular pathogens such as Chlamydia [57].ActivBiotics is evaluating rifalazil(39)in Phase II trials for carotid artery atherosclerosis and Phase IlI trials for intermittent claudication associated with peripheral arterial disease,in which rifalazil(39)has FDA Fast Track status. Ramoplanin is a lipopeptide antibiotic complex isolated from Actino planes sp.ATCC33076,which consists of factors A1,A2 and A3 [58,59]. Factor A2('ramoplanin)(41)is the major component of the complex and is being evaluated in Phase II trials by Oscient Pharmaceuticals for the treatment of Clostridium difficile-associated diarrhoea(CDAD)[60,61] Ramoplanin (41)has been evaluated for the treatment of vancomycin- resistant Enterococci (VRE)but no trials are ongoing.Ramoplanin (41) exerts its antibacterial activity by binding to the peptidoglycan interme-
Mark S. Butler and David J. Newman 12 vancomycin (35), is being evaluated in Phase III trials for treatment of patients whose infections are due to MRSA in both Gram-positive cSSSI and CAP by Theravance and Astellas. Oritavancin (Nuvocid™, LY-333328) (32) is a semi-synthetic derivative of the vancomycin analogue chloroeremomycin (36) [48], which Targanta Therapeutics acquired the rights to in December 2005 from InterMune, who had licensed it originally from Eli Lilly. Phase III clinical trials of oritavancin (32) for the treatment of cSSSI have been completed and an NDA is planned for 2007. Targanta also has Phase II clinical trials for the treatment of catheter-related bacteremia and nosocomial pneumonia in progress. There are two semi-synthetic derivatives of the macrolide erythromycin (17), the ketolides cethromycin (ABT-773) (37) and EP-420 (EP-013420, S-013420) (38), in active clinical development [28, 49]. Advanced Life Sciences have been evaluating cethromycin (37) [50, 51] in Phase III trials for the treatment of CAP. Advanced Life Sciences licensed the worldwide rights to cethromycin (37) from Abbott Laboratories, except in Japan where it had been licensed previously by Taisho. EP-420 (38) [52, 53] is a novel, bridged bicyclic derivative developed by Enanta Pharmaceuticals, which is being evaluated in Phase II trials for treatment of CAP by both Enanta and Shionogi. The only rifamycin derivative under late stage evaluation is rifalazil (ABI-1648, KRM-1648) (39), a semi-synthetic of rifamycin B (40) [54] developed by Kaneda Corporation [55] and licensed to ActivBiotics [56]. Rifalazil (39) and related compounds are bactericidal and can effectively penetrate target tissues and cells, which may enable them to be used to eliminate intracellular pathogens such as Chlamydia [57]. ActivBiotics is evaluating rifalazil (39) in Phase II trials for carotid artery atherosclerosis and Phase III trials for intermittent claudication associated with peripheral arterial disease, in which rifalazil (39) has FDA Fast Track status. Ramoplanin is a lipopeptide antibiotic complex isolated from Actinoplanes sp. ATCC33076, which consists of factors A1, A2 and A3 [58, 59]. Factor A2 (‘ramoplanin’) (41) is the major component of the complex and is being evaluated in Phase II trials by Oscient Pharmaceuticals for the treatment of Clostridium difficile-associated diarrhoea (CDAD) [60, 61]. Ramoplanin (41) has been evaluated for the treatment of vancomycinresistant Enterococci (VRE) but no trials are ongoing. Ramoplanin (41) exerts its antibacterial activity by binding to the peptidoglycan interme-
Mother nature's gifts to diseases of man diate Lipid II (C3s-MurNAc-peptide-GlcNAc)and disrupting bacterial cell wall synthesis [62-64]. GlaxoSmithKline(GSK)has filed an NDA in February 2006 for the pleu- romutilin(42)derivative,retapamulin (Altabax,SB-275833)(43),for use as a topical antibiotic to treat skin infections [65,66].Pleuromutilins are fun 3
Mother nature’s gifts to diseases of man 13 diate Lipid II (C35-MurNAc-peptide-GlcNAc) and disrupting bacterial cell wall synthesis [62–64]. GlaxoSmithKline (GSK) has filed an NDA in February 2006 for the pleuromutilin (42) derivative, retapamulin (Altabax®, SB-275833) (43), for use as a topical antibiotic to treat skin infections [65, 66]. Pleuromutilins are fun-
Mark S.Butler and David J.Newman gal-derived compounds that exert their antimicrobial activity by binding to the 50S bacterial ribosome [67].GSK has two other pleuromutilin deriva tives,565154 and 742510,in Phase I clinical trials as oral antibiotics. Tiacumicin B(PAR-101,OPT-80)(44)is the major component of the tiacu micin antibiotic complex produced by Dactylosporangium aurantiacum subsp. hamdenensis NRRL 18085,which originally was isolated by Abbott [68,69] and is identical to lipiarmycin A3 [70]and clostomicin B1 [71].Tiacumicin B(44)displays potent antibacterial activity and is being evaluated in Phase IIb/IlI clinical trials by Par Pharmaceuticals(and Opitmer Pharmaceuticals) for the treatment of CDAD [72-75].Tiacumicin B(44)has been proposed to exert its antibacterial activity through inhibition of RNA synthesis 76]. Finally,the cationic peptide [77,78],omiganan(45),which was devel- oped by MIGENIX,has been licensed to Cadence Pharmaceuticals for catheter-related infections and Cutanea Life Sciences for dermatological diseases [79,80].The structure of omiganan(45)is based on indolicidin (46),a potent antibacterial and antiviral peptide originally purified from the cytoplasmic granules of bovine neutrophils.Omiganan(coded as Omi gardTM,CPI-226,MBI-226)(45)is being developed by Cadence for the treatment of catheter-related infections.Omiganan(45)showed promis ing results in a Phase Ill trial but its primary endpoint of a reduced rate of infections was not achieved and additional Phase IlI trials are underway in both the USA and Europe using a gel-based formulation.Omiganan (coded as CLS001,MX-594AN)(45)has completed two Phase II trials for the treatment of acne and Cutanea plan to initiate a Phase II trial for the treatment of Rosacea in 2007. 2.2 Antifungals As fungi are eukaryotes,the number of potential targets where there are significant differences between the microbe and its host (the human or animal/plant)are much smaller compared to bacteria,as they have intrin sic differences in primary metabolic processes,as well as the architecture of their cell walls and membranes.As a consequence,a significant number of bacterial targets do not have eukaryotic counterparts. In general,the targets are the cell walls of the fungi or subtle differences in membrane structure or in the biosynthesis of the sterol precursors lead- 14
Mark S. Butler and David J. Newman 14 gal-derived compounds that exert their antimicrobial activity by binding to the 50S bacterial ribosome [67]. GSK has two other pleuromutilin derivatives, 565154 and 742510, in Phase I clinical trials as oral antibiotics. Tiacumicin B (PAR-101, OPT-80) (44) is the major component of the tiacumicin antibiotic complex produced by Dactylosporangium aurantiacum subsp. hamdenensis NRRL 18085, which originally was isolated by Abbott [68, 69], and is identical to lipiarmycin A3 [70] and clostomicin B1 [71]. Tiacumicin B (44) displays potent antibacterial activity and is being evaluated in Phase IIb/III clinical trials by Par Pharmaceuticals (and Opitmer Pharmaceuticals) for the treatment of CDAD [72–75]. Tiacumicin B (44) has been proposed to exert its antibacterial activity through inhibition of RNA synthesis [76]. Finally, the cationic peptide [77, 78], omiganan (45), which was developed by MIGENIX, has been licensed to Cadence Pharmaceuticals for catheter-related infections and Cutanea Life Sciences for dermatological diseases [79, 80]. The structure of omiganan (45) is based on indolicidin (46), a potent antibacterial and antiviral peptide originally purified from the cytoplasmic granules of bovine neutrophils. Omiganan (coded as Omigard™, CPI-226, MBI-226) (45) is being developed by Cadence for the treatment of catheter-related infections. Omiganan (45) showed promising results in a Phase III trial but its primary endpoint of a reduced rate of infections was not achieved and additional Phase III trials are underway in both the USA and Europe using a gel-based formulation. Omiganan (coded as CLS001, MX-594AN) (45) has completed two Phase II trials for the treatment of acne and Cutanea plan to initiate a Phase II trial for the treatment of Rosacea in 2007. 2.2 Antifungals As fungi are eukaryotes, the number of potential targets where there are significant differences between the microbe and its host (the human or animal/plant) are much smaller compared to bacteria, as they have intrinsic differences in primary metabolic processes, as well as the architecture of their cell walls and membranes. As a consequence, a significant number of bacterial targets do not have eukaryotic counterparts. In general, the targets are the cell walls of the fungi or subtle differences in membrane structure or in the biosynthesis of the sterol precursors lead-
Mother nature's gifts to diseases of man 5-fluoe ing to membrane synthesis.Although a very considerable amount of time and effort was expended in the early days of antibiotic discovery,only three general use antifungal agents were developed from that work. Perhaps the best known clinically is the heptaene polyene,ampho- tericin B(47),originally isolated from Streptomycetes nodosus collected in Venezuela and reported in 1956,whose full structure was reported in two contemporaneous papers in 1970,by X-ray crystallography [81]where the absolute configuration was determined using the iodo-derivative and by mass spectroscopy [82]. Though many polyenes with varying numbers of conjugated double bonds have been reported since those early days,only one other com- pound of this class,in fact the first identified(in 1950)of this general structure class,the tetraene nystatin (48),has gone into general clinical use and like amphotericin B(47),its primary indication is for candidiasis. It was first reported from Streptomyces noursei and,as with 47,its structure was reported in the 1970 time frame by two groups,one using classical chemical degradation plus proton NMR [83]and the other via mass spec- troscopy [84].The proposed hemiketal structures of amphotericin B(47) and nystatin(48)were later confirmed in Rinehart's laboratory in 1976 851 Probably the first clinically used antifungal NP(originally reported in 1939),has also survived the test of time,and this is griseofulvin(49)whose non-polyene structure was defined in a series of papers in 1952 using clas. sical techniques [86].Even today,over 70 years after it was first described, griseofulvin (49)is still in clinical use against dermatophytes.In fact
Mother nature’s gifts to diseases of man 15 ing to membrane synthesis. Although a very considerable amount of time and effort was expended in the early days of antibiotic discovery, only three general use antifungal agents were developed from that work. Perhaps the best known clinically is the heptaene polyene, amphotericin B (47), originally isolated from Streptomycetes nodosus collected in Venezuela and reported in 1956, whose full structure was reported in two contemporaneous papers in 1970, by X-ray crystallography [81] where the absolute configuration was determined using the iodo-derivative and by mass spectroscopy [82]. Though many polyenes with varying numbers of conjugated double bonds have been reported since those early days, only one other compound of this class, in fact the first identified (in 1950) of this general structure class, the tetraene nystatin (48), has gone into general clinical use and like amphotericin B (47), its primary indication is for candidiasis. It was first reported from Streptomyces noursei and, as with 47, its structure was reported in the 1970 time frame by two groups, one using classical chemical degradation plus proton NMR [83] and the other via mass spectroscopy [84]. The proposed hemiketal structures of amphotericin B (47) and nystatin (48) were later confirmed in Rinehart’s laboratory in 1976 [85]. Probably the first clinically used antifungal NP (originally reported in 1939), has also survived the test of time, and this is griseofulvin (49) whose non-polyene structure was defined in a series of papers in 1952 using classical techniques [86]. Even today, over 70 years after it was first described, griseofulvin (49) is still in clinical use against dermatophytes. In fact
Mark S.Butler and David J.Newman griseofulvin (49)is only active against this class of fungi and long-term treatment is necessary due to its insolubility One other NP-derived molecule also in clinical use is the modified pyrim- idine nucleoside,5-fluorocytosine(flucytosine)(50),which although made synthetically,can be considered to be derived from a NP.Following transport nto Candidaor Cryptococcus viaa cytosine permease,5-fluorocytosine(50)is deaminated to give 5-fluorouracil(51),which can interfere with both RNA and DNA metabolism.It is relatively selective for fungal cells as a result of the lack or very low levels of cytosine deaminase in mammalian cells. 2.2.1 Antifungals:current status Three NP-derived antifungal drugs from the echinocandin class [87,88] caspofungin(2001,Cancidas,Merck)(52)[89],micafungin(2002,Myca mine/Funguard,Astellas)(53)[90]and anidulafungin (2006,Eraxis, Pfizer)(54)[91],have been launched since 2000.These drugs are semi synthetic derivatives of NPs (caspofungin (52)/pneumocandin Bo(55), micafungin(53)/FR901379(56)and anidulafungin(54)/echinocandin B (57))and their antifungal activity is caused by inhibition of 1,3-B-D-glu- can synthesis in the fungal cell wall.A very recent publication by Aperis and co-workers [92]details the clinical utility of these echinocandins and how they may be used for individualized therapy in conjunction with other agents(some of which are synthetic).Finally,another echinocandin, aminocandin (HMR-3270)(58),which is a semi-synthetic derivative of deoxymulundocandin(59),is currently undergoing Phase I evaluation for treatment of systemic fungal infections [93,94]. There is only one NP or NP-derived compound in Phase II antifungal clinical trials or above.SPK-843(60),the diascorbate salt of a semi-syn- thetic derivative of patricin A(61),is in Phase II clinical trials for treatment of systemic mvcosis by Kaken Pharmaceuticals 95-98 and detailed infor mation on SPK-843 is available on the Aparts BV web site [99].Patricin A (61)is a 38-membered heptaene polyene member first described as part of the aureofacin antibiotic complex isolated from Streptomyces aureofaciens SPK-843(60)has comparable activity to amphotericin B(47)but is consid- erably more water soluble and its antifungal activity is caused by destabili- zation of fungal cell membrane in a similar fashion to other polyenes. 6
Mark S. Butler and David J. Newman 16 griseofulvin (49) is only active against this class of fungi and long-term treatment is necessary due to its insolubility. One other NP-derived molecule also in clinical use is the modified pyrimidine nucleoside, 5-fluorocytosine (flucytosine) (50), which although made synthetically, can be considered to be derived from a NP. Following transport into Candida or Cryptococcus via a cytosine permease, 5-fluorocytosine (50) is deaminated to give 5-fluorouracil (51), which can interfere with both RNA and DNA metabolism. It is relatively selective for fungal cells as a result of the lack or very low levels of cytosine deaminase in mammalian cells. 2.2.1 Antifungals: current status Three NP-derived antifungal drugs from the echinocandin class [87, 88], caspofungin (2001, Cancidas®, Merck) (52) [89], micafungin (2002, Mycamine®/Funguard®, Astellas) (53) [90] and anidulafungin (2006, Eraxis®, Pfizer) (54) [91], have been launched since 2000. These drugs are semisynthetic derivatives of NPs (caspofungin (52)/pneumocandin B0 (55), micafungin (53)/FR901379 (56) and anidulafungin (54)/echinocandin B (57)) and their antifungal activity is caused by inhibition of 1,3-`-D-glucan synthesis in the fungal cell wall. A very recent publication by Aperis and co-workers [92] details the clinical utility of these echinocandins and how they may be used for individualized therapy in conjunction with other agents (some of which are synthetic). Finally, another echinocandin, aminocandin (HMR-3270) (58), which is a semi-synthetic derivative of deoxymulundocandin (59), is currently undergoing Phase I evaluation for treatment of systemic fungal infections [93, 94]. There is only one NP or NP-derived compound in Phase II antifungal clinical trials or above. SPK-843 (60), the diascorbate salt of a semi-synthetic derivative of patricin A (61), is in Phase II clinical trials for treatment of systemic mycosis by Kaken Pharmaceuticals [95–98] and detailed information on SPK-843 is available on the Aparts BV web site [99]. Patricin A (61) is a 38-membered heptaene polyene member first described as part of the aureofacin antibiotic complex isolated from Streptomyces aureofaciens. SPK-843 (60) has comparable activity to amphotericin B (47) but is considerably more water soluble and its antifungal activity is caused by destabilization of fungal cell membrane in a similar fashion to other polyenes