Chapter 11. Antibiotics

Chapter 11. Antibiotics

A N N U A L REPORTS I N M E D I C I N A L C H t h l l S I KY- S e c t i o n I11 Editor: - 103 - Ii C h e m o t h e r a p e u t i c Agents George...

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George B. Whitf i e l d , The Upjohn Company , Kalamazoo, Michigan C h a p t e r 11. A n t i b i o t i c s Herman Hoeksema and L o r r a i n e C . Davenport The Upjohn Company, Kalamazoo, Michigan

T h i s c h a p t e r w i l l b e l i m i t e d t o t h o s e a n t i b i o t i c s f o r which a n t i b a c t e r i a l a c t i v i t y h a s been d e m o n s t r a t e d . A n t i b i o t i c s which a r e d e s c r i b e d e x c l u s i v e l y a s a n t i t u m o r , a n t i f u n g a l and a n t i v i r a l a g e n t s a s w e l l a s s u b j e c t s r e l a t e d t o b i o s y n t h e s i s are excluded. Included is a very limited s e c t i o n on 6-lactam a n t i b i o t i c s .

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G e n e r a l - The 1 7 t h I n t e r s c i e n c e C o n f e r e n c e on A n t i m i c r o b i a l Agents and Chemotherapy, f o r which a b s t r a c t s were p u b l i s h e d was concerned w i t h i t s u s u a l wide v a r i e t y of a n t i b i o t i c s u b j e c t s . Z u r i c h h o s t e d t h e 1 0 t h I n t e r n a t i o n a l Congress of Chemotherapy which emphasized c l i n i c a l t o p i c s i n t h e a n t i b i o t i c f i e l d . 2 The p i l o t volume of a p r o j e c t e d new s e r i e s , c a l l e d Topics i n A n t i b i o t i c Chemistry, w a s p u b l i s h e d . A m i n o c y c l i t o l s - L a r g e numbers of c l i n i c a l r e p o r t s on e x p e r i e n c e s w i t h aminoc c l i t o l a n t i b i o t i c s c o n t i n u e d t o a p p e a r , i n c l u d i n g a r a t h e r e x t e n s i v e review‘ on v a r i o u s a s p e c t s of t h e i r u s e . C l i n i c a l e f f o r t on new aminoc y c l i t o l s a p p e a r e d t o c e n t e r on n e t i l m i c i n , 1 - N - e t h y l s i s o m i c i n , which i s a c t i v e a g a i n s t some of t h e g e n t a m i c i n - r e s i s t a n t o r g a n i s m s . In general the p r e l i m i n a r y i n f o r m a t i o n which w a s r e p o r t e d l a s t y e a r h e l d up i n t h e c u r r e n t expanded s t u d i e s . I n c o m p a r a t i v e p h a r m a c o l o g i c a l s t u d i e s 5 of g e n t a m i c i n , 2 , and n e t i l m i c i n , t h e l a t t e r a p p e a r e d t o produce more p r e d i c t a b l e blood l e v e l s . Another s t u d y 6 r e p o r t e d f a v o r a b l e c l i n i c a l r e s p o n s e s f o r 70% of p a t i e n t s i n f e c t e d w i t h s u s c e p t i b l e s t r a i n s of Enterobacteriaceae and Pseudomonas aeruginosa. D e s p i t e lower n e p h r o t o x i c i t y i n e x p e r i m e n t a l a n i m a l s , some of t h e s e p a t i e n t s d i s p l a y e d some r e n a l i n v o l v e m e n t , a s s u g g e s t e d by e l e v a t e d BUN and serum c r e a t i n i n e and t h e a p p e a r a n c e of g r a n u l a r c a s t s . S e v e r a l o t h e r report^^,^,^^ l o o n l y showed v e r y low i n c i d e n c e s of t o x i c i t y . A new h i g h - p r e s s u r e l i q u i d c h r o m a t o g r a p h i c a s s a y of n e t i l m i c i n i n plasma’ gave r e s u l t s which c o r r e l a t e d w e l l w i t h microbiological assays.

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S y n t h e t i c m o d i f i c a t i o n s of g e n t a m i c i n and kanamycin a f f o r d e d a number of a c t i v e compounds. Hydroxy-amino-acylates of g e n t a m i c i n B , 2. and 4 , had g r e a t l y enhanced a n t i m i c r o b i a l a c t i v i t y , b u t t h e i r t o x i c i t i e s were correspondingly higher. Two l a b o r a t o r i e s r e p o r t e d ’ 3 9 1 4 c o n v e r s i o n s of kanamycin B , 5, t o kanamycin C , 6, and 6’-deoxykanamycin C , utilizing n i t r o u s a c i d d e a m i n a t i o n a t t h e 6’ p o s i t i o n of s u i t a b l y p r o t e c t e d i n t e r m e d i a t e s . Only weak a c t i v i t y w a s shown by _Z a g a i n s t most of t h e microorganisms t e s t e d . A n o v e l d e r i v a t i v e , l-N-[(S)-4-amino-2-hydroxybutyl]

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Pssudomonas a e r u g i n o s a GN573 w a s used i n t h e p r e s e n c e of ATP and MgS04 t o p h o s p h o r y l a t e kanamycin B s p e c i f i c a l l y a t t h e 3 ’ p o s i t i o n . T r e a t m e n t w i t h s i l y l a t i n g a g e n t s g a v e t h e c h l o r i d e which w a s s u b s e q u e n t l y h y d r o g e n a t e d t o g i v e kanamycin B. S i n c e i n a c t i v a t i o n of s p e c t i n o m y c i n o c c u r s by a d e n y l a t i o n a t t h e 9p o s i t i o n , t h e a n a l o g s 9-chloro-9-deoxy-4(R)-dihydrospectinomycin, and i t s 9-e i m e r , and 9-deoxy-8,9-epimino-4(R)-dihydrospectinomycin were p r e p a r e d . 2g A l l t h r e e were d e v o i d of a n t i b a c t e r i a l a c t i v i t y . A s p e c t i n o mycin r e s i s t a n t Neissericr g o n o r r h o e a e w a s s t u d i e d 2 7 w i t h no f i n d i n g of spectinomycin i n a c t i v a t i o n . Chromosomal m u t a t i o n w a s s u g g e s t e d a s c a u s a tive

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S t r a i n s of Staph lo and gentamicin2‘ phosphot r a n s f e r a s e s . Another s t r a i n of t h a t o r g a n i s m a l s o produced a n a m i k a c i n modifying 3 ’ - p h o s p h o t r a n s f e r a s e w h i l e remaining s e n s i t i v e t o t h e a n t i b i o t i c . 3 0 F i v e s t r a i n s of E s c h e r i c h i a c o l i h a v e been i s o l a t e d which i n a c t i v a t e e x t r a c e l l u l a r streptomycin i n l a r g e q u a n t i t i e s . 31 Alkaline p h o s p h o t a s e l i b e r a t e d i n o r g a n i c p h o s p h a t e from t h e i n a c t i v e compound b u t t h e r e m a i n i n g s t r e p t o m y c i n - l i k e compound had no a c t i v i t y . Plasmid-induced r e s i s t a n c e of a c l i n i c a l l y i s o l a t e d Pseudomonas aeruginosa s t r a i n t o kanamycin, t e t r a c y c l i n e , c h l o r a m p h e n i c o l , and s t r e p t o m y c i n w a s r e l a t e d t o decreased c e l l permeability r a t h e r than t o i n a c t i v a t i n g d e r i v a t i z a t i o n . 32 More i n a c t i v a t i n g enzymes h a v e been f o u n d .

coccus a u r e u s e l a b o r a t e d b o t h kanamycin-neomycin*’

Among t h e new m i c r o b i a l l y produced a m i n o c y c l i t o l s were s e v e n g e n t a m i c i n - r e l a t e d s u b s t a n c e s , 17-23, i n t h e b r o t h of a Mieromonospora s p e c i e s which produced e i g h t e e n a d d i t i o n a l known a n t i b i o t i c s . 3 3 B i o l o g i c a l d e t a i l s were n o t r e p o r t e d beyond a m e n t i o n of b r o a d a n t i b a c t e r i a l a c t i v i t y . a Nocardia-produced a m i n o c y c l i t o l , had myo-inosamine a s t h e LL-BM123aY a m i n o c y c l i t o l m o i e t y . 34

24,

F o r t i m i c i n C , 25, e l a b o r a t e d by Micromonospora o l i v o a s t e r o s p o r a was a c t i v e a a i n s t kanamycin-, g e n t a m i c i n - , and t o b r a m y c i n - r e s i s t a n t E. c o l i strains. $5 Neomycin C h a s now been s y n t h e s i z e d by r e g i o s e l e c t i v e g l y c o s i d a t i o n between s u i t a b l y p r o t e c t e d r i b o s t a m y c i n and neosamine C . 36

8-Lactams - C l i n i c a l e v a l u a t i o n s t u d i e s were i n i t i a t e d f o r SCE-963, 2 6 , a new b r o a d s p e c t r u m p a r e n t e r a l c e p h a l o s p o r i n . 3 7 9 38 A n o t h e r new p a r e n t e r a l cephalosporin f o r c l i n i c a l i n v e s t i g a t i o n i s CGP 7174E (SCE-129), 27, a compound which compared f a v o r a b l y w i t h g e n t a m i c i n i n t h e treatment of experimental Pseudomonas a e r u g i n o s a i n f e c t i o n s . 3 9 9 4 0 FR13301 i s a t h i r d p a r en t era1 c e p h a l o s p o r i n r e c e i v i n g

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clinical attention. I t i s most a c t i v e a g a i n s t Gram-negative o r g a n i s m s 4 ' a s i s a f o u r t h c l i n i c a l c a n d i d a t e , FR10024, 28.42 R e p o r t s on new m i c r o b i a l l y - p r o d u c e d 6-lactam a n t i b i o t i c s i n c l u d e d N - a c e t y l t h i e n a m y c i n , 3, from Streptomyces c a t t l e y a , 4 3 t h r e e compounds and MM 4550, from Streptomyces olivaceus (MM 1 7 8 8 0 , 30,44MM 13902, 31,45 3 2 4 5 ) , and f o u r e p i t h i e n a m y c i n s from SLrepLomyces f l a v o g r i s e u s . 4 6 The e p i t h i e n a m y c i n s showed a n t i m i c r o b i a l a c t i v i t i e s and B-lactamase s u s c e p t i b i l i t i e s which v a r y w i d e l y amongst e a c h o t h e r . 4 7 The t h i e n a m y c i n s s h a r e a c h a r a c t e r i s t i c i n s t a b i l i t y . 48 The f i r s t t o t a l s y n t h e s i s of t h e B-lactamase i n h i b i t o r , c l a v u l a n i c a c i d , 33, w a s r e p o r t e d . 4 9 The s t a r t i n g compound w a s (?)-4-methylthioazetidin-2-one, 34. M a c r o l i d e s - I n a symposium on t h e m a c r o l i d e a n t i b i o t i c s h e l d a t t h e 1 7 3 r d Meeting of t h e American Chemical S o c i e t y , 50 b i o l o g i c a l a c t i v i t i e s were c o r r e l a t e d w i t h s t r u c t u r e . R o s a m i c i n , a b a s i c m a c r o l i d e w i t h a 16-membered r i n g , h a s shown some c l i n i c a l p r o m i s e i n t h e t r e a t m e n t of b a c t e r i a l p r o s t a t i t i s . 5 1 SP127, a p r o t e i n , h a s been found t o enhance t h e a c t i v i t y of m a c r o l i d e a n t i b i o t i c s by promoting t h e i r a b i l i t y t o p e n e t r a t e t h e b a c t e r i a l c e l l . 52 53 The p r o d u c t i o n by Micromonospora c a p i l l a t a of t h r e e new m a c r o l i d e s , These a n t i b i o t i c s , 3 7 , w i t h 16-membered r i n g s w a s r e p o r t e d . 5 4 9 5 5 M-4365AlX1, and G 2 g e n e r a l l y i n h i b i t e d t h e same o r g a n i s m s t h a t were s e n s i t i v e t o r o s a m i c i n and t h e j u v e n i m i c i n s which were coproduced i n t h e f e r m e n t a t i o n . The r e v i s i o n of t h e s t r u c t u r e s of o l i g o m y c i n s A and C 3 8 , 3 9 , showed them t o b e c l o s e l y r e l a t e d t o o l i g o m y c i n B and r u t a m y c i n . 5635,

36,

A r e v i e w on t h e s y n t h e s i s of m a c r o l i d e compounds57 i n c l u d e d n o t o n l y t h e m a c r o l i d e a n t i b i o t i c s b u t ansamycins, m a c r o t e t r a l i d e s , m a c r o d i l i d e s , e t c . None of t h e m a j o r 1 4 o r 16-membered m a c r o l i d e a n t i b i o t i c s h a s y e t been s y n t h e s i z e d , a l t h o u g h a s e m i s y n t h e s i s of carbomycin B , 2, from c a r b o n o l i d e B and t h e two c a r b o h y d r a t e f r a g m e n t s w a s a c c o m p l i s h e d . 5 8 C l a d i n o s e a n a l o g s of carbomycin B were p r e p a r e d and found t o a p p r o x i m a t e t h e i n v i t r o a n t i b a c t e r i a l a c t i o n of carbomycin B. 59

5, 42,

A s t u d y c o r r e l a t i n g t h e s t r u c t u r e and a c t i v i t y of t h e a c y l a t e d l e u c o m y c i n s , 43, showed t h a t a f r e e 9-hydroxyl g r o u p i s n o t e s s e n t i a l f o r r i b o somal b i n d i n g . However, 4"-O-acylation d i d a f f e c t b i n d i n g which d e c r e a s e d

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Antibiotics

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P e p t i d e s - S e v e r a l new m i c r o b i a l l y produced members of t h e l a r g e s t c l a s s of The c h e m i s t r y , b i o g e n e s i s , and f u n c t i o n s of a n t i b i o t i c s were d e s c r i b e d . t h e s e p e p t i d e s were r e c e n t l y r e v i e w e d . 6 1 Polymyxin F from Bacillus circuZans,62and polymyxins S 1 , 44, and T I , 45, from BacilZus poZyrnyxa63,64 were r e c e n t l y i s o l a t e d and r e p o r t e d t o h a v e t h e u s u a l polymyxin a n t i b a c t e r i a l s p e c t r a , a l t h o u h T i s more a c t i v e a g a i n s t G r a m - p o s i t i v e ~~ organisms. T a l l y s o m y c i n s g 5 7 6 k a r e b l e o m y c i n - l i k e , w h i l e n o ~ i h e p t i d eand micrococcin P68 are r e l a t e d t o t h i o s t r e p t o n , p l a u r a c i n is i n t h e v i r g i n i a mycin sub-group. 69 S t r u c t u r e s a r e u n a v a i l a b l e f o r s e v e r a l o t h e r new p e p t i d e s , NRC-501, 70 compound 4 1 , 0 1 2 , " and FCRC-53. 7 2 Two u n i q u e d i p e p t i d e s were i s o l a t e d , plumbemycin A , 46,73and c a i r o m y c i n B , The l a t t e r had a n t i f u n g a l and a n t i b a c t e r i a l p r o p e r t i e s . LL-BM547, viomycinl i k e , i s a n a n t i t u b e r c u l a r a n t i b i o t i c produced by a Nocardia s p e c i e s . 75 N e w o r r e v i s e d s t r u c t u r e s a p p e a r e d f o r a number of t h e o l d e r a n t i b i o t i c s s u c h as t h e b a c i l l o m y c i n s L, 76 t h e c y c l o s p o r i n s , 49-51, 77 978 and b e r n i n a m y c i n , 52. 79 Sulfomycin I w a s found t o c o n t a i n 2 , 5 - b e r n i n a m y c i n i c a c i d . 8 o S t r u c t u r e s f o r t h e p e p t a i b o p h o 1 8 ' sub-group, a l a m e t h i c i n I and 11, e m e r i c i n s IV and 111, _ 55, _ 5 6 , 8 2 and a n t i a m o e b i n I, 57,83 were -953 -954 e l u c i d a t e d . S t e n o t h r i c i n w a s found t o b e a complex of p e p t i d e s v a r y i n g i n t h e k e t o a c y l m o i e t y of t h e g e n e r a l f o r m u l a s , 6-ketoacyl-D-cys (0 3H)-L-Val.DSer-LLys-Sar-DaThr-LSer-LDap-OH. 84

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Chemotherapeutic Agents

W h i t f i e l d , Ed.

A 19-residue peptide with alamethicin-like a c t i v i t y i n l i q u i d b i l a y e r membranes h a s been s y n t h e s i z e d and t e s t e d . 85 V i r g i n i a m y c i n S r e d u c t i o n p r o d u c t s were p r e p a r e d , b u t t h e y were l e s s a c t i v e t h a n v i r g i n i a m y c i n S . 86 EM-49 was c o n v e r t e d t o a number of a c t i v e d e r i v a t i v e s by a c y l a t i o n and a l k y l a t i o n o f t h e t e r m i n a l amino g r o u p s of t h e 2 , 4 - d i a m i n o b u t y r i c a c i d r e s i d u e s . 8 7 Good a c t i v i t y was f r e q u e n t l y s e e n i n t h e G r a m - p o s i t i v e a r e a s w i t h d e c r e a s e d a n t i p s e u d o m o n a l a c t i v i t y . Plasmid-mediated p r i s t i n a m y c i n a c e t y l t r a n s f e r a s e , produced by a S t a hylococcus s t r a i n , 0 - a c e t y l a t e d t h a t a n t i b i o t i c , t h e r e b y i n a c t i v a t i n g i t . 518

When polymyxin B , immobilized on a g a r o s e b e a d s , was used t o s p e c i f i c a l l y d i s r u p t t h e o u t e r membrane of Gram-negative b a c t e r i a , s y n e r g i s m w i t h b a c i t r a c i n , r i f a m y c i n , o r lysozyme was s t i l l i n e f f e c t . Th;;,$;lymyxin B p l a y s i t s r o l e i n t h e s e c o m b i n a t i o n s a t t h e o u t e r membrane. P o l y e t h e r s - Mass s p e c t r a l d a t a g 1 r e q u i r e d t h e a s s i g n m e n t of t h e 4+ & R ttr , HOOC 0 methylsalinomycin s t r u c t u r e t o CH n a r a s i n , 58. A n a l y s e s of t h e k : Et C H I CH, E t H '~C-NMR s p e c t r a o f s a l i n o m y c i n , 58 RI=CHi. R)=OH. R 3 = H 59,92 and n a r a s i n g 3 i n d i c a t e d a n 59 R,=R,=H, R:=OH 60 RI=CHI: R ? . R,*O 61 RI=R:=Ri=iI equatorial orientation for the new m e t h y l group. Another ionop h o r e , A28086B, 9, d i f f e r s from n a r a s i n i n t h e C-ring o n l y , w i t h a keto function replacing t h e s e c o n d a r y h y d r o x y l . 9 1 Streptomyces albus (ATCC12838) OH e l a b o r a t e d deoxy- (0-8) s a l i n o mycin, 61, and a second p o l y e t h e r d i f f e r i n g from 6 1 by e p i m e r i z a t i o n at position 17 Mutalomycin, 6 2, produced by Streptomyces M mutabiZis (NRRL 8 0 8 8 ) , i s a c t i v e 63 against Gram positive bacteria and Eimeria t e n e l l a . 95 C a r r i o m y c i n , 63, a n o t h e r new p o l y e t h e r , c o n t a i n s t h e s u g a r r e s i d u e t h a t i s p r e s e n t i n s e p t a m y c i n , A130A ( l e n o r e m y c i n ) and A-204A a c c o r d i n g t o a c r y s t a l l o g r a p h i c s t r u c t u r e a n a l y s i s of t h e t h a l l i u m s a l t . 9 6 The a g l y c o n e was similar t o lonomycin. 3

.-

& ..

H

OH

64

0

0

T e t r a c y c l i n e s - EMD33,330, 64, w a s one of a number of 6t h i a t e t r a c y c l i n e s of s y n t h e t i c o r i g i n . 9 7 I t s minimum i n h i b i t o r y c o n c e n t r a t i o n s f o r a broad r a n g e of o r g a n i s m s were lower t h a n t h o s e of d o x y c y c l i n e and t e t r a c y c l i n e , e x c e p t f o r Pseudomoms aeruginosa where i t was less a c t i v e . T e t r a c y c l i n e - r e s i s t a n t s t r a i n s were s e n s i t i v e . High and p r o l o n g e d serum c o n c e n t r a t i o n s were s e e n i n mice and d o g s , w i t h p e a k s 2-3 t i m e s t h o s e of d o x y c y c l i n e .

M i s c e l l a n e o u s A n t i b i o t i c s - The s e a r c h f o r new a n t i b i o t i c s a g a i n a f f o r d e d a number of new a c t i v i t i e s which a r e summarized i n T a b l e 1.

Chap.

11

Antibiotics

Hoeksema, Davenport

109

-.

TABLE I

NEW ANTlBIOTIC ENTITIES

s t r u c t u r e or StructurelType

A c t iv i t y

'G

A-35512 Baumycins C h l o q u i nomyci n CP-41043 CP-41494 CP-42752 CP-43038 CP-43139 OernethylblaSticldin 5 3-epi-Oeaxynegamycin Olhydrogranaticln Oihydromocimycin FrUStUlosinol G-7063-2 Glydnothricin Hydraxynybomycin K-520

Glyc~peptldelVancomycln Anthracycline

G + . AT G'

1

1

6'. Gt,

G-

AF

G'. c+

G-

Gt. G'. G'.

G - , AP Vihrio q G - . AF G-

.'G

G', ,'G ,'G

Leucyl-3-e~i-deoxynegamycin

MR-144 Complex Mdrcellomycin MUIettdrnyCl" Nocamycln Norplicacetin 01-1804 05.4742 Pseudomonlr A c i d B R h o d i r u b i n r A. B Saframyci"s

102 N Y C I e a r l de Hydrazlde/hina Acid 65 Hocimyci n 66 67 Streptothricio Nybonycin

-

h l no A c i d l Hydra21 de Anthracycllne Anthrdcycllne Anthrdcycl Ine

'G

AF, AT G - , AT G - , AT AT

-

G', G'. G t , r&cobvcserio GI, 6 - . AF 6'. AT G'

68

c

Anthracycline 69 Anthracycline

-

SC30532

Secalomr Acld F striatins 1.41348 Trichorin A 299 ( B i r a n h y d r o g r a n a t i c i n , ] 19

.'G

G'.

G-

70 Secdlonic A d d s

-

6 - . AF

Phenazine

G-

epiPolythladiketoplpera2lne 71 72

G+ G'

792

.

.'G

.

n

103 104

105 106 107

108

109 110 111 104 112 113.114 113.114 115 116

117

118 119 120 121 122 123 !24 125 126 105 105 127

11

CH,-C-CH 71 R=CHOHCHj.

ti0

in

-

G - , AF. AT

-72 R=cocn,. -

h

98 99 100 101

G-

G'.

Refereace

R-=H R;=H

Me

S t r u c t u r e s were p u b l i s h e d f o r a number of a n t i b i o t i c s which have been knuwn L o r sljiiie time i n c l u d i n g nogalamycin, Zl2* s t e f f imycin and s t e f f i lZ9 p l u r a m y c i n A , and n e o p l u r a m y c i n , 76, 3 0 a l l of mycin B , 74, 75, which show b o t h a n t i b a c t e r i a l and a n t i t u m o r a c t i v i t y . E l u c i d a t i o n s of t h e s t r u c t u r e s of n e o t h r a m y c i n s A and B , 7 8 , 7 9 , ' 3 1 LA-1 3,'3 2 g r i s e o r h o d i n A 8 1 , 1 3 3 m e l i n a c i d i n s 11, I11 82, 83,*4 a n d a m b r u t i c i n 8 4 , ( f o r m e r l y a c i d S)n5 were a l s o d i s c l o s e d . Halomicins A and C , 85, x y i 3 b , r e ansamycins and t h e s i l v e r s a l t of aplasmomycin, was shown by c r y s t a l l o g r a p h y t o b e a m a c r o c y c l i c d i l a c t o n e w i t h boron i n t h e c e n t e r . 1 3 7 The c o n f i g u r a t i o n a l a s s i g n m e n t s of a l b o n o u r s i n , 88, were made by s y n t h e s i z i n g t h e f o u r p o s s i b l e i s o m e r s . 3 8 R e v i s i o n s of s t r u c t u r e s f o r e v e r n i n o m i c i n ' 3 9 a t t h e C-3 of 14' and e v e r n i t r o s e , 89, a n t h e l m y c i n ( h i k i z i m y c i n ) , 90, 140 r i m o c i d i n , 91, f r u s t u l o s i n , 92, O 7 were p u b l i s h e d .

77,'

87,

'

T o t a l s y n t h e s e s f o r m i s c e l l a n e o u s a n t i b i o t i c s u b s t a n c e s were r e p o r t e d T h e s e i n c l u d e d o x a ~ i n o m y c i n , ' e~l~a i o m y c i n 1 4 3 d l for the f i r s t time. c e r u l e n i n , 1 4 4 7 1 4 5 9 1 4 6 (t)-methylenomycin A,147 minosaminomycin, 1 4 8 l y d i mycin ( a - d e h y d r o b i o t i n ) ,149 d l - o r f i r o m y c i n , 1 5 0 mitomycins A and C , 1 5 1 v e r m i c u l i n e ' 5 2 and mimosamycin. 7 5 3

110

S e c t . I11

-

C h e m o t h e r a p e u t i c Agents

W h i t f i e l d , Ed.

noom: CH

,o

RR

OH

~

87 -

k

V a r i o u s s t u d i e s f o r e c a s t e d p o t e n t i a l b e n e f i t s f o r t h e u s e of a n t i b i o t i c s i n combination. B e n z y l p e n i c i l l i n displayed remarkable a c t i v i t y a g a i n s t a number of Bacteroides frayilis s t r a i n s when combined w i t h c l a v u l a n i c a c i d . 1 5 4 C l i n i c a l t r i a l s f o r a m i x t u r e of r i f a m y c i n and t r i m e t h o p r i m were recommended on t h e b a s i s o f in vitro s t u d i e s showing t h a t t h e m i x t u r e d e c r e a s e d t h e i n c i d e n c e of r e s i s t a n c e . 5 5 A n o t h e r r e p o r t s t a t e d t h a t n o v o b i o c i n e f f e c t i v e l y e l i m i n a t e d p l a s m i d s from s e v e r a l b a c t e r i a l s p e c i e s . 1 5 6 Polymyxin B and r i f a m y c i n w a s a n e f f e c t i v e combinat i o n f o r 8 o u t of 1 2 p a t i e n t s w i t h r e s i s t a n t n o s o c o m i a l Serratia marcescens i n f e c t i o n s . 157 Novobiocin d e m o n s t r a t e d a " p r o b e n i c i d e f f e c t " w i t h 8 - l a c t a m a n t i b i o t i c s i n t h e t r e a t m e n t of e x p e r i m e n t a l SalmonElla schottmuelleri i n f e c t i o n s i n mice. 1 5 * Combinations o f f o s f o m y c i n w i t h c h l o r a m p h e n i c o l o r a m p i c i l l i n were e f f e c t i v e i n t h e t r e a t m e n t of Salmonella t y p h i i n f e c t i o n s i n humans.159 Fosfomycin, a l o n e , w a s a l s o shown t o b e p a r t i c u l a r l y e f f e c t i v e i n t h e t r e a t m e n t of humans i n f e c t e d w i t h G r a m n e g a t i v e b a c i l l i and G r a m - p o s i t i v e c o c c i . 160

Chap. 11

Ant ib io tic s

Hoeksema, Davenport

111

REFERF,NCES

1. 2.

3. 4. 5. 6.

7.

8.

9.

in. 11. 12. 13. 14.

15.

16. 17. 18, 19. 20.

21. 22.

23. 24. 25. 26. 27. 28, 29. 10 31. 32. 33. 34. 15. 36. 37.

38. 39.

40. 41. 42.

4J. 44. 45. 46. 47. 4H. 49.

50. 51. 52.

53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67.

6H .

69. 70.

71. 72.

73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83.

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A . Ahou-Zeid. M . M . Ahd E l - t i m i d and Y. M. S h e h a r a . 2 . A l l & . M l k r o h i a l . 16,337 ( 1 9 7 6 ) . U n i t e d S t a t e 6 P a t e n t 4 , 0 0 1 , 3 9 7 . January 4 , 1977. J . A . Chan, T. 'I. Wei, C . C . K a l i t a . D . 1. Warnick. A . I.. Carretsaii and A. A . Aaralos, I. A n t i h i o t . 0. 1140 ( 1 9 7 7 ) . 8. K . P a r k , A . l i l r o t a and H . S a k a i , Agrir. B i o l . Chem. 573 ( 1 9 7 7 ) . I . R . Shirni, N . A b e d a l l a h and S . f a t h y . A n t i m i ~ r o h . A g . Chemotherap. 11,373 ( 1 9 7 7 ) . W . .It McCahren, C. 0 . Morton. M . P . Kunstrnann and C . A . E l l e s t a d . J . Org. Chem. 42. 1282 ( 1 9 7 7 ) . F . B e s s o n , F. Peypoox, G . M i c h e l . and L. Delcambe. E o r . 1. Biochem. 61 (1977). R . T r a b e r , M . Kuhn, t i . L o o s l i , W. P a c h e and A . v o n w a r t h u r g . Ilelv. Chim. A c t a 60, 1568 ( 1 9 7 7 ) . R . T r a b e r , H. Kuhn, A . Rbegger, H. I . i c h t i , H . 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Sect. I11

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Chemotherapeutic Agents

Whitfield, Ed.

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Tetrahedron Lett., 863 (1977). 139. A. K. Ganguly. 0 . Z. S a r r e . A. T. McPhail and K. D. Dnan. J . C . S . Chrm. Canm., 313 (1977). 140. S . E n n i f a r and 8. C. DBS, S . M. Nash. R . Nagarajan, 41 (1977). 141. R. C. Pandey and K. L. Rinehart. J r . , J . Antihiot. 0, 146 (1977). 142. S. Desernardo and H. Weigele. J . Org. Chem. 42, 109 (1977). 143. R. A. Hose and M. Matsuo. J . Am. Chem. S O C . 99. 1643 (1977). 144. R. K. Boeckman. Jr. end E. W. ?hornas, ibid. 99, 2R05 (1977). 145. A. A. .Jakubowski, F. S . G u r i e c . J r . arid H . Tishler. Tetrahedron Lett.. 2399 (1977). 146. E. J . Corey and D. R. Williame, 3847 (1977). 147. R. H . Scarborough. J r . and A. 8. Smith, 111, J . Am. Chem. S O C . 99, 7085 (1977). 148. K. Inuma. S. Kondo. K. Haeda and H. Umezswa, Bull. Chem. S O C . J a p . 1850 (1977). 149. C. F. Field. W. J. Zally, L. H. Sternbach and J . F. Blount. J . Org. Chem. Q. 3853 (19%). 150. F . Nakatsubo, T. Fukuyama. A . J . Cocuzza and Y. Kishi, .I. Am. Chem. Soc. 9.8115 (1977). 151. T. Fukuyama, F. Nakatsubo, A. J . Cocuzza and Y . Kiahi, Tetrahedron Lett., 4295 (1977). 152. D. Seebach. B . S e w i n g , H. Kalinavski. W. hbosch and 8. Renger, Angew. Chem. Int. Ed. Engl. 16. 264 (1977). 153. H. Fukumi, H. Kurlhara, T. Hsta, C. Tamura and R . Hiehima, A. Kubo, T. A r n i , Tetrahedron Lett., 3825 (1977). 154. R. Wise. Lancet 2 , 145 (1977). 155. V. Arioli, H. Berti. G. Camiti. E. Rosei and L. C. SIIve8tri, J . Antimicrob. Chemother. 2, 87 (1977). 1 5 6 . G. 1.. McHugh and N. M. Swartr, Antimicrob. Ag. Chemotherap. 12, 423 (1977). 157. R . C. Ostmsoo, B. T. Field8 and C. M. Nolan, ibid. 12. 655 (1977). 158. A. K. Hiller, E . Celozzi and 8 . A. Pelak, J . Antibiot. 30, 893 (1977). 159. A. Rodriguez. A. Gallego, T. Olay and J . M. Mate, Chemotherapy 12,Suppl. 1, 247 (1977). 160. R. F u j i i , ibid. 23, Suppl. 1, 234 (1977).

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