Chapter 13. β-Lactam Antibiotics

Chapter 13. β-Lactam Antibiotics

SECTION 111-Chemotherapeutic Agents Editor: Frank C. Sciavolino, f f i z e r C e n t r a l Research Groton, Connecticut 06340 C h a p t e r 13. R-Lact...

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SECTION 111-Chemotherapeutic Agents Editor: Frank C. Sciavolino, f f i z e r C e n t r a l Research Groton, Connecticut 06340 C h a p t e r 13. R-Lactam Antibiotics

George L. Dunn Smith Kline & French Laboratories, Philadelphia, PA 19101 Introduction - Though t h e 13-lactam antibiotics a r e probably t h e m o s t thoroughly studied single class of t h e r a p e u t i c agents, new discoveries continue to emerge. Notable among t h e newer developments in 1984 was t h e discovery by t h r e e industrial research groups of a new class of naturally-occurring 7a-substituted cephalosporins. In addition, a new semisynthetic 7 a s u b s t i t u t e d penicillin having increased stability to B-lactamases was described. An emerging problem of potential significance to t h e t h e r a p e u t i c use of t h e n e w e r 8-lactam antibiotics is t h e development o f resistance to t h e s e drugs during therapy by pathogens which produce a n inducible, chromosomally-mediated B-lactamase.1 The most frequent c a u s a t i v e organisms a r e Enterobacter, Serratia and Pseudomonas species. This t y p e of resistance is expressed across -31 classes. Reviews h a v e a p p e a r e d on B-lactams and resistance,2 clinical perspectives on t h e 3rd generation ~ e p h a l o s p o r i n s , ~ - 5and broad-spectrum penicillins.6,7 Reviews also appeared discussin t h e relationship between 13-lactam s t r u c t u r e and 13-lactamase stabilityJr9 properties of t h e n e w e r cephalosporins,lo historical development of t h e cephalosporins,ll chemistry of monobactams,12 synthesis and SAR of aminothiazole cephalosporins,l chiral syntheses of B-lactams, l 4 X-ray studies on penicillins and cephalosporins,l5 and penicillin binding proteins (PBPs). 16 A review of t h e properties, biosynthesis and fermentation of carbapenems was published17 as was a comprehensive t w o p a r t set of books devoted to t h e discovery, fermentation, biosynthesis, SAR and clinical use of t h e f i - l a ~ t a m s . l 8 * ~ 9Several c h a p t e r s of a n o t h e r book also described t h e properties, biosynthesis and fermentation of t h e B-lactams.20 The proceedings of a n international FEMS symposium on t h e a r c h i t e c t u r e a n d growth of b a c t e r i a l cell walls was published in book form.21 One review22 and several publication^^^-^^ reported studies on t h e mechanisms of B-lactam rin opening. Several studies a t t e m p t i n g to c o r r e l a t e spectra1,*5-27 electronic28,2g and X-ray30,31 d a t a with biological a c t i v i t y w e r e published. Cephalosporins - A new class of cephalosporins containing a 7a-formamido group, typified by chitinovorin A (I-), was isolated from t h e fermentations of t h r e e different e n e r a of bacteria. Research groups from S q ~ i b b ,S ~h i~0 n o g i 3 ~and Takeda34-37 reported t h e discovery a l m o s t simultaneously. These compounds, named chitinovorins o r cephabacins, also have a unique p e p t i d e c o n t a i n i n g substituent at t h e 3-position. Though t h e derivatives reported had weak antibacterial activity, t h e 7 a -formamido group imparted good 13-lactamase stability. The focus of semisynthetic modifications in t h e B-lactam antibiotics has been directed toward derivatives having broad-spectrum a c t i v i t y with increased potency against both g r a m p o s i t i v e organisms and Pseudomonas o r derivatives with improved pharmacokinetics. Several new analogs containing 7-heterocyclyl-u-oximino-acetamido side chains having broad-spectrum a c t i v i t y and improved pharmacokinetics w e r e reported. Extensive SAR studies38-40 led to t h e new parenteral compound FR17126 (2) whose s p e c t r u m of a c t i v i t y

A N N U A L REPORTS IN MEDICINAL CHEMISTRY-20

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is comparable to ceftazidime's b u t is 2-4 t i m e s more potent versus s o m e Pseudomonas, Proteus and Enterobacter species.41 9 4 2 Two 74aminothiazolyloximino]cephalosporins with unique substituents a t t a c h e d to t h e oxime w e r e reported. DN9550 (2)is reported to have a spectrum and potency similar to ~ e f t a z i d i m e ' s ~ 3 9while 4 ~ YM 14408 (3)has increased C r a m p o s i t i v e a c t i v i t y b u t is weakly a c t i v e against Pseudomonas.45 L-105 (2), a s t r u c t u r a l analog of c e f o t a x i m e with a similar s p e c t r u m of activity, exhibited increased potency versus Gram-positive b a c t e r i a compared to o t h e r third generation ce halosporins.46-48 Two o t h e r analogs, YM-I3115 ($149 and SKF 88070 ( I ) , g - 5 3 w e r e reported t o show antibacterial and pharmacokinetic profiles similar to t h o s e of ceftriaxone. The synthesis and SAR studies of analogs in which t h e 2-aminothiazole moiety has been oxidized to t h e N-oxide led to F C E 20635 (2)

dOOH

N-N

x= -s-(N$ CH2CH,NHS0,H

which is similar to c e f o t a x i m e in i t s jn- vitro and in vivo a n t i b a c t e r i a l properties.54 C G P 31 523A (2) is reported to hav-oad-speTtruEXctivity similar to HR810 but with superior activity versus 5. aureus.55 CGP17520 a parenteral cephalosporin with asecond generation spectrum of activity, showed t h e r a p e u t i c efficacy against S. a u r e u s and several o t h e r Gram-positive b a c t e r i a l infections in mice superior to t h a t of cefuroxime o r cefoxitin even though in s o m e instances i t s in vitro activity was inferior.56-58 An oxacephem, 2 3 5 5 4 (El, showed potent broad-spectrum a c t i v i t y similar to t h a t of 6315-S (12)b u t had a superior pharmacokinetic profile.59,60 The synthesis and SAR study of a s e r i e s of

(u),

Chap. 13

B-Lactam A n t i b i o t i c s

Dunn

129

coon

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carbacephems also was reported.61 The most a c t i v e compound f r o m t h e series, KT-4697 (131,retained b r o a d s p e c t r u m a c t i v i t y against Gram-negative b a c t e r i a including Pseudomonas, but in vivo activity was weak. Penicillins andcephalosporins with 7clsubstitu?Gtsother than methoxy generally show reduced antibacterial activities. However, a research group f r o m Beecham has synthesized a s e r i e s of 7a-hydroxymethylcephalosporins having t h e piperacillin/cefoperazone-type of 7-acyl side chain. These a g e n t s exhibit a c t i v i t y versus Gram-negative b a c t e r i a superior to cefoperazone's, b u t t h e y h a v e l i t t l e a c t i v i t y against Gram p o s i t i v e organisms.62 Researchers a t Eli Lilly carried o u t extensive SAR studies o n 7-arylglycyl cephalosporins in searching f o r a n oral a g e n t with a long duration of action. Two analogs w e r e s e l e c t e d f o r m o r e extensive e v a l u a t i o n . 6 3 ~ ~ 4The -in v i t r o activities of LY164846 (14) a n d LY171217 (15) a r e limited to Gram-positive b a c t e r i a and H. influenzae with potencies s i m r a r to those of cephalexin and c e f a r l o r . 6 5 , ~ Both w e r e well-absorbed orally i n laboratory animals but t h e i r routes of elimination varied dramatically a m o n g t h e species t e ~ t e d . 6 7 9 ~ 8C G P l 9 3 5 9 (161,a n o t h e r oral cephalosporin with a s p e c t r u m of activity like cephalexin and cefaclor, was well-absorbed orally in man and produced prolonged serum concentration^.^^ Interest in p r o d r u g forms of parenteral cephalosporins has continued with f u r t h e r studies on T-2588,70

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c e f u r o x i m e axeti171-74 aiid w a t e r soluble e s t e r s of aminothiazole derivatives.75 Publications also appeared describing SAR studies on t h e cephamycin MT-I 41,76977 and laboratory and/or clinical studies on cefpimizole (U-63 I 96E), 789 79 cefodizime,80-83, B M Y -28 14 2 , 8 4 4 6 ce f pi rom e ( HR -8 I 0) 879 88 and cefonicid.89

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Penicillins - Researchers at Beecham synthesized t h e 60,-formamidopenicillins and 7 a-formamidocephalosporins from t h e corresponding 6 a o r 7 a-methylthio derivatives b a single, m e r c u r y c a t a l y z e d , reaction with N,N-bis(trimethylsily1)f o r m a m i d e . 9 l This work paralleled t h e discovery of t h e naturally-occurring 7a-formamidocephalosporins. BRL36650 (El,t h e parenteral 7a-formamidopencillin having a piperacillin-like 7-acyl function, displays potent, broad-spectrum activity with MIC values below 1.0 ug/ml against most Gram-negative b a c t e r i a , including Pseudomonas. It is essentially devoid of a c t i v i t y against Gram-positive bacteria comparing well both in vitro and in vivo with c e f t a z i d i m e against Pseudomonas species and with c e f o t a x i m e and a z t r e o n a m versus t h e Enterobacteriacae. BRL36650 is stable to bacterial l3-lactamases, e v e n t h e chromosomally-mediated Type 1 13-lactamases produced by Enterobacter and Pseudomonas species. Preliminary pharmacokinetic studies in man show it to b e well t o l e r a t e d and to exhibit a favorable pharmacokinetic p r 0 f i l e . ~ 5 The synthesis, a n t i b a c t e r i a l activity and 8-lactamase stability of a group of 6 a-hydroxymethylpenicillins was reported.96 Penicillin analogs also were reported in which t h e 2-position E m d i m e t h y l groups h a v e been removed97, t h e 6-amide NH group was replaced by 0, C and S,98 and t h e 6-amide function was replaced by a vinyl group.99 Additional papers w e r e published on pharmacokinetic studies in laborator animals and man of t h e orally-absorbed p r o d r u g s lenampicillin (KBT-1585)104101 and bacmecillinam. 102 Penems - The synthesis and biological evaluation of a series of 2-alkyl(aryl)oxy and 2-alkylthiopenems w e r e r e p 0 r t e d . 1 ~ 3 - ~ 0 5 Extensive in vitro and in vivo laboratory evaluations of t h e parenteral penem SCH34343 showni m have potent activity against a broad-spectrum of Cram-positive and Gram-negative b a c t e r i a including Bacteroides species but not Pseudomonas aeruginosa.106-109 SCH34343 is s t a b l e to a variety of plasmid and chromosomal B-lactamases.l10 Following parenteral dosing in rats and dogs 41-45% of unchanged drug was e x c r e t e d in t h e urine.ll1 Like t h e y a r e with thienamycin, PBPs 2, l a and I b a p p e a r t o b e t h e primary t a r g e t s f o r 18.112 The syntheses and in vitro antibacterial activities of a series of 2-heteroc clylthiomethylpenems, s o m e of which displayed potent activity, w e r e published. I d

rE-

Carbapenems - The t o t a l synthesis of L646,591 (19) and a comparison of i t s essential chemical and biological properties w i t h t h o s e of thienamycin w a s published.1 l 4 2 is chemically stable, highly resistant to renal dipeptidase-I and retains high & vitro a n t i b a c t e r i a l activity. A SAR study of a group of 5 , 6 c i s c a r b a p e n e m s related to epithienamycin concluded t h a t relative affinities f o r e s s e n t i a l PBPs a r e m o r e important in determining antibacterial a c t i v i t y than

Chap. 13

@-Lactam Antibiotics

Dunn

a r e permeability effects and 13-lactamase production.1 The syntheses o f 2-B-alanyloxymeth 1, 2-glycyloxymethyl and 2-methyl analogs of thienamycin w e r e described.l y6 These analogs showed only weak a c t i v i t y against P. aeruginosa though t h e y displayed potent, broad-spectrum a c t i v i t y towa-d Gram p o s i t i v e and o t h e r Gram-negative bacteria. Analogs of thienamycin and compound 19 in which t h e 3 c a r b o x y l group w a s replaced by a t e t r a z o l e rin w e r e t e n times less a c t i v e & & v than their carboxyl counterparts.lT7 A stereocontrolled, t o t a l synthesis of (2) thienarnycin was published.118 Carbapenams OA-6129D and -E w e r e isolated from fermentation of a Streptomyces and postulated to b e intermediates in t h e biosynthesis of t h e corresponding carbapenems.11 CH

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SCH CH OCONH

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Monocyclic B-lactams - 5482,531 (201, a n orally-adsorbed p r o d r u g e s t e r of t h e parenteral monobactam SQ82,291 w a s reported.120 In t h e s e compounds t h e N-1 sulfonate group present in a z t r e o n a m was replaced by a n oxyacetic a c i d moiety. H e r e also, rnethylation at C-4 improves antibacterial activity and 13-lactamase stability.1 21 Compound 21 exhibited poor activity against Gram-positive and anaerobic b a c t e r i a b u r with t h e exception of Pseudomonas species, displayed potent a c t i v i t y against t h e Enterobacteriaceae comparing favorably with amoxicillin, cephalexin, c e f a c l o r and c e f u r o x i m e against susceptible organisms. Like a z t r e o n a m , has highest affinity f o r PBP-3. A f t e r oral administration of 2 to mice, 18% was recovered as in t h e urine.122 T h e carboxyl group of t h e N-1 -oxyacetic acids was replaced with t e t r a z o l e , sulfonate, phosphonate and phosphinate groups; & v a c t i v i t y against susceptible Gram-negative bacteria decreased in t h e o r d e r C O O H = SO H > t e t r a z o l e = P(R)02H.123 Comprehensive reviews w e r e published on SAR13%125 and on t h e influence of ring-activating substituents at t h e N-1 position of monocyclic 13-lactams.126 Substitution of t e t r a z o l e or tetrazole-N-acetic acid moieties f o r t h e N-1 sulfonate group produced derivatives having only m o d e r a t e to poor activities.1 279128 The 4- a-fluoromethyl derivative BO-1165 (2) is m o r e potent in vitro than a z t r e o n a m against t h e Enterobacteyiaceae, is similar against Pseudomonas, and is s t a b l e to most 8-lactamases.1 L y Papers w e r e published o n t h e synthesis and in v i t r o a c t i v i t i e s of 4-hydroxymethyl, 4-acyloxymethy1130 and 4-alkoxycarbonyl analogs of aztreonam. 13l Human pharmacokinetics of Rol7-2301 (AMA-1080) w e r e reported. 132 A chlorinated analog of nocardicin A was isolated f r o m a Streptomvces species. 339134

(g,

20

-R

-X

CH,

coon

2

H

-OCH,COOCH,COOCICH3

F

-SO,H

I,

l.2

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13-Lactamase Inhibitors - A novel penicillanic acid sulfone, YTR-830 (2), was shown to b e more e f f e c t i v e than sulbactam in reducing t h e MICs of ampicillin o r amoxicillin against G r a m p o s i t i v e a n d Gram-negative organisms and compared favorably with o r , in s o m e cases, was superior to clavulanic acid.135,137 A brief overview of t h e 13-lactamases and t h e i r inhibition w a s pub1ished.l 38 Several publications described studies on t h e n a t u r e of inactivation of 13-lactamases by various inhibitors. Penicillanic acid sulfone appears to inhibit irreversibly t h e RTEM B-lactamase f r o m E. coli by forming a crosslink within t h e enzyme. The crosslink is a 13-aminoacrylaie f r a g m e n t derived f r o m C-5, C-6, C-7 of t h e inhibitor.139 The novel inhibitor 2 a l s o a p e a r s to i n a c t i v a t e t h e RTEM 13-lactamase by t h e s a m e kind of r n e c h a n i ~ m . ~ 4 0The E-isomer of 24 is not a substrate, inhibitor o r inactivator of t h e enzyme. Easton and K n o w l e s n l studied t h e effectiveness of five different n-lactams at inhibiting t h e TEM-2 B-lactamase. They c o r r e l a t e d inhibition of t h e isolated e n z y m e with t h e ability of t h e inhibitors to reduce t h e MICs of ampicillin in i n t a c t cells which produce this 13-lactamase. The best inhibitors in whole cells w e r e those t h a t required t h e f e w e s t number of molar equivalents to inhibit t h e purified enzyme. By this criteria, t h e effectiveness of inhibitors studied decreased in t h e o r d e r carbapenems > clavulanic acid > quinacillin sulfone > sulbactam. Unlike clavulanic a c i d and sulbactam, which are irreversible inhibitors o f 13-lactamases, t h e c a r b a e n e m SF2103A was found to act as a tight-binding, c o m p e t i t i v e inhibitor 1 t 2

.

23

3

Enzymatic Synthesis of Novel B-Lactams - The progress made in r e c e n t y e a r s in unraveling t h e biosynthetic pathway t h a t converts t h e Arnstein tripeptide, L- a -aminoadipyl-Lcysteinyl-D-valine (ACV), into penicillins and cephalosporins has opened a new avenue to synthesizing novel B-lactams. The research of Baldwin and Demain and Wolfe has demonstrated t h a t tripeptides r e l a t e d to ACV c a n act as substrates f o r t h e normal biosynthetic enzymes and thereby produce modified 13-lactams. Thus, using purified enzyme preparations AC-(D-allylglycine), AC-(D-isoleucine) and AC-(D-norvaline) h a v e been converted by this method into 2-ally1 and 2-ethyl penicillins accompanied by varying proportions of cephams, homocephams and homocephems. 143,144 More recently, f o u r pathway enzymes f r o m Streptomyces clavuligerus h a v e been immobilized on a n ion-exchange resin, and, in t h e presence of appropriate cofactors, s e l e c t e d tripeptides w e r e converted into modified penicillins o r cephalosporins.145 Enzyme specificity requirements d i c t a t e t h a t L- a -aminoadipyl-Lcysteinyl moieties comprise t h e first t w o a m i n o acids of t h e tripeptide. Modified penicillins thus w e r e produced by substituting t h e appropriate D-aminoacid f o r D-valine. Using this approach t h e nucleus of ceftizoxime, containing a D-a -aminoadipyl side chain on t h e 7-amino group, was synthesized. References I. 2.

3. 4.

5.

6. 7. 8. 9.

C.C. Sanders and W.E. Sanders, Jr., Rev. Infect. Dis., 5, 639 (1983). J.E. Bryan, ed., "Antimicrobial Drug Resistance", Academic Press, New York, N.Y., 1984, C h a p t e r s 1-3. L.J. R i f f a n d P. Hedrick, R e c e n t Adv. Clin. Ther., 3, 19 (1983). S.L. Barriere and J.F. Flaherty, Clin. Pharm., 2, 351 (1984). R. Kemp, Med. 1. Aust., 437 (1984). G.L. Drusano, S.C. Schimpff and W.L. Hewitt, Rev. Infect. Dis., 6 , I 3 (1984). L.J. Riff a n d E. Chow-Tung, R e c e n t Adv. Clin. Ther., 3, 3 (1983); 27 ( 1 982). L. Cama, Fortschr. Antirnikrob. Antineoplast. ChemotKer., C.M. Cimarusti, J. Med. Chern., 27, 247 (1984).

Lc,

I,

Ir).

I I. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 2 2. 2 3. 24. 25. 26. 27. 28. 29. 30. 31. 32. 3 3. 34. 35. 36. 37. 38. 39. 40. 41.

4 2. 4 3. 44.

4 5. 46. 4 7.

48. 49.

50. 51. 5 2. 5 3. 5 4. 5 5. 5 6. 57. 58. 59. 60. 61. 62.

6 3.

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C.H. O'Callaghan, Med. Lab. Sci., 2, 279 (1984). I (1982). C.H. O ' C a l l a g h a n , Forstchr. Antirnikroh. Antineoplast. Chemother., 7 (I982). H. Breuer, Fortschr. Antimikrob. Antineoplast. Chernother., W. D u e r c k h e i m e r , Forstchr. Antirnikrob. Antineoplast. Chernother., 17 (1982). I 1 0 3 (1984). R. Labia and C. Morin, 1. Antibiot., 2, M. Brufani a n d L. Cellai in "X-Ray Crystallogr. Drug Action, 9 t h C o u r s e Int. Sch. Crystallogr.", A.S. Horn, C.J. D e R a n t e r , eds., Oxford Univ. Press, Oxford, UK, 1984, p. 389. A. Tornasz, C o n t e m p . Issues Infect. Dis., I (1984). Y. F u k a g a w a a n d 1. Tomoyulti, Drugs P h a r m . Sci., 3, 237 (1984). A.L. Demain a n d N.A. Solomon, eds., "Antihiotics Containing t h e Beta-Lactarn S t r u c t u r e " , P a r t I, Springer-Verlag, New York, N.Y., 1983. A.L. Demain a n d N.A. Solomon, eds., "Antihiotics C o n t a i n i n g t h e B e t a - L a c t a t n Structure", P a r t II, Springer-Verlag, New York, N.Y., 1983. E. J. Vandarnme, ed., "Biotechnology of Industrial Antihiotics", Marcel Dekker, New York, N.Y., 1984, C h a p t e r s 3-7. K. Hakenbeck, J-V. Holtje a n d H. Lahischinski, ed., "Target Penicillin: Murein S a c c u l u s B a c t . Cell Walls Archit. G r o w t h , Proc., Int. FER4S Syrnp., d e c r u y t e r , Berlin, FRG, 1983. M.I. Page, Acc. Chem. Res., 17,I 4 4 (1984). V.1. P a g e a n d P. P r o c t o r , J. Am. C h e m . SOC., 1_06,3820 (1984). W.S. F a r a c i a n d R.F. P r a t t , J. Am. C h e m . SOC., 1 0 6 , 1489 (1984). 1. Nishikawa and K. Tori, 1. Med. Chern., g,165771984). 8. C o e n e , A. Schanck, 1. D e r e p p e a n d V. Van Lleerssake, 3. Med. Chem., 3,694 (1984). B.J. Graves, D.B. Boyd a n d K.R. Lipkowitz, J. Antibiot., 2, 1642 (1984). J. Lamotte-Brasseur, G. Dive a n d 1. Ghuysen, Eur. 7. Med. Chem., 19,319 (1984). D.B. Boyd, J. Med. Chern., 11,6 3 (1984). M.J. Scanlan, I.H. Hillier, E.E. Hodgkin, R.P. S i d e b o t h a m , C.M. Warwick a n d R.H. Davies, Int. 7. Q u a n t u m Chern., lo,231 (1983). 227 (1984). D.B. Boyd, J. Antihiot., P.D. Singh, M.G. Young, J.H. lohnson, C.M. C i m a r u s t i a n d R.R. Sykes, J. Antihiot., 2,7 7 3 (I 984). I. Shoji, T. Kato, R. Sakazaki, W. N a g a t a , Y. Terui, Y. Nakagawa, M. Shiro, K. Matsurnoto, T. 1486 (1984). H a t t o r i , T. Yoshida a n d E. Kondo, J. Antihiot., 2, H. Ono, Y. Nozaki, N. K a t a y a m a a n d H. O k a z a k i , 1. Antihiot., 11,1 5 2 8 (1984). S. H a r a d a , S. Tsubotani, H. On0 a n d H. O k a z a k i , 1. Antihiot., 71536 (1984). 5. Tsubotani, T. Hida, F. K a s a h a r a , Y. Wada a n d S. Harada, J. Antihiot., 2,1546 (1984). Y. Nozaki, K. Okonogi, N. Katayarna, H. Cno, 5. H a r a d a , M. K o n d o a n d H. O k a z a k i , J. Antihiot., 2, 1 5 5 5 (1984). 1. Goto, K. S a k a n e , Y. Nakai, T. Teraji a n d T. Kamiya, 1. Antihiot., 5 3 2 (1984). J. Goto, K. S a k a n e , Y. Nakai, T. Teraji a n d T. Kamiya, I. Antibiot., 2, 546 (1984). J. G o t o , K. S a k a n e a n d T. Teraji, J. Antihiot., 37, 557 (1984). K. Sakane, T. K a m i m u r a , Y. Yokota, Y. M a t s u m o t o , Y. Mine, H. Kikuchi, S. G o t o a n d S. Kuwahara, 24th ICAAC, 731 (1984). Y. Mine, H. S a k a m o t o , T. Hirose, 5. Nakarnoto a n d H. Kikuchi, 24th ICAAC, 7 3 2 (1984). T. Une, T. Ikeuchi, Y. Osada, H. O g a w a , K. S a t o a n d 5. Mitsuhashi, 24th ICAAC, 729 (1984). H. T a c h i z a w a , K. Matsubayashi, T. K u r a t a , S. S h i n t a n i a n d 0. O k a z a k i , 24th ICAAC, 7 3 0 (1984). I. Nakayarna, N. Nagano, K. Nakano, T. Shihanuma, Y. Murakarni a n d 5. Susaki, 24th ICAAC, 737 (1984). S. Goto, S. Miyazaki, M. O g a w a , Y. Kaneko a n d 5. Kuwahara, 24th ICAAC, 7 3 4 (1984). T. Yokota, R. Yoshida and E. Suzuki, 24th ICAAC, 736 (1984). M. Nakashirna, M. Mizumura, H. Hiruma a n d L1. K i t a m u r a , 24th ICAAC, 738 (1984). H. klatsui, M. Korniya, C. lkeda and A. Tachihana, Antimicroh. A g e n t s Chernother., 3,204 (1984). S.F. Grappel, L. Phillips, C.L. Dunn, D.R. 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W.E. Wright, J.A. Eudaly and R.J. Johnson, 24th ICAAC, 228 (1984). D.A. Preston, F.T. Counter, P.W. Ensminger, J.L. O t t and J.R. Turner, 24th ICAAC, 229 (1984). F.T. Counter, P.W. Ensminger, J.L. O t t , D.A. Preston and J.R. Turner, 24th ICAAC, 230 (1984). J.R. Turner, D.L. Kau, C.E. Pasini, J.F. Quay, J.F. Stucky 11, and H.R. Sullivan, 24th ICAAC, 231 (1984). H.W. Culp, W.D. Daniels, D.L. Kau, C.E. Pasini, J.F. Quay, J.F. Stucky I1 and H.R. Sullivan, 68. 24th ICAAC, 232 (1984). 69. W. Tosch, R. Schnell and 0. Zak, 24th ICAAC, 233 (1984). T. Yasuda, A. Yotsuji, 5. O k a m o t o and S. IMitsiihashi, 24th ICAAC, 224 (1984). 70. 71. D. Sommers, M. VanWyk, P.E.O. Williams and S.M. Harding, Antimicrob. Agents Chernother., 25, 344 (1984). 72. S.M. Harding. P.E.O. Williams and J. Ayrton, Antimicrob. Agents Chernother., 25, 7 8 ( I 984). A.B. Straughn, V.C. Veyer, A.L. Finn and J.M. Chubh, 24th ICAAC, 592 (1984): 7 3. 74. C.M. Ginsburg, G.H. McCracken, Jr. and L. 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Finegold, 24th ICAAC, 219 (1984). 110. H.C. Neu, N.X. Chin and P. Labthavikul, 24th ICAAC, 740 (1984). C. Lin, J. Veals, H. Kim, M. Chung, E. Radwanski and S. Symchowicz, 24th ICAAC, 591 (1984). Ill. 64. 65. 66. 67.

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117. 118. 119. 120.

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123. 124.

125.

126. 127. 128. 129. 130. 131. 132.

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