Mother nature's gifts to diseases of man OH cne16明R In order to give extra 'medicinal life'to B-lactams that were no longer resistant to the common B-lactamases.in the late 1960s and earlv 1970s efforts were made,particularly by Beecham(now part of GlaxoSmithKline) and Pfizer to find molecules that would have similar pharmacokinetics to the B-lactams but would inhibit the 'regular'B-lactamases that were part of the pathogenic microbe's defense systems.Beecham discovered the clavulanate family with clavulanic acid(9)being incorporated into the combination known as Augmentin a 1:1 mixture of amoxicillin and clavulanic acid(9)launched in 1981,thus extending the franchise of this particular B-lactam well beyond its original patent date. Along with the search for the B-lactamase inhibitors,efforts were under- way to produce the simplest B-lactam,the monobactam.Following many years of unsuccessful research at major pharmaceutical houses,predomi- nately in the synthetic areas,came the reports from Imada et al.in 1981 [18] and a Squibb group led by Sykes [19],who both demonstrated the same basic monobactam nucleus(10).What is important to realize is that no molecules synthesized before the discoveries of these NPs had a sulfonvl group attached to the lactam nitrogen,which is an excellent method for stabilizing the sin- gle ring.Since that time a significant number of variations upon that theme have been placed into clinical trials and in some cases,into commerce 7
Mother nature’s gifts to diseases of man 7 In order to give extra ‘medicinal life’ to `-lactams that were no longer resistant to the common `-lactamases, in the late 1960s and early 1970s, efforts were made, particularly by Beecham (now part of GlaxoSmithKline) and Pfizer to find molecules that would have similar pharmacokinetics to the `-lactams but would inhibit the ‘regular’ `-lactamases that were part of the pathogenic microbe’s defense systems. Beecham discovered the clavulanate family with clavulanic acid (9) being incorporated into the combination known as Augmentin® a 1:1 mixture of amoxicillin and clavulanic acid (9) launched in 1981, thus extending the franchise of this particular `-lactam well beyond its original patent date. Along with the search for the `-lactamase inhibitors, efforts were underway to produce the simplest `-lactam, the monobactam. Following many years of unsuccessful research at major pharmaceutical houses, predominately in the synthetic areas, came the reports from Imada et al. in 1981 [18] and a Squibb group led by Sykes [19], who both demonstrated the same basic monobactam nucleus (10). What is important to realize is that no molecules synthesized before the discoveries of these NPs had a sulfonyl group attached to the lactam nitrogen, which is an excellent method for stabilizing the single ring. Since that time a significant number of variations upon that theme have been placed into clinical trials and in some cases, into commerce
Mark S.Butler and David J.Newman 2.1.2 Actinomycins,aminoglycosides,tetracyclines and erythromycins Concomitantly with the early development of the penicillins,Waksman was working at Rutgers University in New Jersey in the late 1930s/early 1940s,specializing in investigation of the actinomycetes (which at that time were considered to be fungi),with the aim of finding a treatment for tuberculosis.His initial finding in 1940,however,was the identification of chromooligopeptides of the actinomycin class(e.g.,actinomycin D(11)). which though not useful as antibacterials,led to what was the first use of such secondary metabolites as a treatment for cancer(Wilms'tumor)[20]. In 1943,the aminoglycoside antibiotic streptomycin(12)was isolated from Streptomyces griseus and,in addition to being active against Myco- bacterium tuberculosis,was active against a wide range of other patho- nge mum otmnu a group they have a major biological Achilles heel in the sense that they are easily inactivated by plasmid-mediated acetylation or phosphorylation and multiply resistant organisms have evolved.However,aminoglycosides still have utility particularly in conjunction with B-lactams with whom they exhibit true synergy. The fourth series of molecules to be reported was a previously unknown molecule with four fused rings (a tetracycline).The parent molecule was not used to any great extent as an antibacterial but the naturally occurring chlorinated analogue,Aureomycin(13),was.This tetracycline skeleton has given rise to a large number of semi-synthetic molecules with three of these,doxycycline(14),minocycline(15)and tigecycline (16),being used today,particularly against the causative agent of Lyme disease. The macrolide antibiotics,exemplified by erythromycin (17),are as equally famous and long-lived as the other classes previously dis. cussed.Even today,erythromycin (17)is still prescribed,particularly for pediatric patients.This class of antibiotics has yet another claim to fame as it was one of the first molecules for which the biogenetic sys- tem was described in 1990 using classical mutation studies [21],which later developed into the system known as combinatorial biosynthesis whereby non-naturally occurring metabolites are made by 'mixing and matching'gene clusters [22].More current details can be found in the 8
Mark S. Butler and David J. Newman 8 2.1.2 Actinomycins, aminoglycosides, tetracyclines and erythromycins Concomitantly with the early development of the penicillins, Waksman was working at Rutgers University in New Jersey in the late 1930s/early 1940s, specializing in investigation of the actinomycetes (which at that time were considered to be fungi), with the aim of finding a treatment for tuberculosis. His initial finding in 1940, however, was the identification of chromooligopeptides of the actinomycin class (e.g., actinomycin D (11)), which though not useful as antibacterials, led to what was the first use of such secondary metabolites as a treatment for cancer (Wilms’ tumor) [20]. In 1943, the aminoglycoside antibiotic streptomycin (12) was isolated from Streptomyces griseus and, in addition to being active against Mycobacterium tuberculosis, was active against a wide range of other pathogenic organisms. Further work over the next twenty or so years yielded a large number of similar glycosidic-based antibacterials. Unfortunately, as a group they have a major biological Achilles heel in the sense that they are easily inactivated by plasmid-mediated acetylation or phosphorylation and multiply resistant organisms have evolved. However, aminoglycosides still have utility particularly in conjunction with `-lactams with whom they exhibit true synergy. The fourth series of molecules to be reported was a previously unknown molecule with four fused rings (a tetracycline). The parent molecule was not used to any great extent as an antibacterial but the naturally occurring chlorinated analogue, Aureomycin® (13), was. This tetracycline skeleton has given rise to a large number of semi-synthetic molecules with three of these, doxycycline (14), minocycline (15) and tigecycline (16), being used today, particularly against the causative agent of Lyme disease. The macrolide antibiotics, exemplified by erythromycin (17), are as equally famous and long-lived as the other classes previously discussed. Even today, erythromycin (17) is still prescribed, particularly for pediatric patients. This class of antibiotics has yet another claim to fame as it was one of the first molecules for which the biogenetic system was described in 1990 using classical mutation studies [21], which later developed into the system known as combinatorial biosynthesis whereby non-naturally occurring metabolites are made by ‘mixing and matching’ gene clusters [22]. More current details can be found in the
Mother nature's gifts to diseases of man 24 25 recent overview by Demain and the references therein 1231 together with the excellent review by Baltz et al.on the use of genetic constructs in developing further congeners of daptomycin (18)[24]and from a historical to current perspective,the excellent review by von Nussbaum and co-workers covering the older and modern literature from a medici- nal chemistry/lead discovery and optimization aspect should definitely be consulted [25]. 2.1.3 Antibacterials:current status Since 2000,six new NP-derived drugs have been launched:ertapenem (200l,Invanz,Merck)(19[26,27，telithromycin(2001,Ketek®，Sanofi 9
Mother nature’s gifts to diseases of man 9 recent overview by Demain and the references therein [23], together with the excellent review by Baltz et al. on the use of genetic constructs in developing further congeners of daptomycin (18) [24] and from a historical to current perspective, the excellent review by von Nussbaum and co-workers covering the older and modern literature from a medicinal chemistry/lead discovery and optimization aspect should definitely be consulted [25]. 2.1.3 Antibacterials: current status Since 2000, six new NP-derived drugs have been launched: ertapenem (2001, Invanz®, Merck) (19) [26, 27], telithromycin (2001, Ketek®, Sanofi-
Mark S.Butler and David J.Newman Aventis)(20)[28,29],biapenem (2002,Omegacin,Meiji)(21)[30,31], daptomycin(20,)(1)[31,doripenem (00,Fini- bax,Shionogi Co;Phase III (US),J&J)(22)[33,34]and tigecycline (2005,Tygacil Wyeth)(16)[35-39].Ertapenem(19),biapenem(21)and doripenem(22)are carbapenem antibiotics(part of the B-lactam family), which are produced synthetically but their lead structure was the NP thienamycin(23).Tigecycline(16)is a semi-synthetic derivative of tetra- cycline,while telithromycin(20)is a semi-synthetic derivative of erythro- mycin(17).Daptomycin(18)is a lipopeptide NP used for the treatment of complicated skin and skin structure infections(cSSSi)and Staphylococcus aureus bloodstream infections or bacteremia including right-sided infec- tive endocarditis.In terms of sales,daptomycin (18)has had the most successful launch for an IV antibiotic in US history.Daptomycin(18)rep- resents only one of three new antibiotic classes launched since 1970:the other two being the topical antibiotic NP mupirocin(24)in 1985 and the synthetic oxazolidinone linezolid(25)in 2000. There are total of four B-lactams,two cephalosporins,ceftobripole medo caril (26)and ceftaroline acetate (27),and two carbapenems,R1558(28) and tebipenem(29),in Phase II or Phase IlI clinical trials or undergoing drug registration.Ceftobiprole medocaril(26)is a fourth generation cepha- losporin that has potent bactericidal activity against methicillin resistant Staphylococcus aureus (MRSA)and penicillin resistant Streptococcus pneumoniae (PRSP)[40].Basilea and Johnson and Johnson Pharmaceutical Research and Development LLC (&)are evaluating ceftobiprole medocaril(26)for the treatment of cSSSi,nosocomial pneumonia and hospitalized community acquired pneumonia(CAP)in various Phase III trials.Ceftaroline (PPI-0903, TAK-599)(27)is being evaluated by Cerexa in Phase II trials and both cefto- biprole(26)and ceftaroline(27)have been granted FDA fast-track status [40, 41].The carbapenems R1558(Ro4908463,CS-023,Sankyo and Roche)(28) [40,42]and tebipenem pivoxil (ME-1211,Meiji Seika)(29)are being evalu ated in Phase II clinical trials as a broad spectrum antibiotics [43]. There are three semi-synthetic glycopeptides [32,44,45],dalbavancin (30),telavancin(31)and oritavancin (32),in late stage clinical investiga- tion and their antibacterial mechanism is through inhibition of cell wall production.Dalbavancin (Zeven)is a semi-synthetic derivative of BO- A40926 factor(33)[46],a glycopeptide related to teicoplanin (34),and a New Drug Application(NDA)for the treatment of skin and soft tissue 10
Mark S. Butler and David J. Newman 10 Aventis) (20) [28, 29], biapenem (2002, Omegacin®, Meiji) (21) [30, 31], daptomycin (2003, Cubicin®, Cubist) (18) [24, 32], doripenem (2005, Finibax®, Shionogi & Co; Phase III (US), J&J) (22) [33, 34] and tigecycline (2005, Tygacil®, Wyeth) (16) [35–39]. Ertapenem (19), biapenem (21) and doripenem (22) are carbapenem antibiotics (part of the `-lactam family), which are produced synthetically but their lead structure was the NP thienamycin (23). Tigecycline (16) is a semi-synthetic derivative of tetracycline, while telithromycin (20) is a semi-synthetic derivative of erythromycin (17). Daptomycin (18) is a lipopeptide NP used for the treatment of complicated skin and skin structure infections (cSSSi) and Staphylococcus aureus bloodstream infections or bacteremia including right-sided infective endocarditis. In terms of sales, daptomycin (18) has had the most successful launch for an IV antibiotic in US history. Daptomycin (18) represents only one of three new antibiotic classes launched since 1970; the other two being the topical antibiotic NP mupirocin (24) in 1985 and the synthetic oxazolidinone linezolid (25) in 2000. There are total of four `-lactams, two cephalosporins, ceftobripole medocaril (26) and ceftaroline acetate (27), and two carbapenems, R1558 (28) and tebipenem (29), in Phase II or Phase III clinical trials or undergoing drug registration. Ceftobiprole medocaril (26) is a fourth generation cephalosporin that has potent bactericidal activity against methicillin resistant Staphylococcus aureus (MRSA) and penicillin resistant Streptococcus pneumoniae (PRSP) [40]. Basilea and Johnson and Johnson Pharmaceutical Research and Development LLC (J&J) are evaluating ceftobiprole medocaril (26) for the treatment of cSSSi, nosocomial pneumonia and hospitalized community acquired pneumonia (CAP) in various Phase III trials. Ceftaroline (PPI-0903, TAK-599) (27) is being evaluated by Cerexa in Phase II trials and both ceftobiprole (26) and ceftaroline (27) have been granted FDA fast-track status [40, 41]. The carbapenems R1558 (Ro4908463, CS-023, Sankyo and Roche) (28) [40, 42] and tebipenem pivoxil (ME-1211, Meiji Seika) (29) are being evaluated in Phase II clinical trials as a broad spectrum antibiotics [43]. There are three semi-synthetic glycopeptides [32, 44, 45], dalbavancin (30), telavancin (31) and oritavancin (32), in late stage clinical investigation and their antibacterial mechanism is through inhibition of cell wall production. Dalbavancin (Zeven®) is a semi-synthetic derivative of B0- A40926 factor (33) [46], a glycopeptide related to teicoplanin (34), and a New Drug Application (NDA) for the treatment of skin and soft tissue
Mother nature's gifts to diseases of man scglarn infections was filed in February 2005 by Vicuron Pharmaceuticals(now part of Pfizer).Pfizer received an Approvable Letter on 21 June 2006 from the FDA for dalbavancin(30)and its launch has been delayed until 2007. Telavancin (TD-6424)(31)[47],which is a semi-synthetic derivative of
Mother nature’s gifts to diseases of man 11 infections was filed in February 2005 by Vicuron Pharmaceuticals (now part of Pfizer). Pfizer received an Approvable Letter on 21 June 2006 from the FDA for dalbavancin (30) and its launch has been delayed until 2007. Telavancin (TD-6424) (31) [47], which is a semi-synthetic derivative of