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18 Enzymes Modifying Aminocyclitol Antibiotics and Their Roles in Resistance Determination and Biosynthesis JULIAN DAVIES
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Department of Biochemistry, University of Wisconsin—Madison, Madison, WI 53706 The aminocyclitol antibiotics constitute a group of highly active antibacterial agents that are used extensively in the treatment of severe Gram-negative infections (1). At present a number of these compounds are in use (Table 1); they can be con veniently divided into several distinct chemical classes. The 4,5-disubstituted and 4,6-disubstituted 2-deoxystreptamines represent the two largest subclasses; with the exception of the novel compound apramycin, the remaining aminocyclitol antibiotics do not contain 2-deoxystreptamine but other cyclitols. The recent development of new aminocyclitols, either iso lated from nature (e.g., sorbistin, fortimicin) or by the chemical modification of existing compounds (e.g., amikacin, netilmicin) indicates that interest in this important group of agents is maintained, and one can anticipate that aminocyclitols will con tinue to be of use in the treatment of infectious disease. The continuing development of new members of this group is necessitated by the continued appearance of new forms of anti biotic resistance in clinical isolates (2). Whereas, r e s i s t a n c e to a n t i b i o t i c s such as the 3-lactams i s due to the presence of one type of enzymatic m o d i f i c a t i o n (3-lactamase), r e s i s t a n c e to the a m i n o c y c l i t o l s has been shown to i n v o l v e any of s e v e r a l d i f f e r e n t enzymatic m o d i f i c a t i o n s that i n c l u d e ^ - p h o s p h o r y l a t i o n , O-adenylylation, or N - a c e t y l a t i o n . To date, some 12 d i f f e r e n t enzymatic m o d i f i c a t i o n s have been c h a r a c t e r i z e d i n c l i n i c a l i s o l a t e s of Gram-negative and Gramp o s i t i v e b a c t e r i a (Table 2). As we w i l l discuss l a t e r , s i m i l a r types of a c t i v i t i e s are found i n a n t i b i o t i c - p r o d u c i n g organisms. The s t r u c t u r e m o d i f i c a t i o n s occur at s e v e r a l of the hydroxyand amino-groups as e x e m p l i f i e d i n the case of kanamycin Β (Figure 1). Not a l l of these m o d i f i c a t i o n s are known to occur simultaneously, although there are a number of examples i n which b a c t e r i a l s t r a i n s encode as many as four of these d i f f e r e n t m o d i f i c a t i o n s at the same time (3). The enzymatic m o d i f i c a t i o n s are u s u a l l y plasmid-coded and o f t e n t r a n s f e r a b l e ; aminoglycoside r e s i s t a n c e i s a common c h a r a c t e r i s t i c of r e s i s t a n c e plasmids i s o l a t e d from b a c t e r i a i n c l i n i c a l s i t u a t i o n s . W i t h i n each 0-8412-0554-X/80/47-125-323$05.00/0 © 1980 American Chemical Society
Rinehart and Suami; Aminocyclitol Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
324
AMINOCYCLITOL
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Table I.
ANTIBIOTICS
Aminocyclitol Antibiotics in Clinical Use (Human and Veterinary)
STREPTOMYCIN
NEOMYCIN
KANAMYCIN A , B
AMIKACIN
DlHYDROSTREPTOMYCIN
PAROMOMYCIN
TOBRAMYCIN
NETILMICIN
LlVIDOMYCIN
GENTAMICIN
RIBOSTAMYCIN
SISOMICIN
SPECTINOMYCIN
Table II.
APRAMYCIN
Enzymes Modifying Aminocyclitol Antibiotics Found in
Resistant Gram-Negative
Modification
Enzyme
Acetylation
and Gram-Positive Isolates
Typical Substrates*
A A C (2')
Gentamicin, tobramycin
A A C (6')
Tobramycin, kanamycin, amikacin,
A A C (3)
Gentamicin, tobramycin,
AAD
Amikacin, tobramycin,
neomycin Adenylylation
Phosphorylation
(4')
(gentamicin^) kanamycin
kanamycin
A A D (2")
Gentamicin, tobramycin,
A A D (3")
Streptomycin, spectinomycin
AAD
Streptomycin
(6)
Α Ρ Η (3')
Kanamycin,
Α Ρ Η (3")
Streptomycin
Α Ρ Η (2")
Gentamicin
Α Ρ Η (5")
Ribostamycin
kanamycin
neomycin
* N o t all substrates are listed; each e n z y m e exists i n a variety o f f o r m s w i t h d i f f e r e n t sub strate ranges. "•"Gentamicin C,
is a s u b s t r a t e f o r A A C ( 6 ' ) , a n o t h e r c o m p o n e n t o f t h e g e n t a m i c i n c o m -
|Q
p l e x , g e n t a m i c i n C . , is n o t .
Rinehart and Suami; Aminocyclitol Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
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18.
DAVIES
Enzymes Modifying Aminocyclitol Antibiotics
325
group o f enzymes (modifying a given s i t e ) there e x i s t s d i f f e r e n t isozymic v a r i a n t s o f the enzymes that d i f f e r i n t h e i r aminoglycos i d e s u b s t r a t e range. The d i f f e r e n t forms appear to be e l i c i t e d i n response t o d i f f e r e n t a n t i b i o t i c s e l e c t i o n pressures; f o r example, the o r i g i n a l i s o l a t e s of gentamicin r e s i s t a n t organisms (that were s e n s i t i v e to tobramycin) possessed a 3-N-acetyltransf e r a s e that favored gentamicin as s u b s t r a t e (4-). (Apparently) w i t h i n c r e a s i n g use of other aminoglycosides, new 3-N-acetylt r a n s f e r a s e s w i t h broader s u b s t r a t e ranges, a s s o c i a t e d w i t h broader r e s i s t a n c e phenotypes, have been c h a r a c t e r i z e d (5) (Table 3). Newer r e s i s t a n c e phenotypes i n b a c t e r i a may imply new r e s i s t a n c e mechanisms, but they can a l s o be the r e s u l t of combin a t i o n s of p r e - e x i s t i n g types. The enzyme content of a r e s i s t a n t s t r a i n cannot be p r e d i c t e d on the b a s i s of r e s i s t a n c e phenotype alone. The f u n c t i o n of the aminoglycoside-modifying enzymes i s o b v i o u s l y r e l a t e d t o the r e s i s t a n c e mechanism. The enzymatic m o d i f i c a t i o n can be shown to be d i r e c t l y r e l a t e d to the determination of r e s i s t a n c e by the i s o l a t i o n of p o i n t mutants t h a t reduce or e l i m i n a t e the enzyme a c t i v i t y ( 6 ) , and a l s o by the e x i s t e n c e o f transposable r e s i s t a n c e elements t h a t have coding c a p a c i t y s u f f i c i e n t only f o r the aminoglycoside modifying enzyme (7). I n s p i t e of these s t u d i e s the exact b i o c h e m i c a l mechanism of R-plasmid coded aminoglycoside r e s i s t a n c e i s not known. The aminoglycosides exert t h e i r i n h i b i t o r y a c t i o n on bact e r i a by b i n d i n g to ribosomes and i n t e r f e r i n g w i t h p r o t e i n s y n t h e s i s (8). Drugs such as amikacin and gentamicin b i n d t o both ribosome subunits (9) ( F i g . 2) i n c o n t r a s t t o streptomycin, that binds only t o the 30 S subunit (10). The mechanism of r e s i s t a n c e could be due to d e t o x i f i c a t i o n of the drug o r i n t e r ference w i t h drug t r a n s p o r t as a r e s u l t of enzymatic m o d i f i c a t i o n . Since b i n d i n g to ribosomes i s b e l i e v e d to be an e s s e n t i a l component of the entry of aminoglycosides i n t o the c e l l , i t i s d i f f i c u l t t o d i s t i n g u i s h between these two p o s s i b i l i t i e s . Studies w i t h r a d i o a c t i v e l y - l a b e l l e d gentamicin have shown that drug uptake i s d r a s t i c a l l y reduced i n r e s i s t a n t s t r a i n s , and that there i s no d e t o x i f i c a t i o n of a n t i b i o t i c i n the c u l t u r e medium (7). Bryan and h i s c o l l a b o r a t o r s have proposed a reasonable model f o r aminoglycoside t r a n s p o r t and r e s i s t a n c e , but conv i n c i n g proof i s l a c k i n g (11). A r o l e f o r a s p e c i f i c polyaminet r a n s p o r t system i n the uptake of aminoglycosides has been i n d i c a t e d (12). Notwithstanding t h i s controversy, the r o l e of the aminoglycoside-modifying enzymes i n r e s i s t a n t c l i n i c a l i s o l a t e s i s c l e a r . A n t i b i o t i c m o d i f i c a t i o n and r e s i s t a n c e are correlated. However, the r o l e s of these enzymes i n other b a c t e r i a l s t r a i n s i s l e s s evident. I n s t u d i e s of the p o s s i b l e o r i g i n s of aminoglycoside-modifying enzymes, i t has been shown that most aminoglycoside-producing organisms (Streptomyces) possess enzyme
Rinehart and Suami; Aminocyclitol Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
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326
AMINOCYCLITOL
ANTIBIOTICS
adenylylation
Figure 1.
Enzymatic modification of kanamycin Β by resistant strains
Ο
0.4
0.8
Gentamicin
1.2
1.6
concentration
2.0
(μ,Μ)
Figure 2. Binding of H-gentamicin to 30S (O) and 50S (A) ribosome subunits of resistant E. coli. Experiments performed by equilibrium dialysis (S. Perzynski). 3
Rinehart and Suami; Aminocyclitol Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
18.
DAVIES
Enzymes Modifying Aminocyclitol Antibiotics
a c t i v i t i e s s i m i l a r to those found i n c l i n i c a l i s o l a t e s (13) (Table 4). The a c t i v i t i e s are s i m i l a r i n that they c a t a l y z e the same type o f r e a c t i o n (e.g., 3'-(^-phosphorylation) and share many of the same s u b s t r a t e s . However, examination of p o s s i b l e sequence homologies, a t the n u c l e i c a c i d or p r o t e i n l e v e l , between aminoglycoside-modifying enzymes i n r e s i s t a n t c l i n i c a l i s o l a t e s and those of aminoglycoside-producing s t r a i n s , have proved negative (14). Thus, there i s no d i r e c t evidence that producing organisms are the o r i g i n s of the r e s i s t a n c e determinants. That they can serve as r e s i s t a n t determinants i s evident from gene t r a n s f e r experiments; the 3 -^-phosphotransferase of B a c i l l u s c i r c u l a n s (producing b u t i r o s i n ) a c t s as t y p i c a l phosphotransferase r e s i s t a n c e determinant i n _E. c o l i (15). Even i f the aminoglycoside-modifying enzymes of r e s i s t a n t i s o l a t e s d i d o r i g i n a t e i n the corresponding a n t i b i o t i c producing organisms, the e v o l u t i o n of the plasmid encoded enzymes may have been so divergent as to e l i m i n a t e any d i r e c t sequence homologies i n the genes. I t i s of i n t e r e s t to note t h a t plasmid encoded mechanisms of r e s i s t a n c e t o s e v e r a l d i f f e r e n t a n t i b i o t i c s i n c l i n i c a l i s o l a t e s are i d e n t i c a l t o those found i n producing organisms or c l o s e l y r e l a t e d Streptomyces (Table 5 ) . What i s the f u n c t i o n of aminoglycoside-modifying enzymes i n producing s t r a i n s ? The two obvious r o l e s are: a) t o p r o t e c t the producing organism from the a n t i b i o t i c ( s ) that i t makes, or b) t o c a t a l y z e the formation of a s p e c i f i c a l l y p r o t e c t e d or a c t i v a t e d i n t e r m e d i a t e . Of course, a dual f u n c t i o n might a l s o be i n v o l v e d . One might a l s o imagine that the aminoglycosidemodifying enzymes p l a y no r o l e i n the b i o s y n t h e s i s or r e s i s t a n c e to an a n t i b i o t i c , and might be i n v o l v e d w i t h other f u n c t i o n s . In t h i s case, the aminoglycoside would be assumed to be a g r a t u i t o u s member of the enzyme's s u b s t r a t e range. Studies of the e f f e c t s of s o - c a l l e d " c u r i n g " agents, have thrown some l i g h t on t h i s matter. These chemicals promote the s e g r e g a t i o n of p l a s m i d - f r e e progeny during b a c t e r i a l c e l l d i v i s i o n ; t h i s i s t h e i r primary mode of a c t i o n . Since the presence of plasmids has now been i m p l i c a t e d i n the b i o s y n t h e s i s of s e v e r a l d i f f e r e n t a n t i b i o t i c s (Table 6 ) , we can examine the e f f e c t s of c u r i n g agents on b i o s y n t h e s i s and r e s i s t a n c e i n aminoglycoside-producing organisms. The most e x t e n s i v e s t u d i e s , so f a r , have been done by Yagisawa et_ a l . (23) , who examined neomycin r e s i s t a n c e and 3'-O-phosphotransferase p r o d u c t i o n i n a number of v a r i a n t s of Streptomyces f r a d i a e obtained by treatment w i t h the c u r i n g agent, a c r i d i n e orange. I n a d d i t i o n , the a b i l i t y of the "cured" s t r a i n s to s y n t h e s i z e neomycin when grown i n the presence of the p r e c u r s o r 2-deoxystreptamine, was t e s t e d . The r e s u l t s of these experiments can be summarized as follows : 1. Treatment of neomycin-producing Streptomyces f r a d i a e w i t h a c r i d i n e orange, produces a t l e a s t two d i s t i n c t c l a s s e s of neomycin nonproducing v a r i a n t s . 1
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Rinehart and Suami; Aminocyclitol Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
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AMINOCYCLITOL ANTIBIOTICS
Table III.
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I
GENTAMICIN,
II
III
IV
GENTAMICIN,
GENTAMICIN,
GENTAMICIN,
Aminocyclitol-3-N-Acetyltransferases of Different Substrate Ranges SISOMICIN
SISOMICIN,
SISOMICIN,
SISOMICIN,
TOBRAMYCIN
TOBRAMYCIN,
TOBRAMYCIN,
NEOMYCIN
NEOMYCIN,
APRAMYCIN
Table IV. Aminocyclitol-Modifying Enzymes in Aminocyclitol-Producing Strains
A n t i b i o t i c Produced
Strain
M o d i f y i n g Enzyme f
_S. f r a d i a e
neomycin
AAC(3), APH(3 )
Ά·
butirosin
AAC(3), APH(3 )
M. chalcea
neomycin
AAC(3), APH(3 )
S_. t e n e b r a r i u s
tobramycin
A A C ( 6 ) , AAC(2 )
S_. kanamycelicus
kanamycin
AAC(6 )
Streptomycin
APH(3"), APH(6)
circulans
ri
.§.· g s e u s
f
f
f
?
f
S. b i k i n i e n s i s
Rinehart and Suami; Aminocyclitol Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
18.
DAVIES
Enzymes Modifying Aminocyclitol Antibiotics
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Table V .
329
Antibiotic Resistance Mechanisms in Streptomycetes
Antibiotic
Organism
Mechanism of R e s i s t a n c e Reference
Aminoglycosides
Numerous Enzymatic m o d i f i c a t i o n Streptomyces m o d i f i c a t i o n of amino and r e l a t e d o r hydroxy groups species
Chloramphenicol
Numerous Enzymatic a c e t y l a t i o n Streptomyces of hydroxy-group (chlaramphenicol a c e t y l transferase)
16
3-Lactarns
Numerous Enzymatic h y d r o l y s i s of Streptomyces β-lactam r i n g (β-lactaand r e l a t e d mase) species
17
Erythromycin and other macrolides
Streptomyces Enzymatic m o d i f i c a t i o n erythreus of 23S ribosomal RNA
18
Thiostrepton
Streptomyces Enzymatic m o d i f i c a t i o n azureus of 23S ribosomal RNA
19
Lincomycin
Numerous Enzymatic m o d i f i c a t i o n Streptomyces of hydroxy-group
20
see Table IV
Rinehart and Suami; Aminocyclitol Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
AMINOCYCLITOL ANTIBIOTICS
Table VI.
Antibiotic Biosynthesis in Which Plasmid Involvement Has Been Suggested
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Antibiotic
Reference
Kasugamycin, a u r e o t h r i c i n
21
Chloramphenicol
22
Neomycin
23
Kanamycin
24
Methylenomycin
25
Ac t inomy c i n
26
Streptomycin
27
Macrolides
28
Tetracycline
29
Leupeptin
30
D - glucose
2-deoxystreptamine I
β
glucosamine (neosamine)
( paromamine) (neamine)
butirosin
Figure 3.
, neomycin (paromomycin)
Outline of the biosynthetic pathway to neomycin
Rinehart and Suami; Aminocyclitol Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
18.
DAVIES
331
Enzymes Modifying Aminocyclitol Antibiotics
2.
One c l a s s of nonproducers ( I ) was n e o m y c i n - r e s i s t a n t , synthesized normal amounts of 3 -0-phosphotransferase and would produce a n t i b i o t i c when grown i n the presence of 2 deoxystreptamine. 3. The second c l a s s o f nonproducers ( I I ) was neomycins e n s i t i v e , d i d not c o n t a i n phosphotransferase, and would not produce a n t i b i o t i c on 2-deoxystreptamine feeding. Although there are o b v i o u s l y s e v e r a l i n t e r p r e t a t i o n s of these d a t a , i t has been suggested t h a t , i n jS. f r a d i a e , both 3 -0phosphotransferase and a t l e a s t p a r t of the neomycin b i o s y n t h e t i c pathway (that concerned w i t h 2-deoxystreptamine s y n t h e s i s ) a r e plasmid encoded. The 3 -O-phosphotransferase i s r e q u i r e d f o r neomycin r e s i s t a n c e i n S^. f r a d i a e and p o s s i b l y a l s o f o r a step i n b i o s y n t h e s i s , although there i s no evidence f o r the l a t t e r . The c l a s s I nonproducers have presumably l o s t the c a p a c i t y to s y n t h e s i z e deoxystreptamine but r e t a i n the r e s t of the neomycin b i o s y n t h e t i c pathway. These s t r a i n s w i l l produce neomycin when supplemented w i t h 2-deoxystreptamine, s i n c e they are neomycin r e s i s t a n t (they have the 3'-0-phosphotransferase). S i m i l a r r e s u l t s have been obtained w i t h the paromomycin-producer S_. rimosus forma ρaromomycinus and the neomycin-producer, Micromono spora c h a l c e a (31). The f i n d i n g of plasmids i n a n t i b i o t i c - p r o d u c i n g Streptomyces and t h e i r i m p l i c a t i o n i n a n t i b i o t i c b i o s y n t h e s i s , has a number of i n t e r e s t i n g consequences f o r s t u d i e s of a n t i b i o t i c p r o d u c t i o n . In the f i r s t p l a c e , c u r i n g agents can be used to produce a new c l a s s of i d i o t r o p h s (32). I n the past N-methyl-N'-nitro-Nn i t r o s o g u a n i d i n e (NTG) has been favored f o r the p r o d u c t i o n of a n t i b i o t i c nonproducing d e r i v a t i v e s that can be used f o r " f e e d i n g " of p r e c u r s o r s t o produce n o v e l a n t i b i o t i c s (33). Since NTG i s a powerful mutagen that i s known to cause m u l t i p l e mutations (34, 35), the use of c u r i n g agents might i n c r e a s e the chances of o b t a i n i n g plasmid d e r i v a t i v e s s p e c i f i c a l l y i n v o l v e d w i t h a n t i b i o t i c (or other secondary m e t a b o l i t e ) s y n t h e s i s . I n a d d i t i o n , NTG may cause a number o f l e t h a l mutations and mutations i n primary metabolism that a f f e c t both c e l l growth and the a b i l i t y to produce a n t i b i o t i c s , that could not be supplemented exogeno u s l y . Once can a n t i c i p a t e that c u r i n g agents, that would not a f f e c t primary metabolism, may give d i f f e r e n t c l a s s e s of i d i o trophs i n which normal c e l l metabolism would not be a f f e c t e d . The evidence f o r plasmid involvement i n a n t i b i o t i c s y n t h e s i s i n Streptomyces i s s t i l l l a r g e l y c o i n c i d e n t a l . But, i f one considers the b i o s y n t h e s i s of an a n t i b i o t i c such as neomycin ( F i g . 3) i t can be reasoned that s e v e r a l of the steps i n v o l v e primary metabolism more c r i t i c a l l y than others. For example, the b i o s y n t h e s i s of r i b o s e i s a primary m e t a b o l i c f u n c t i o n , being r e q u i r e d f o r c e l l - w a l l b i o s y n t h e s i s among other t h i n g s . On the other hand, 2-deoxystreptamine i s almost c e r t a i n l y a secondary m e t a b o l i t e , concerned only w i t h a n t i b i o t i c b i o s y n t h e s i s . The ,
1
f
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T
Rinehart and Suami; Aminocyclitol Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
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b i o s y n t h e s i s of 2-deoxystreptamine i s l i k e l y to be plasmiddetermined w h i l e r i b o s e i s chromosomally encoded. Consistent w i t h t h i s n o t i o n i s the f a c t that a high p r o p o r t i o n of the i d i o t r o p h s of S^. f r a d i a e producing by c u r i n g agents, w i l l produce a n t i b i o t i c on supplementation w i t h 2-deoxystreptamine (23). As we know more about the b i o s y n t h e t i c pathways, other i n t e r mediates may be used f o r feeding; f o r example, we were able to o b t a i n one i d i o t r o p h of S^. rimosus forma paromomycinus that would produce a n t i b i o t i c i n the presence of paromamine but not 2-deoxystreptamine (31). This c o n s t i t u t e d a new c l a s s of i d i o troph f o r t h i s organism. I t i s probable t h a t , i n many i n s t a n c e s , mechanisms of a n t i b i o t i c r e s i s t a n c e i n Streptomyces (being concerned w i t h secondary metabolites) may a l s o be plasmid-encoded. This suggests the p o s s i b i l i t y of moving these a n t i b i o t i c r e s i s t a n c e s i n t o other members of the species (or even d i f f e r e n t genera) where an augmentation of a n t i b i o t i c r e s i s t a n c e might lead to higher c a p a c i t y f o r the production of an a n t i b i o t i c . In c o n c l u s i o n , s t u d i e s of the nature, d i s t r i b u t i o n , and f u n c t i o n of aminoglycoside-modifying enzymes have provided us w i t h d i r e c t i o n s t o new aminoglycosides, and t h e i r i s o l a t i o n i n new producing s t r a i n s can be used to p r e d i c t probable r e s i s t a n c e mechanisms to appear i n c l i n i c a l i s o l a t e s . The presence of plasmids i n Streptomyces that determine both a n t i b i o t i c b i o s y n t h e s i s and r e s i s t a n c e (although s t i l l not proven) i n d i c a t e s that much of the "genetic engineering" w i t h respect to a n t i b i o t i c b i o s y n t h e s i s has already been done by Nature. What i s r e q u i r e d now i s a greater knowledge of the b i o s y n t h e t i c pathways i n v o l v e d , and the r o l e s of plasmid-coded f u n c t i o n s ( d i r e c t l y and i n d i r e c t l y ) i n these pathways. With t h i s knowledge i t should be p o s s i b l e to use recent developments i n the genetics to Streptomyces, such as transformation (36) and f u s i o n (37), to make i n t e l l i g e n t approaches to improving the y i e l d s of a n t i b i o t i c s (not only the a m i n o c y c l i t o l s ) and i n producing modified compounds by microb i o l o g i c a l methods. Acknowled gement The author acknowledges the generous support of the N a t i o n a l I n s t i t u t e of Health and the N a t i o n a l Science Foundation i n t h i s work.
Rinehart and Suami; Aminocyclitol Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
18.
DAVIES
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