Aminocyclitol Antibiotics - American Chemical Society

18 Enzymes Modifying Aminocyclitol Antibiotics and Their Roles in Resistance Determination and Biosynthesis JULIAN DAVIES

Downloaded by UNIV LAVAL on July 11, 2016 | http://pubs.acs.org Publication Date: August 4, 1980 | doi: 10.1021/bk-1980-0125.ch018

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


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 .



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



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


18.

DAVIES


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


327


328

AMINOCYCLITOL ANTIBIOTICS

Table III.


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


18.

DAVIES



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



Table VI.

Antibiotic Biosynthesis in Which Plasmid Involvement Has Been Suggested


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


18.

DAVIES

331


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


T



332


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.


18.

DAVIES


333


References 1.

Daniels, P. J. L. "Aminoglycosides"; Kirk-Othmer, Encylo pedia of Chemical Technology", John Wiley and Sons, Inc. New York, 1978; 2, p. 819.

2.

Davies, J.; Smith, D. I. Ann. Rev. of Microbiol., 1978, 32, 464.

3.

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K. L. Jr. Pure Appl. Chem., 1977, 49, 1361.

November 15, 1979.


Aminocyclitol Antibiotics - American Chemical Society

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