Chapter 13. Macrolide Antibiotics

Chapter 13. Macrolide Antibiotics

Chapter 13. Macrolide Antibiotics Herbert A. Kirst, Lilly Research Laboratories Eli Lilly and Company, Indianapolis, Indiana, 46285 Introduction - Th...

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Chapter 13. Macrolide Antibiotics Herbert A. Kirst, Lilly Research Laboratories Eli Lilly and Company, Indianapolis, Indiana, 46285

Introduction - The therapeutic utility of rnacrolide antibiotics is well established in both clinical and veterinary medicine; erythromycin, spiramycin, and tylosin remain important antimicrobial agents (1-6). An excellent book covers work prior to 1984 (7). Over the past decade, several newer macrolides possessing advantageous features have been prepared and evaluated in preclinical tests (8-13). Results are now emerging from clinical trials, which will determine the therapeutic value of these products. In addition to those cited above, other reviews have focused on various aspects of the chemistry and biology of macrolides (14.17). This chapter will summarize some of the more important trends within the class of traditional 14- and 16-membered rnacrolide antibiotics. under acidic conditions Newer Derivatives of Ervthromvcin - Decomposition of erythromycin (1) has been thought to proceed via the 8,9-anhydro-6,9-hemiketal 2,which is subsequently converted into the 6,9;9,12-spiroketal 9.A different mechanism, in which 2 and 3 arise from 1 independently rather than sequentially, has been recently proposed from kinetic studies (18,19). Trans-lactonization of 2 into the ring-contracted 8,9-anhydro-6,9-hemiketal 4 has also been reported (20,21). Since the intramolecular cyclization of erythromycin destroys its antibiotic activity, much effort has been spent to diminish or completely block this degradative pathway. One approach to preventing this decomposition has utilized water-insoluble, acid-stable salts, esters, and/or formulations to protect erythromycin during its passage through the stomach. The synthesis of new ester derivatives to improve the bioavailability of erythromycin is still being pursued (22,23). One recent example, 2'0acetylerythrornycin stearate (erythromycin acistrate), is reported io exhibit less liver toxicity and is now in clinical trial (24). In a different approach, two salts of 2'-O-propionylerythromycin (N-acetylcysteinate and mercaptosuccinate), which attempt to combine antibiotic and mucolytic activities into a single agent, are also under clinical investigation (25,26). Another successful strategy for inhibiting intramolecular cyclization of erythromycin has been directed toward modification of the functional groups on carbon atoms 6-12 of the macrocyclic ring (erythronolide). Many of the derivatives prepared from this approach have exhibited desirable features such as increased stability to acid, greater oral bioavailability, higher serum concentrations, better tissue penetration, and longer body half-life than erythromycin. The most advanced member of this next generation of macrolides is roxithromycin (3); its 9-oxime is less prone to participate in intramolecular cyclization than is the 9-ketone of erythromycin (27). Roxithromycin has been launched in France and is undergoing clinical trial in other countries (28). 9(S)-Erythromycylamine (5) is an older derivative of erythromycin in which the 9-ketone had been converted into an amino group. Dirithromycin a more recent oxazine derivative of erythromycylamine, is now in clinical trial; it is a pro-drug which improves the oral bioavailability of erythromycylamine (29). Azithromycin (8) is the result of a third route to modification of the 9ketone of erythromycin; a Beckmann rearrangement of erythromycin-9-oxime expanded the lactone to a 15-membered-ring intermediate, which was subsequently reduced and N-methylated (30,31). Azithromycin has recently been launched in Yugoslavia and is undergoing clinical trial elsewhere (28).

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Structural modification of erythromycin at sites other than its 9-ketone has also proven successful in providing new derivatives with improved biological features. The 6-0-methyl derivative of erythromycin, clarithromycin (9), has demonstrated higher stability to acidic conditions and superior pharmacokinetic properties when compared with erythromycin (32). Clinical trials of clarithromycin are currently being conducted. Still another approach to blocking the degradation of erythromycin to 2 has involved replacement of the C-8 proton of erythromycin by fluorine; this modification has been achieved by both bioconversion and chemical methods to produce flurithromycin (1Q)(33). A variety of more recent derivatives of erythromycin have been reported which are less advanced in their development than those described in the preceding paragraphs. Building upon the previously known 11,12-carbonate derivative of erythromycin, a series of 11,12-cyclic carbamates were synthesized which had improved properties in vivo when compared with activity, but lacked superior erythromycin (34). An 11,lZ-methylene acetal had good efficacy against infections in mice (35). A series of new 9-N-alkyl derivatives of 9 ( S ) erythromycylamine (5) showed better efficacy and bioavailability than erythromycin when administered orally in animal infection models (36). A series of azacyclic derivatives prepared from 9 ( R)-erythromycylamine showed similar in vivo advantages over erythromycin (37). Modifications of the 9-keto and 11-hydroxyl groups of erythromycin inhibited hydrolysis of the lactone by an esterase from Escherichia coli which may be involved in bacterial resistance to rnacrolides (38). From this series of derivatives of erythromycin, its 9-methoxime-1 1-[(2dimethylaminoethyt)oxymethyl] derivative (ER 42859) was selected on the basis of good antibiotic activity and pharmacokinetics in animals; however, it gave lower blood levels than erythromycin when administered to humans (39). Work in this area has continued with 9-oxime11,lZ-carbonate and 9-dihydro-9,ll -cyclic acetal derivatives, but no clinical candidate has been reported (40,41). A novel series of 9,12-epoxy derivatives has shown unexpectedly good oral efficacy and bioavailability; such activity was not expected since these compounds resulted from further chemical modification of the intramolecular cyclization product 2 (42). Attempts to correlate the conformation of a variety of derivatives of erythromycin with their antibiotic activity have met with only limited success (43,44).

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Newer Derivatives of 16-Membered Macrolid% - Among the 16-membered macrolides. josamycin (1L),spiramycin (16)and tylosin (l7J are well established antibiotics. The most advanced of the newer 16-membered macrolide derivatives are rokitamycin and miokamycin (l5),which have been launched for clinical use in Japan (28). They are, respectively, a 3"-O-acylated derivative of leucomycin A5 (Q) and a 3",9-di-O-acylated derivative of midecamycin (14). Products derived from 3"-O-acylations of the neutral sugar (mycarose) in these 16-membered macrolides have demonstrated pharmacokinetic advantages such as a longer in vivo half-life (45.46).

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Two new derivatives of tylosin are now in field trials for veterinary applications. The first of has demonstrated activity against tylosin-resistanl these, 3-O-acetyl-4"-O-isovaleryltylosin organisms and greater oral bioavailability in animals (47,48); a clinically useful derivative of tylosin which exploits these features is also being sought (49-51). The second derivative, tilmicosin (22). has expanded the spectrum of tylosin to cover Pasteurella species responsible for pneumonia in pigs and cattle (52-54); since modification of the aldehyde of desmycosin (19) improved its activity, a clinically useful derivative within this series is also being sought (55.56). Another related 16-membered rnacrolide is miporamicin (mycinamicin ll), which is being investigated for its potential utility (57). 9-Oxime and 3-0-cladinosyl derivatives of tylosin have been prepared, which represent structural hybrids between tylosin and either roxithromycin or erythromycin (58,59) The beneficial effects of dialkylamino groups, which have been previously observed in other series, have now been further explored with modifications of the 9-keto group of niddamycin (60).

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Structures of 16-Membered Macrolides

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Myc mycarosyl, iVal-Myc = 4-0-isovalerylmycarosyl, N R 2 = 3,5-dimethylpiperidinyl Antimicrobial Activity - In vitro studies of the newer macrolides are too numerous to completely cover in this review; some have been previously summarized (8). Results are now available from extensive hm side-by-side comparisons of many of the macrolides which are currently in clinical trial (61-65). While all of these were potent antibiotics against bacteria traditionally covered within the macrolide spectrum, their activity relative to each other was dependent upon the particular bacterium and test conditions (such as presence of serum, etc.) (61,62,66). Azithromycin has achieved the largest expansion in antimicrobial spectrum by increasing in vitrQ activity against Gram-negative bacteria (66,67); its activity against Haemophilus influenzae, Branhamella catarrbalis and Neisseria gonorrhoeae has increased 2-8 fold over that of erythromycin (67-69). It was orally effective against a middle ear infection in gerbils caused by H. influenzae (70). Roxithromycin and clarithromycin have shown efficacy superior to that of erythromycin against experimental infections, including Legionella pneumophila infections in guinea pigs (27,71-73). Given once a day subcutaneously, dirithromycin was more efficacious than erythromycin against experimental infections in mice (74). A high proportion of bacteria which have been implicated in dental diseases have proven susceptible to spirarnycin (75). Despite their well established, traditional antibiotic spectrum. opportunities still exist to expand the therapeutic utility of macrolides. Helicobacfer pylori (formerly Campylobacter) is highly susceptible to macrolides in vitrQ, but treatment of gastric disorders due to this organism has not yet been established (63,76). Azithromycin was effective against infections in rodents caused by Borrelia burgdorferi, the causative agent of Lyme disease (77,78). The activity of macrolides against Mycobacferium avium complex is being pursued by several groups (79-82); (83,84), and efficacy against M. leprae in other mycobacteria are susceptible to macrolides a mouse leprosy model has been reported (85). Although spirarnycin is used to treat toxoplasmosis, more effective agents are being sought (86,87). Toward that end, several groups have reported activity by newer macrolides against acute toxoplasmosis or toxoplasnic encephalitis in mice (88-90). Spiramycin was tried but was fouild to be ineffective against an acute

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diarrhea due to Crypfosporidium in pediatric patients (91,92). Roxithromycin was active in a mouse model of chlamydia1 salpingitis and a rabbit model of syphilis (93,94);it had in vitrQ activity superior to erythromycin against Rickettsia sp. (95). Azithromycin inhibited Entamoeba histolytica and organisms responsible for bacterial vaginosis and chancroid (96,97). These results illustrate current efforts to expand the clinical use of macrolides; however, most of these studies concluded that despite in vitrQ activity and efficacy in animal models, effectiveness in clinical trials must be proven before clinical utility can be claimed for any of these indications. Macrolides are believed to inhibit bacterial growth by inhibition of protein synthesis; however, this process is complex and full details are unknown (16,98). One approach to better understanding of the macrolide-ribosome interaction has used photoaffinity labeling (99). Macrolides are lipophilic compounds which can penetrate many biological barriers; their accumulation in Bacferoides fragilis has been correlated with their antibiotic activity and hydrophobicity (100). Bacterial resistance, always a concern in medicine, is usually due to modification of an antibiotic target site, enzymatic inactivation of the antibiotic, or reduced uptake into cells. Modification of the ribosomal binding site of macrolides involves methylation of 2 3 s rRNA by an inducibly or constitutively derived methylase (101); some of the structural modifications of 2 3 s rRNA which are correlated with macrolide resistance have been proposed (102,103). One advantage of 16-membered macrolides is their activity against bacteria which are inducibly resistant to erythromycin, although they lack activity against strains which are constitutively resistant to erythromycin (61,62). Recently, derivatives of erythromycin and clarithromycin which were substituted on their 11,12- and/or 4"-hydroxyl groups have shown activity against both types of MLS-resistant bacteria (104,105). Enzymatic inactivation of macrolides has now been found with esterases (106), phosphorylases (107,108), and glycosidases (109). The possible origin of these bacterial enzymes in macrolide-producing organisms is a subject of current debate (1 10). Resistance due to reduced uptake into bacterial cells has been proposed (111,112). Pharmacokinetics and Pharmacolow - Although expanding the antibiotic spectrum of macrolides is desirable, improvements in their pharmacokinetic properties, such as greater oral bioavaiiability and higher and more persistent concentrations in fluids and tissues than erythromycin, will also contribute significantly toward the realization of new therapeutic applications. Such improvements have already been partially achieved with the newer macrolides. Although details of their individual pharmacokinetic parameters are beyond the scope of this chapter, monographs for individual compounds (5,lO-13,24)and reviews comparing several macrolides are available (9,113-115). The difficulty with animal models as predictors of human pharmacokinetics has also been discussed (1 16). One beneficial feature of macrolides is their capability for intracellular penetration, which is important but not sufficient for killing intracellular pathogens (117-119). Several new macrolides have achieved higher concentrations and greater antibacterial activity within macrophages than erythromycin (1 20-125). Understanding the interactions between macrolides and components of the host's defense system is the subject of much current research (117-127). Treatment of infections associated with inflammation has been suggested (128,129), and reversal of drug resistance in multidrug-resistant (MDR) cells has been reported (130). Macrolides achieve high concentrations in certain tissues such as pulmonary and prostate that exceed concentrations in serum (1 13,114);this feature may permit therapeutic concentrations of antibiotic to be achieved at the site of localized infections Interactions between erythromycin and other drugs have been reviewed (131).The principal route of excretion is via the liver; consequently, the effects of macrolides on hepatic metabolic enzymes, especially cytochrome P-450, have been studied in order to reduce interference with

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the metabolism of other drugs (132-134). Some of the newer macrolides are metabolized to products which retain antibiotic activity, thereby giving more persistent antibiotic levels b VJVO. Clarithromycin is oxidized to its 14(R)- and 14(S)-hydroxy derivatives; the former has antimicrobial activity comparable to that of its parent (135). Dirithromycin was previously mentioned as a pro-drug of erythromycylamine (29). Both rokitamycin and miokamycin undergo deacylations, yielding various factors of the leucomycin family (136,137). The principal side effects associated with erythromycin are gastrointestinal problems. Erythromycin has been recently identified as an agonist of motilin, a natural peptide responsible for stimulating contractility in the gastrointestinal tract (138). Although reduced promotion Of gastrointestinal contractility in dogs has been used to select for rnacrolides with reduced potential to cause gastrointestinal problems, proof of this approach has not yet emerged from clincial studies. A different application of this work has been the development of macrolides related to 2 for the treatment of gastrointestinal motility disorders (139,140). Clinical Resulk - Most clinical experience with the newer macrolides has been with miokamycin, rokitamycin and roxithromycin (11-13); many of the early results from the former two compounds and clarithromycin have been published by Japanese investigators (141 -143). A monograph on azithromycin has just appeared (10). Most of the initial trials with the newer macrolides have focused on the same indications for which erythromycin has been used. Because of its increased h activity against H. influenzae, an initial failure of azithromycin to eradicate that organism in a chronic bronchitis study was noteworthy (144). A review of erythromycin-induced hearing loss has recently been published (145). Conclusion - Modification of macrolides by both chemical and bioconversion methods continues

to generate new antibiotics with potentially useful properties (6,15). Fermentation remains an invaluable source of new macrolides, aided by new screening methods such as ELISA-based assays (146) and studies of biosynthetic pathways (147-149). Molecular biology is now employing its tools to create hybrid and genetically-engineered products (150-154). New therapeutic applications of macrolides are being sought in both clinical and veterinary medicine, and discoveries are being made on the mechanisms by which these agents kill microorganisms and interact with the host's defense systems. It certainly appears that macrolide research is alive and well, offering potential scientific and medical rewards (155). References 1.

2. 3. 4. 5. 6. 7.

8. 9. 10. 11.

12. 13. 14. 15.

D.C. Brittain. Med. Clin. North America, 71. 1147 (1987). J.D. Nelson, Ed., Pediatr. Infect. Dis., 3, 118 (1986). J.A. Washington and W.R. Wilson, Mayo Clin. Proc.,fi0, 189 (1985). 271 I , (1985). J.A. Washington and W.R. Wilson, Mayo Clin. Proc., & P. Davey. J.-C. Pechere and D. Speller, Eds., J. Antimicrob. Chemother., 2,Suppl. B (1988). Y. Fukagawa, K. Kiyoshima and T. Yoshioka, Life Chemistry Reports. 6,267 (1988). S. Ornura, Ed., "Macrolide Antibiotics: Chemistry, Biology and Practice." Academic Press, Orlando, Florida, 1984. H.A. Kirst and G.D. Sides, Antimicrob. Agents Chemother., 3, 1413 (1989). H.A. Kirst and G.D. Sides, Antirnicrob. Agents Chemother.. 3,1419 (1989). Suppl. A (1990). D.A. Leigh and G.L. Ridgway. Eds., J. Antimicrob. Chemother., H.C. Neu and J.F. Acar, Eds., Brit. J. Clin. Pract., Suppl. 55 (1988). 1. Phillips, J. Pechere. A. Davies and D. Speller, Eds., J. Antimicrob. Chemother., Suppl. B (1987). J.P. Butzler, Ed., "Macrolides:A Review with an Oullook on Future Developments,"Excerpta Medica, Amsterdam, The Netherlands, 1986. R.K. Boeckman and S.W. Goldstein in "The Total Synthesis of Natural Products." Vol. 7, J. ApSimon, Ed., John Wiley & Sons, New York, N. Y., 1988, p. 1. H.A. Kirst in "Recent Progress in the Chemical Synthesis of Antibiotics." G. Lukacs and M. Ohno. Eds., Springer-Verlag,Heidelberg, Germany, 1990, in press.

a,

z,

a,

Chap. 13

Macrolide Antibiotics

lrst

125

16. I. Phillips and J.D. Williams, Eds.. J. Antimicrob. Chemother., 16,Suppl. A (1985). 17. R.W. Auckenthaler. A. Zwahlen and F.A. Waldvogel in "Antimicrobial Agents Annual 3," P.K. Peterson and J. Verhoef, Eds.. Elsevier Science Publishers, Amsterdam, The Netherlands, 1988, p. 122. 18. Th. Cachet, G. Van den Mooter. R. Hauchecorne, C. Vinckier and J. Hoogmartens, Int. J. Pharm., 59 (1989). 19. C. Vinckier, R. Hauchecorne, Th. Cachet, G. Van den Mooter and J. Hoogmartens. Int. J. Pharm.. 67 (1989). 20. 1.0.Kibwage. R. Busson, G. Janssen, J. Hoogmattens, H. Vanderhaeghe and J. Bracke, J. Org. Chem., 2 , 9 9 0 (1987). 21. H.A. Kirst, J.A. Wind and J.W. Paschal, J. Org. Chem., 52,4359 (1987). 22. L. Dall'Asta, A. Cornini, E. Garegnani, D. Alberti, G. Coppi, G. Quadro, J. Antibiotics, 41, 139 (1988). 159 (1989). 23. B. Steffansen and H. Bundgaard, Int. J. Pharm., 24. P. Davey and R. Williams, Eds., J. Antimicrob. Chemother., 21,Suppl. D (1988). 25. G. Ricevuti. D. Pasotti, A. Mazzone, G. Gazzani and G. Fregnan, Chemother. (Easel). &L 374 (1988). 26. E. Concia, P. Marone, G.C. Moreo, C. Sardi and R. Braschi, J. Int. Med. Res., 14.137 (1986). 27. J.-F. Chantot. A. Bryskier and J . 4 . Gasc. J. Antibiotics, 3, 660 (1986). 28. J. Hardcastle, Ed., "Pharrnaprojects (Therapeutic Categories, Main Volume)," PJB Publications, Richmond, United Kingdom, Volume 10, 1989, p. a616. 29. G. Bozler, G. Heinzel, U. Lechner, K. Schumacher and U. Busch, Proc. 28th ICAAC, Los Angeles, Calif., October 23-26, 1988, Abstr. No. 924. 30. S. Djokic, G. Kobrehel, N. Lopotar, B. Kamenar. A. Nag1 and D. Mrvos, J. Chem. Res. (S). 152 (1988). 31. G.M. Bright, A.A. Nagel, J. Bordner, K.A. Desai, J.N. Dibrino, J. Nowakowska, L. Vincent, R.M. Watrous, F.C. Sciavolino, A.R. English, J.A. Retsema, M.R. Anderson, L.A. Brennan, R.J. Borovoy, C.R. Cirnochowski, J.A. Faiella, A.E. Girard, D. Girard. C. Herbert, M. Manousos and R. Mason, J. Antibiotics, 41. 1029 (1988). 32. Y. Kohno. H. Yoshida, T. Suwa and T. Suga, Antimicrob. Agents Chemother.. U,751 (1989). 33. L. Toscano. G. Fioriello, S. Silingardi and M. Inglesi, Tetrahedron, 4Q, 2177 (1984). 34. W.R. Baker, J.D. Clark, R.L. Stephens and K.H. Kim, J. Org. C h e n . 3 , 2340 (1988). 1644 (1988). 35. E. Hunt, D.J.C. Knowles, C. Shillingford and 1.1. Zomaya, J. Antibiotics, 36. H.A. Kirst, J.F. Quay, S.R. Johnston, M.K. Buening and L.S. Finch, Proc. 29th ICAAC, Houston, Texas, Sept. 17-20, 1989, Abstr. No. 1021. 37. K. Marsh, S. Culbertson. L. Klein, C. Maring. R. Pariza and P. Lartey, Proc. 29th ICAAC, Houston, Texas, Sept. 17-20, 1989, Abstr. No. 1026. 38. J. Wilson, J. Durodie and M. Foulstone. J. Antimicrob. Chemother., 2. 84 (1988). 39. J.M. Wilson, P.C.T. Hannan, C. Shillingford and D.J.C. Knowles, J. Antibiotics, 42, 454 (1989). 40. P.C.T. Hannan, C. Shillingford and J.M. Wilson, Proc. 29th ICAAC, Houston. Texas, Sept. 17-20, 1989, Abstr. No. 1022. 41. E. Hunt, D.J.C. Knowles, C. Shillingford, J.M. Wilson and 1.1. Zomaya. J. Antibiotics, 42, 293 (1989). 42. D.J. Hardy, R.N. Swanson, L.A. Freiberg, P.A. Lartey and J.J. Clement, Proc. 29th ICAAC. Houston, Texas, Sept. 17-20, 1989. Abstr. No. 1030. 43. J.R. Everett, I.K. Hatton, E. Hunt, J.W. Tyler, D.J. Williams, J. Chem. SOC. Perk. Tran. 11, 1719 (1989). 44. K.H. Kim and Y.C. Martin, Prog. Clin. Biol. Res.. 291. 325 (1989). 45. J.R. Prous, Ed., Drugs of the Future, 8, 790 (1983). 46. J.R. Prous, Ed.. Drugs of the Future, JQ, 486 (1985). 47. T.M. Jacks, F.R. Judith, S.D. Feighnerand R.O. Likoff, Amer. J. Vet. R e s . , g , 2325 (1986). 48. B.J. Skelly. D. Andersen. M. Pruss and R. Pellegrino, Avian Diseases, 2,505 (1986). 49. K. Kiyoshirna, M. Sakamoto, H. Nomura, T. Yoshioka, R. Okamoto, T. Sawa. H. Naganawa and T. Takeuchi. J. Antibiotics, 42, 1661 (1989). 50. A.K. Mallams and R.R. Rossman, J. Chem. SOC.Perkin Trans I, 775 (1989). 51. A.G. Fishman, A.K. Mallams and R.R. Rossman, J. Chem. SOC.Perkin Trans. I, 787 (1989). 52. H.A. Kirst, K.E. Willard. M. Debono, J.E. Toth, B.A. Truedell, J.P. Leeds, J.L. Ott, A.M. FeltyDuckworth. F.T. Counter, E.E. Ose, G.D. Crouse, J. Tustin, S. Omura, J. Antibiotics, 42. 1673 (1989). 53. M. Debono. K.E. Willard, H.A. Kirst. J.A. Wind, G.D. Crouse, E.V. Tao, J.T. Vicenzi, F.T. Counter, J.L. Ott, E.E. Ose and S.Omura, J. Antibiotics, 42. 1253 (1989). 54. R.N. Gourlay, L.H. Thomas, S.G. Wyld and C.J. Smith, Research Vet. Science, 42, 84 (1989). 55. T. Fujiwara, H. Watanabe, Y. Kogami. Y. Shiritani and H. Sakakibara, J. Antibiotics, 42, 903 (1989). 56. H.A. Kirst, J.E. Toth. M. Debono, K.E. Willard, B.A. Truedell, J.L. Ott, F.T. Counter, A.M. FeltyDuckworth and R.S. Pekarek, J. Med. Chem., 3,1631 (1988).

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57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93.

94. 95. 96. 97. 98. 99.

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M. Sasaki, K. Sano, A. Sumi, K. Motoyarna, J. Yano, K. Matsurnoto and H. Yarnarnoto. Japan. J. Antibiotics, 42, 2412 (1989). C. Ruggeri, M. Laborde, A. Dessinges, L. Ming, A. Olesker, G. Lukacs. J. Antibiotics. 42,1443 (1989). A.K. Mallarns and R.R. Rossrnan, J. Chern. SOC.Perkin Trans. I, 799 (1989). L.A. Freiberg, C.J. Maring, P.A. Lartey, C.M. Edwards, D. Grampovnik, D. Hardy and P. Fernandes, Proc. 29th ICAAC, Houston, Texas, Sept. 17-20, 1989, Abstr. No. 1032. D.J. Hardy, D.M. Hensey, J.M. Beyer, C. Vojtko, E.J. McDonald and P.B. Fernandes, Antimicrob. 1710 (1988). Agents Chemother., 3, P.B. Fernandes and D.J. Hardy, Drugs Exptl. Clin. Res.. 14, 445 (1988). D.J. Hardy, C.W. Hanson. D.M. Hensey, J.M. Beyer, P.B. Fernandes, J. Antirnicrob. Chemother.. 22. 631 (1988). K. Chirgwin, P.M. Roblin and M.R. Hamrnerschlag, Antimicrob. Agents Chernother., 23, 1634 (1989). J.E. Hoppe and A. Eichhorn, Eur. J. Clin. Microbiol. Infect. Dis., 8, 653 (1989). J. Retserna and L. Brennan, Proc. 29th ICAAC, Houston, Texas, Sept. 17-20, 1989. Abstr. No. 1034 H.C. Neu, N.X. Chin, G. Saha and P. Labthavikul, Eur. J. Clin. Microbiol. Infect. Dis., Z,541 (1988). A.L. Barry, C. Thornsberry and T.L. Gavan, Eur. J. Clin. Microbiol. Infect. Dis., 8, 544 (1989). A.L. Barry, R.N. Jones and C. Thornsberry. Antimicrob. Agents Chemother.. 32, 752 (1988). A.E. Girard, D. Girard, A.R. English, T.D. Gootz, C.R. Cirnochowski, J.A. Faiella, S.L. Haskell and J.A. Retsema. Antirnicrob. Agents Chernother.. 2,1948 (1987). P.B. Fernandes, R.N. Swanson. D.J. Hardy, E.J. McDonald and N.Rarner, Drugs Exptl. Clin. Res., 441 (1988). S. Kohno. H. Koga. K. Yamaguchi, M. Masaki, Y. Inoue, Y. Dotsu, Y. Masuyama, T.Hayashi, M. Hirota, A. Saito and K. Hara, J. Antirnicrob. Chemother., 3, 397 (1989). 462 (1989). R.B. Fitzgeorge and A.S.R. Featherstone, J. Antirnicrob. Chernother., U. Lechner, K.-R. Appel, R. Maier and E. Woitun, Proc. 8th lnt. Syrnp. on Future Trends in Chemotherapy, Tirrenia (Pisa), Italy, Mar. 28-30, p. 31. E.C.S. Chan, W. Al-Joburi, S:L. Cheng, F. Delorrne, Antimicrob. Agents Chemother., 33, 2016 ( 1 989). J.A. Garcia-Rodriguez, J.E. Garcia Sanchez, M.I. Garcia Garcia, E. Garcia Sanchez and J.L. Munoz Bellido, Antirnicrob. Agents Chernother.. 3,1650 (1989). R.C. Johnson, C. Kodner and M. Russell, Proc. 27th ICAAC, New York, Oct. 4-7, 1987, Abstr. No. 235. V. Preac-Mursic, B. Wilske. G. Schierz, E. Suss and B. Gross, Eur. J. Clin. Microbiol., 8, 651 (1989) N. Khardori, K. Rolston, 8. Rosenbaurn. S. Hayat and G.P. Bodey, J. Antirnicrob. Chemother., 2,667 (1989). S.Naik and R. Ruck, Antimicrob. Agents Chernother.,3,1614 (1989). 994 and 1095 (1989). C.B. Inderlied. P.T. Kolonoski. M. Wu and L.S. Young, J. Infect. Dis., P.B. Fernandes, D.J. Hardy, D. McDaniel, C.W. Hanson and R.N. Swanson. Antimicrob. Agents Chemother.. 3,1531 (1989). J. Maugein, J. Fourche, M. Mormede and J.L. Pellegrin, Pathol. Biol., 3,565 (1989). O.G.W. Berlin, L.S. Young, S.A. Floyd-Reising, D.A. Bruckner, Eur. J. Clin. Microbiol., 8, 486 (1987) N. Ramasesh, J.L. Krahenbuhl and R.C. Hastings, Antimicrob. Agents Chernother., 33, 657 (1989). R. McCabe and J.S. Rernington. New Eng. J. M e d . , u , 313 (1988). S. Charnberland, H.A. Kirst and W.L. Current, Proc. 29th ICAAC, Houston, Texas, Sept. 17-20, 1989. Abstr. No. 1036. B.J. Luff, Eur. J. Clin. Microbiol., 8, 479 (1987). H.R. Chang, F.C. Rudareanu and J.-C. Pechere, J. Antirnicrob. Chernother., 22,359 (1988). F.G. Araujo. D.R. Guptill and J.S. Rernington, Antimicrob. Agents Chemother., 2, 755 (1988). X. Saez, C.M. Odio. M.A. Urnana and M. Morales, Proc. 28th ICAAC, Los Angeles, Calif., Oct. 23-26. 1988, Abstr. No. 45. 131 (1989). D.F. Wittenberg, N.M. Miller and J. van den Ende, J. Infect. Dis., J. Zana. M. MuffatJoly, D. Thomas, J. Salat-Baroux, J. Orfila and J.J. Pocidalo. Proc. 29th ICAAC, Houston, Texas, Sept. 17-20, 1989, Abstr. No. 1317. S.A. Lukehart and S.A. Baker-Zander, Antirnicrob. Agents Chernother., 2,187 (1987). M. Drancourt and D. Raoult. Antimicrob. Agents Chemother., 3,2146 (1989). J.I. Ravdin and J. Skilogiannis, Antirnicrob. Agents Chernother.. 3,960 (1989). B.M. Jones, G.R.Kinghorn and B.I. Duerden, Eur. J. Clin. Microbiol. Infect. Dis., 1,551 (1988). M. DiGiarnbattista, G. Chinali and C. Cocito, J. Antimicrob. Chemother., 2,485 (1989). M.A. Arevalo, F. Tejedor, F. Polo and J.P.G. Ballesta. J. Med. Chem., 2, 2200 (1989).

u.

a,

mc

m,

Chap 13

Macrolide Antibiotics

Kirst

127

100. Y. Muto, K. Bandoh, K. Watanabe, N. Katoh and K. Ueno, Antirnicrob. Agents Chernother., 33, 242 (1989). 101. B. Weisblum, Brit Med. Bull., 4p, 47 (1984). 102. S. Douthwaite, T. Powers, J.Y. Lee and H.F. Noller, J. Mol. Biol., 2Q9, 655 (1989). 103. M. Zalacain and E. Cundliffe, J. Bacteriol., 4254 (1989). 104. P.B. Fernandes, W.R. Baker, L.A. Freiberg. D.J. Hardy and E.J. McDonald, Antirnicrob. Agents Chernother., 3,78 (1989). 105. R.C. Goldrnan and S.K. Kadarn, Antimicrob. Agents Chernother., 33,1058 (1989). 106. M. Arthur, A. Brisson-Noel, and P. Courvalin, J. Antimicrob. Chernother., 783 (1987). 107. V.P. Marshall, W.F. Liggett and J.I. Cialdella, J. Antibiotics, 42, 826 (1989). 108. K. OHara, T. Kanda, K. Ohmiya, T. Ebisu, M. Kono. Antimicrob. Agents Chernother., 3,1354 (1989). 109. M . 4 . Kuo, D.G. Chirby. A.D. Argoudelis, J.I. Cialdella, J.H. Coats and V.P. Marshall, Antimicrob. Agents Chernother., 3,2089 (1989). 110. A. Brisson-Noel, P. Delrieu, D. Samain and P. Courvalin. J. Biol. Chem., 15880 (1988). 11 1. B.C. Lampson. W. von David and J.T. Parisi, Antimicrob. Agents Chernother.. 32, 653 (1986). 112. G. Palu. S. Valisena, M.F. Barile and G.A. Meloni, Eur. J. Epidemiology, 5,146 (1989). 113. P. Periti, T. Mazzei, E. Mini and A. Novelli, Clin. Pharmacokinetics, 16,193 (1989). 114. P. Periti, T. Mazzei. E. Mini and A. Novelli, Clin. Pharmacokinetics, 16,261 (1989). 115. J.E. Riviere, A.L. Craigmill and S.F. Sundlof, Ed., "Comparative Pharmacokinetics and Residues of Veterinary Antimicrobials." CRC Press, Boca Raton. Florida, 1990, Chapter 5, in press. 116. G.S. Duthu, J. Pharm. Sci., 24,943 (1985). 117. L. Madgwick. S. Mayer and P. Keen, J. Antirnicrob. Chemother.. 24. 709 (1989). 118. M. Raghoebar. E. Lindeyer, W.B. van den Berg and C.A M. van Ginneken, Biochem. Pharm., 3Z, 3221 (1988). 119. M.L. Villa. F. Valenti, F. Scaglione, M. Falchi, F. Fraschini, J. Antimicrob. Chernother.. 24, 765 (1989). 120. A.M. Cuffini. N.A. Carlone, V. Tullio and M. Borsotto, Microbios. 58, 27 (1989). 121. R.P. Gladue, G.M. Bright, R.E. lsaacson and M.F. Newborg. Antimicrob. Agents Chemother., 33,277 (1989). 122. R. Anderson, G. Joone and C.E.J. van Rensburg, J. Antimicrob. Chernother., 22,923 (1988). 123. M. Ishiguro. H. Koga, S. Kohno. T. Hayashi. K. Yamaguchi and M. Hirota, J. Antirnicrob. Chemother., 24, 719 (1989). 124. M.T. Labro and C. Babin-Chevaye, J. Antimicrob. Chemother., 24, 731 (1989). 125. B. Scorneaux and P.M. Tulkens, Proc. 29th ICAAC, Houston, Tex., Sept. 17-20, 1989, Abstr. No. 157. 126. R. Anderson, J. Infect. Dis.. 966 (1989). 503 (1988). 127. A Naess and C.O. Solberg, Acta Pathol. Microbiol. Immunol. Scand., 128. M.T. Labro. J. El Benna and C. Babin-Chevaye, J. Antirnicrob. Chemother., 24, 561 (1 989). 129. 0. Carevic and S. Djokic. Agents and Actions, Z, 124 (1988). 130. E. Hofsli and J. Nissen-Meyer, Int. J. Cancer, 44,149 (1989). 131. T.M. Ludden, Clin. Pharmacokinetics. 1Q.63 (1985). 132. E. Sartori, M. Delaforge and D.Mansuy, Biochem. Pharm., 38,2061 (1989). 133. M. Tinel, V. Descatoire, D. Larrey, J. Loeper, G. Labbe, P. Letteron and D.Pessayre, J. Pharrnacol. Expt. Ther., 746 (1989). 134. T. Miura, M. Iwasaki. M. Kornori, H. Ohi. M. Kitada, H. Mitsui and T. Kamataki, J. Antimicrob. Chemother.. 2.551 (1989). 135. T. Adachi. S. Morimoto, H. Kondoh, T. Nagate, Y. Watanabe and K. Sota, J.Antibiotics, 41,966 ( 1 988). 136. A Sakai, T. Suzuki, M. Morishita, K. Mizuno, T. lshioka and R. Fujii, Proc. 28th ICAAC, Los Angeles, Calif., Oct. 23-26. 1988, Abstr. No. 913. 137. T. Shomura. S. Someya, S. Murata, K. Umemura and M. Nishio, Chem. Pharm. Bull., 2.9, 2413 (1981). 138. T. Peeters. G. Matthijs, I. Depoortere, T. Cachet, J. Hoogmartens and G. Vantrappen, Amer. J. Physiol.. 252, G470 (1989). 139. K. Tsuzuki. T. Sunazuka. S. Marui, H. Toyoda, S. Omura. N. lnatomi and 2. Itoh, Chem. Pharm. Bull.. 3,2687 (1989). 140. T. Sunazuka, K. Tsuzuki, S. Marui. H. Toyoda, S. Omura, N. lnatomi and Z. Itoh, Chem. Pharm. Bull., 3 , 2 7 0 1 (1989). 141. K. Hara, Japan. J. Antibiotics, 4,1851 (1987). 142. K. Sunakawa, H. Akita and R. Fujii, Proc. 28th ICAAC, Los Angeles, Od.23-26, 1988, Abstr. NO.914. 143. H. Meguro, 0. Arimasu, F. Hiruma, K. Sugamata, N. Sugie. A. Higa, T. Shinozaki, T. Abe and R. Fujii. Japan. J. Antibiotics, 42, 255 (1989).

m,

a,

m,

m,

m,

s,

E8

Section 111-Chemotherapeutic Agents

Plattner Ed.

144. 6.1. Davies, F.P.V. Maesen and R. Gubbelrnans, J. Antimicrob. Chernother., 23, 743 (1989). 145. R.E. Brurnrnett and K.E. Fox, Antirnicrob. Agents Chernother., 33,791 (1989). 146. R.C. Yao and D.F. Mahoney. Appl. Environ. Microbiol., s,1507 (1989). 147. K. Kinoshita, S. Takenaka and M. Hayashi. J. Chern. SOC.Chem. Commun., 943 (1988). 148. M.L.B. Huber, J. Paschal, J.P. Leeds, H.A. Kirst, F.D. Miller and J.R. Turner, Proc. 89th Mtg. Arner. SOC. Microbiol., New Orleans, Louisiana., May 14-18,1989.Abstr. No. K-12. 149. D. OHagan, Natl. Prod. Reports, 6,205 (1989). 150. D.A. Hopwood. Phil. Trans. Royal SOC.London €3, U,549 (1 989). 151. C.R. Hutchinson, C.W. Borell. S.L. Otten, K.J. Stutzrnan-Engwall and Y. Wang, J. Med. Chern., z, 929 (1989). 152. E.T. Seno and R.H. Baltz in "Regulation of Secondary Metabolism in Actinomycetes," S . Shapiro. Ed., CRC Press, Boca Raton. Florida, 1989,p. 1, 153.J.A. Robinson, Chern. SOC.Rev., 383 (1988). 154. C.L. Hershberger, S.W. Oueener and G. Hegernan, Eds., "Genetics and Molecular Biology of Industrial Microorganisms," Arner. SOC.Microbiol., Washington, D.C., 1989. 155. R. Wise, J. Antirnicrob. Chernother., 299 (1989).

u,

a,