Agricultural Uses of Antibiotics - American Chemical Society

6

T r e n d s in the U s e o f F e r m e n t a t i o n P r o d u c t s in A g r i c u l t u r e

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on February 12, 2016 | http://pubs.acs.org Publication Date: September 18, 1986 | doi: 10.1021/bk-1986-0320.ch006

R. W. Burg R50G-121, Merck Institute for Therapeutic Research, Rahway, NJ 07065 By far the largest agricultural market for antibiotics is for feed additives. The bulk of this market is taken by antibiotics that are also used in human medicine. However, mounting concern over the hazards of increased resistance to antibiotics has encouraged the search for new types of antibiotics for this use. Some of these newer products are already taking an increasing share of the market. The discovery of the anticoccidial activity of monensin opened an entirely new field for the use of antibiotics in agriculture. The avermectins, a family of compounds with potent anthelmintic, insecticidal and acaricidal activity, have vividly demonstrated that fermentation products can have entirely unanticipated activities. Besides their u t i l i t y in animals, they show great promise for the control of insect pests of plants. Although antibiotics have found only a limited role in the control of plant diseases, the desire to find environmentally acceptable alternatives to the chemicals currently used has prompted new research efforts to discover fermentation products for use as pesticides. There has been a gradual evolution i n the types of fermentation products that have been developed for use i n a g r i c u l t u r e . This evolution has been punctuated by several major discoveries that have served to influence future work. The history begins with the accidental discovery of a new use for an a n t i b i o t i c that was already playing a major role i n the treatment of human diseases. There follows a deliberate search for new a n t i b i o t i c s unrelated to those used i n humans, the detection of a new a c t i v i t y for what had appeared to be a useless a n t i b i o t i c , and, f i n a l l y , the discovery of a family of compounds that has opened up an e n t i r e l y new area for the use of fermentation products i n agriculture and may well play a major role i n the control of both plant and animal diseases. 0097-6156/ 86/ 0320-0061 $06.00/0 © 1986 A m e r i c a n C h e m i c a l Society

In Agricultural Uses of Antibiotics; Moats, William A.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.

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AGRICULTURAL USES OF ANTIBIOTICS


Animal Health The market for animal health products i s estimated to be over $2 b i l l i o n i n the U.S. and nearly as much i n Western Europe. A n t i b i o t i c s dominate the animal health market, and feed additives account for about 50% of that market. A c l a s s i f i c a t i o n of the compounds used for animal health i s shown i n Table I. A n t i b i o t i c s can be used therapeutically to treat b a c t e r i a l , fungal and p a r a s i t i c i n f e c t i o n s . For this purpose, they can be given i n the feed, or administered o r a l l y , parenterally or t o p i c a l l y . A n t i b i o t i c s that are fed at subtherapeutic levels to improve the rate of growth and the feed e f f i c i e n c y are called "growth permittants". They act i n d i r e c t l y by a s t i l l unknown mechanism, although i t seems reasonable that i t i s their antibact e r i a l a c t i v i t y that i s important, and that they must act on a subpopulation of the i n t e s t i n a l f l o r a . Growth promotants act d i r e c t l y , through a physiological mechanism, to enhance growth; and they usually have estrogenic a c t i v i t y . They are administered parenterally, often i n the form of an implant. Table I.

C l a s s i f i c a t i o n of Agents Used for Animals A.

B. C.

Therapeutic Agents 1. A n t i b a c t e r i a l 2. Antifungal 3. A n t i p a r a s i t i c a. Endoparasiticides (1) A n t i c o c c i d i a l s (2) Anthelmintics b. Ectoparasiticides (1) Insecticides (2) Acaricides Growth Permittants Growth Promotants

Table II l i s t s the fermentation products licensed i n the U.S. for parenteral or t o p i c a l administration to animals. Most of these are also used to treat human i n f e c t i o n s . As important as these are for animal health, of far greater economic importance are the a n t i b i o t i c s that are incorporated into animal feeds. Feed Additives. Some a n t i b i o t i c s are also administered i n the feed for the treatment of disease. These are l i s t e d i n Table I I I . For the most part, they are used for the treatment of b a c t e r i a l i n f e c tions and are the same as those l i s t e d i n Table I I . Although these a n t i b i o t i c s are incorporated into the feed, their use d i f f e r s from what has become known as "feed additive a n t i b i o t i c s " or growth permittants. The era of feed additive a n t i b i o t i c s had i t s beginning i n the l a t e 1940's i n a c l a s s i c example of serendipity. Investigators at the Lederle Laboratories were searching for a more convenient source of "animal protein factor", a substance found i n l i v e r and other animal proteins that stimulated the growth of chicks fed a vegetable diet (1). [It had already been demonstrated by workers


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Fermentation Products Administered T o p i c a l l y or Parenterally

Name


in

EN

Type

Amikacin Ampicillin Bacitracin* Cephapirin Chlortetracycline Cloxacillin Dihydrostreptomycin* Erythromycin Gentamicin Hetacillin Kanamycin Lincomycin Neomycin Novobiocin Oxytetracycline Penicillin G Polymyxin B* Spectinomycin Tetracycline Tylosin Griseofulvin

Semisyn. aminocyc. Semisyn. p e n i c i l l i n Peptide Semisyn. cephalosp. Tetracycline Semisyn. p e n i c i l l i n Aminocyclitoi Macrolide Aminocyclitol Semisyn. p e n i c i l l i n Aminocyclitol

Ivermectin

Semisyn. avermectin

Zeranol

Semisyn.

Aminocyclitol Tetracycline Natural p e n i c i l l i n Peptide Aminocyclitol Tetracycline Macrolide Grisan

zearalenone

RE

Use UG

MA

OP

+ + +

+ + +

+ + + + + + + +

+ + + + + + +

+ +

+ +

+

+ + +

+

+ + +

+ + +

+ +

+

+ + +

+ +

+

+

Dermatophytic i n f e c tions Nematodes and arthropods Growth promotant

*Used only i n combinations EN = Enteric

Table compiled

RE = Respiratory tract UG • Uro-genital tract MA = M a s t i t i s OP = Ophthalmic from information obtained from (20).

at Merck and Co. that p u r i f i e d vitamin Βχ2 could replace the pro t e i n factor ( 2 ) ] . One of the materials that was tested was the dried fermentation mash of Streptomyces aureofaciens, the producer of c h l o r t e t r a c y c l i n e . The chicks grew faster and to a greater f i n a l weight than those fed a diet supplemented with l i v e r extract, and the growth was greater than could be accounted for by the con tent of vitamin Ή\2· The component of the fermentation mash responsible for the stimulation of growth was i d e n t i f i e d as chlor t e t r a c y c l i n e (3), and this a b i l i t y to enhance growth was quickly confirmed i n turkeys and swine. The era of feed additive a n t i b i o t i c s was launched. Oxytetracycline, b a c i t r a c i n and p e n i c i l l i n were soon added to the l i s t of a n t i b i o t i c s that could enhance growth and improve feed


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AGRICULTURAL USES OF ANTIBIOTICS Table I I I .

Fermentation Products Used as Feed Additives f o r the Treatment of Disease For Use In:


Name Bacitracin Chlortetracycline Erythromycin Hygromycin Β Lasalocid Lincomycin Monensin Neomycin Novobiocin Nystatin Oxytetracycline Penicillin G Salinomycin Streptomycin* Tylosin Virginiamycin

Poultry

Swine

Β Β Β Η C Β C Β Β F Β Β C Β Β

Β Β

Cattle

Sheep

Use Level (g/ton) 50- 500 50- 400 92- 185 812 68- 113 40- 100 90- 110 70- 140 200- 350 50 50- 500 50- 100 40- 60 75 100-1000 25- 100

Η Β Β

*Used only i n combination Β - antibacterial F • antifungal

C = Anticoccidial Η = Anthelmintic

Table compiled from information provided i n (21). e f f i c i e n c y . Table IV l i s t s the a n t i b i o t i c s used as growth permit tants i n the U.S. The levels at which these a n t i b i o t i c s are fed to increase the rate of gain and to improve feed e f f i c i e n c y are lower by a factor of 5 to 10 ( c f . Table I I I ) . There has been great concern that the feeding of low levels of a n t i b i o t i c s that are also used i n human medicine could lead to serious human health problems. There i s no question that bacteria develop resistance to these a n t i b i o t i c s , and that they can transfer t h e i r resistance to other bacteria, even to other species. There i s also no question that a n t i b i o t i c resistance has become a serious problem i n human medicine. However, the extent to which the feed ing of a n t i b i o t i c s to animals has contributed to the human health problem i s s t i l l unclear and a source of great controversy. In addition to the risks to human health, one must also con sider the benefits i n terms of cheaper meat and the saving of grain. In 1981, the Council for A g r i c u l t u r a l Science and Tech nology estimated that i t would cost consumers an additional $3.5 b i l l i o n per year i f the use of tetracyclines and p e n i c i l l i n were c u r t a i l e d (4). This estimate did not consider the p o s s i b i l i t y that these a n t i b i o t i c s might be replaced by others o f f e r i n g less r i s k .


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Table IV.

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Agriculture

Fermentation Products Used as Growth Permittants i n the U.S. For Use In:


Name Bacitracin Bambermycins Chlortetracycline Erythromycin Lincomycin Oxytetracycline Penicillin G Streptomycin* Tylosin Virginiamycin Lasalocid// Monensin// Salinomycin#

Sheep

Poultry

Swine

Cattle

+ + + + + + + + + +

+ + + +

+ + +

+

+ + + + +

+

+

Use Level g/ton

+ + +

4 -50 1 - 4 10 -50 5 -18 2-4 5 -50 2.4-50 12 -19 4 -50 5 -15 10 -30 5 -30

* Used only i n combination # Rumen additives + Increased rate of gain and improved feed e f f i c i e n c y Table compiled

from information provided i n (21).

Because of the desire to reduce the nontherapeutic use i n a n i mals of a n t i b i o t i c s that are also used i n human medicine, pharmaceutical companies have been searching for new types of a n t i b i o t i c s to be used exclusively as feed additives. B a c i t r a c i n , one of the f i r s t a n t i b i o t i c s to be used as a feed additive would f i t t h i s category. Two newer a n t i b i o t i c s , bambermycins and virginiamyc i n , are licensed for use i n poultry and swine (Table IV). These a n t i b i o t i c s are unrelated to any used i n human medicine and, along with lincomycin and t y l o s i n , are taking an increasing share of the market. Other a n t i b i o t i c s , including enramycin F, sold i n Japan, and avoparcin and tiamulin, sold i n the U.K., also f a l l into this category (Table V). There are some a n t i b i o t i c s s t i l l i n development i n the U.S. Merck i s hard at work on efrotomycin, and L i l l y has avilamycin and actaplanin (Table V). The l a t t e r i s being studied not only as a growth permittant but as a means of improving milk production i n dairy c a t t l e . Unfortunately, progress has been slow and development costs are high because of the stringent requirements of the Food and Drug Administration. Growth Promotants. D i e t h y l s t i l b e s t r o l was the major growth promotant i n use for many years. It was very e f f e c t i v e , increasing weight gain i n steers by 15 to 19% and feed e f f i c i e n c y by up to 12%. However, i t has now been banned i n most countries because of i t s reported carcinogenicity. The discovery of the one fermentation product that i s used as a growth promotant i s an interesting study i n epidemiology (5). In


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AGRICULTURAL USES OF ANTIBIOTICS Table V·

Name

Activity

Avoparcin Enramycin F Tiamulin Actaplanin* Downloaded by UNIV OF CALIFORNIA SAN DIEGO on February 12, 2016 | http://pubs.acs.org Publication Date: September 18, 1986 | doi: 10.1021/bk-1986-0320.ch006

Feed Additives Marketed Outside the or Under Development

Avilamycin* Efrotomycin*

Growth permittant Growth permittant Growth permittant Growth permittant, improved milk prod. Growth permittant Growth permittant

U.S.

Used i n

Poultry, C a t t l e , Swine Poultry, Swine Swine Cattle Poultry, Swine Poultry, Swine

*Under development

the midwestern U.S., there were reports of estrogenic effects i n swine that had been fed moldy corn. The fungus Gibberella zeae was i s o l a t e d from the corn, and extracts were shown to have estrogenic a c t i v i t y . A r e s o r c y l i c acid lactone, zearalenone, was isolated and shown to be responsible for the estrogenic e f f e c t s . The compound selected for commercial development was a reduction product, zearalanol or zeranol. Zeranol does not appear to have carcinogenic a c t i v i t y (5). It i s licensed for use as an implant p e l l e t i n beef c a t t l e and lambs (Table II) where i t has about 30 to 50 percent of the a c t i v i t y of d i e t h y l s t i b e s t r o l (6). A n t i c o c c i d i a l s . A new a n t i b i o t i c , monensin, discovered at the L i l l y Laboratories had an uninteresting gram-positive a n t i b a c t e r i a l spectrum. However, shortly after i t s discovery, i t was found to be cytotoxic to tumor c e l l s i n culture, and was isolated on the basis of that a c t i v i t y . As i s often the practice i n pharmaceutical research, i t was submitted to other assays and was found to have a n t i c o c c i d i a l a c t i v i t y i n a chick assay. It was shown to control infections by the s i x economically important species of Eimeria that infect chickens (7). This was an exciting discovery, and there were extensive discussions between representatives of marketing and research concerning the economic f e a s i b i l i t y of such a product. Fortunately, a dramatic increase i n the fermentation y i e l d was attained, and monensin became the dominant a n t i c o c c i d i a l i n the world. Although i t has a small therapeutic index, i t enjoys the unusual advantage of not succumbing to the development of resistance. Monensin belongs to the family of polyether ionophores. These compounds consist of a series of tetrahydrofuran and tetrahydropyran rings and have a carboxyl group that forms neutral s a l t s with a l k a l i metal cations. Their three-dimensional structure presents a l i p o p h i l i c hydrocarbon exterior with the cation encircled i n the oxygen-rich i n t e r i o r . They probably act by transporting cations through the l i p i d bi-layer of c e l l membranes, thereby preventing the concentration of potassium by the c e l l s . Evidence for this i s



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that high concentrations of potassium incorporated into the medium reverse the a c t i v i t y of ionophores again gram-positive bacteria. After the marketing of monensin began, there was a rush to discover more ionophores. The second ionophore to be licensed as a coccidiostat i n the U.S. was X-537A, f i r s t reported by investigators at the Nutley, NJ laboratory of Hoffmann-LaRoche i n 1951 (8), 16 years prior to the announced discovery of monensin. I t was t h e i r misfortune not to have tested t h e i r compounds against cocc i d i a . X-537A, now named l a s a l o c i d , d i f f e r s from most of the other ionophores i n i t s a b i l i t y to complex with divalent cations. Because of i t s smaller s i z e , two molecules can surround one divalent cation. Salinomycin i s also licensed i n the U.S. (Table I I I ) . At least two other ionophores, narasin and maduramicin, have been introduced elsewhere i n the world. Narasin i s a homologue of s a l i nomycin, and maduramicin i s noteworthy because i t i s e f f e c t i v e at a l e v e l of 5 g/ton, only 5 to 10% of the l e v e l required for the other ionophores· The discovery of the coccidiostat a c t i v i t y of monensin marks the second milestone i n the history of the use of fermentation products i n agriculture. U n t i l this discovery, the emphasis had been on the search for a n t i b i o t i c s with a n t i b a c t e r i a l a c t i v i t y . I t was now evident that fermentation products could be used for the control of p a r a s i t i c i n f e c t i o n s . Rumen Additives. The ionophores were found to possess a second remarkable u t i l i t y . Ruminants are walking fermentation vesseles that are able to convert r e l a t i v e l y useless, high cellulose vegetat i o n such as grass into protein. Although this i s a wonderful a b i l i t y , researchers, who seem never to be s a t i s f i e d with nature, have long sought to improve this fermentation. One product of the rumen fermentation, methane, i s of no value to the ruminant. The major fermentation products used by the ruminant are the short-chain f a t t y acids, acetate, butyrate and propionate. Acetate and butyrate can be used for energy, but propionate i s most useful for the synthesis of protein. I f the fermentation could be shifted to reduce methane, acetate and butyrate production and to increase the propionate, the feed e f f i c i e n c y and growth rate could improved. Monensin was tested i n a rumen fermentation assay at the L i l l y Laboratories, and i t was found to produce the desired s h i f t i n the fermentation (9). Monensin has been licensed i n the U.S. for use i n beef c a t t l e for improved feed e f f i c i e n c y , where i t i s administered at 5 to 30 g/ton i n a complete feed. In this application, the rate of growth i s not increased, but the c a t t l e consume about 10% less food. It i s also licensed for increased rate of weight gain i n c a t t l e weighing more than 400 l b . and on pasture, where i t i s fed i n a supplement at a rate of 50 to 200 mg per head per day. Lasalocid and salinomycin have also been licensed for use i n cattle. There have been a number of reports i n the l a s t four years of studies on salinomycin as a growth permittant i n swine. I t has been administered at a l e v e l of 25 to 100 g/ton of feed where i t gave a s i g n i f i c a n t increase i n weight gain and feed e f f i c i e n c y , quite comparable to t y l o s i n (10) or virginiamycin (11). If these studies lead to the development of salinomyin as a growth permit-


68



tant for non-ruminants, the ionophores could eventually dominate the entire feed additive market. Anthelmintic Agents. One a n t i b i o t i c has been used as an anthelmin t i c agent for many years. Hygromycin Β was isolated at the L i l l y laboratories because of i t s a n t i b a c t e r i a l a c t i v i t y . Although i t i s active against both gram-positive and gram-negative bacteria, i t s a c t i v i t y was too weak to be therapeutically useful. It was tested i n a variety of other assays and was found to be active jLn vivo against the pinworms, A s p i c u l a r i s tetraptera and Syphacia obvelata. The anthelmintic a c t i v i t y was confirmed i n pigs (12). It i s licensed for the control of Ascaris g a l l i , Heterakis gallinae and C a p i l l a r i a obsignata i n chickens when fed at the l e v e l of 8 to 12 g/ton an for the control of Ascaris suum, Oesophagostomum dentatum and T r i c h u r i s suis i n swine, where i t i s fed at 12 g/ton. A number of other fermentation products have been reported to have anthelmintic a c t i v i t y . Among these are the aminoglycoside, G-418, the destomycins, paromomycin, anthelvencin, aspiculamycin, anthelmycin, and the axenomycins. However, none of these has seen commercial use. The third milestone i n the history of the use of fermentation products i n agriculture was the discovery of the avermectins. They were f i r s t detected i n an anthelmintic assay using mice infected with nematospiroides dubius (13). This i s one of the few assays i n which they could have been detected since they lack a n t i b a c t e r i a l and antifungal a c t i v i t y . Further experience has demonstrated that i t was not solely the choice of assay but the great good fortune to have received a group of cultures from the Kitasato Institute and to have made the deci sion to screen these cultures i n the N. dubius assay. One of these cultures, 0S-3153, was active. The screening of several tens of thousands of s o i l isolates i n this assay has f a i l e d to detect any remotely similar anthelmintic a c t i v i t y . Of the fermentation pro ducts discussed, this i s the only one where the a c t i v i t y for which the product was eventually marketed was found by direct screening. (Zeranol might be considered to be another example, but i t was not discovered by screening.) Tests using helminth infections i n a variety of laboratory animals soon revealed that the avermectins had a c t i v i t y against a variety of nematodes but lacked a c t i v i t y toward cestodes and trematodes. During the course of testing i n a number of other assays, they were found active against the f l o u r beetle, Tribolium confusum (14). This a c t i v i t y against arthropods was confirmed i n mice infected with larvae of the bot f l y , Cuterebra f o n t i n e l l a . The avermectins are active against a wide variety of insects and other arthropods, including mites, ticks and l i c e . Moreover, they are active against nematode, insect and acarine infections of animals when administered i n a single dose given o r a l l y or paren t e r a l l y . Equally as exciting as their spectrum i s their extreme potency. For example, avermectin B i exhibits greater than 95% e f f i c a c y against Haemonchus contortus, Ostertagia circumcincta, Trichostrongylus axei, T. colubriformis, Cooperia oncophora and Oesophagostomum columbianum when administered to sheep i n a single o r a l dose of 100 pg/kg (15) · I t i s even more potent against Ancylostoma caninum i n dogs, where i t i s 83 to 100% e f f e c t i v e when given as a single o r a l dose of 3 to 5 yg/kg (15). Undoubtedly the a



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most sensitive ectoparasite i s the larva of the common c a t t l e grub, Hypoderma lineatum, where a single subcutaneous i n j e c t i o n of 0.2 yg/kg gives 100% control (16). This dual a c t i v i t y against both nematode and arthropod para s i t e s of animals was an unexpected bonus from a screen for anthel mintic agents. The reason for this broad a c t i v i t y l i e s i n their mode of action. They act by i n t e r f e r i n g with γ-aminobutyric acid (GABA) mediated neurotransmission. When treated with avermectin, the nematode Ascaris suum becomes paralyzed although i t retains normal muscle tone (17). Picrotoxin, an antagonist of GABA, can reverse the effect of avermectin on neurotransmission i n v i t r o . The absence of GABA-mediated neurotransmission i n cestodes and trema-todes explains the lack of a c t i v i t y of the avermectins against these organisms. The compound ultimately chosen for development was a semi synthetic derivative of the Bj series i n which the 22,23 double bond i s reduced (18). The mixture consisting of at least 80% 22,23-dihydroavermectin B and not more than 20% 22,23-dihydroavermectin B has been named ivermectin. Its use l e v e l i s 200 yg/kg i n horses, c a t t l e and sheep and 300 yg/kg i n swine. It i s injected subcutaneously i n c a t t l e and swine, and there are oral formulations for use i n horses and sheep. l a

l b

Plant Diseases Fermentation products have played a rather minor role i n the control of plant diseases. Table VI gives a c l a s s i f i c a t i o n of agents used on plants. These are divided into pesticides and growth modulators. The pesticides are c l a s s i f i e d as bactericides, fungicides, i n s e c t i c i d e s , miticides, nematicides and herbicides. There are fermentation products i n each of these categories, and these are l i s t e d i n Table VII. Table VI.

C l a s s i f i c a t i o n of Agents Used on Plants

A.

B.

Pesticides 1· Bactericides 2· Fungicides 3. Herbicides 4. Insecticides 5. Miticides 6. Nematicides Growth Modulators

It should be emphasized that although the t o t a l worldwide market for a g r i c u l t u r a l pesticides i s huge (over $10 b i l l i o n ) , the share held by fermentation products i s quite small. Most of the fungicides l i s t e d i n Table VII. are used i n Japan, often for r i c e b l a s t . There are several reasons for this small market share, but the most s i g n i f i c a n t reason i s probably economic. Although the fermentation products that have found commercial application are often much more active than chemical pesticides, this factor i s not often s u f f i c i e n t to compensate for the higher cost of producing them.


/-Ν

CO

CO (U ιΗ 42 CO

CO •Η CO CO ι Η φ CO Ο «Η μ *ο bO * CO CO •Ρ «s •Ρ φ CO •Η bo H φ

CO

•Η

ta

ee


ιΗ (μ 43 CO CO CO

Φ


β Si CO β μ Ο

bo φ

>

u

M Pu

Φ

CO ο Φ φ Ό • ι Η •Η α Ο S Ή

β α, • >ϊ CO Ή Ο μ Ο 43 PU PU Pu Φ

73 •Η Ο β

•Η

Φ

μ «0

4-> «Η

•Η

Ο

Ο

Φ

Ό ·Η Ο ·Η 43 μ Φ

4-1

Ο

CO 43

τΗ Ο φ g β β φ

Φ

ιΗ μ Ο Pu Pu

Η

•

rt

φ ι Η 73 Ο •Η 4-1 ι Η •Η Ο ιΗ μ Ο 4-J Φ

ιΗ Ο

4-1

•Η ιΗ ϋ

ϋ 4J Ο Ο Ο Ο β μ β •Η ο •Η a iS a

•Μ 4-» CO a eu μ •Η Φ •Η 0 43 Φ Φ · Η •H Φ Ο β ι Η τ Η CJ bO 3 ο ρ ο •H μ •Η μ •Η μ CO 3 •Η Φ μ μ •Η Ο υ Ρ* Pu PU PQ > Pu Φ

•

rH Ο μ Ο JS a

>

4->

Φ

4-J

χ)

4-> Φ

CO

β

CO

4-1

•H

Φ

CO φ τΗ 43 CO

ru

4-1 Φ

fr

ta

CO iH

>

73 •Η Ο 4-> •Η Ο φ CO •Η 73 4 J μ •Η CO φ ϋ •Η bo uο •Η 4-3 β CO •Η β PQ S P>u

β •Η β ϋ •Η •Η Χ μ ο CO

β •Η β β Ο •Η •Η >> 4-» ϋ a Ο >> ο CO a 4-> β CO CO 73 Φ μ •Η μ 4-1 rH 4-> Φ CO Η

φ β

*Η

rH β Ο ϋ •Η •Η Ο Ο ιΗ CO Φ μ μ CO 4 J φ bO φ 4-1 43 43 CO > ϊ •Η CO Χ Ο ο



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Agriculture

There are a few companies that are hoping to change t h i s . Several chemical companies that already have a large share of the chemical pesticide market are a c t i v e l y screening fermentation broths. A major motivation for this probably comes from the present concern about our environment. There i s a perception that "natural" pesticides w i l l have a much less serious environmental impact than "chemicals". Whether this advantage i s r e a l or only psychological remains to be seen. Another incentive to this screening may have arisen from the discovery of two remarkably potent families of fermentation products with i n s e c t i c i d a l and a c a r i c i d a l a c t i v i t y , the milbemycins and the avermectins. Abamectin (a mixture of not less than 80% avermectin B i and not more than 20% avermectin B ^ ) i s already seeing limited use i n F l o r i d a for the protection of ornamentals, and there i s a considerable e f f o r t being made to develop the avermectins for use against a wide variety of insect and mite pests. Two examples of the remarkable potency of avermectin B^ are i t s LD9Q of 0.02 to 0.03 ppm against the two-spotted spider mite, Tetranychus u r t i c a e , when applied to bean plants as a f o l i a r spray; and i t s control of the red imported f i r e ant, Solenopsis i n v i c t a , when applied as a bait at a l e v e l as low as 25 to 50 mg per acre (19). To express this extreme potency i n another way, the spray for mites contains 4.5 mg of abamectin per l i t e r whereas malathion spray, also used as a miticide, contains 3,700 mg per l i t e r . This i s over 800 times as much compound to produce the same e f f e c t . a

a

Conclusion Microorganisms are extremely v e r s a t i l e chemists. The wide variety of structures among the r e l a t i v e l y few compounds discussed here i s testimony to that. There are several theories to explain the evolutionary advantage conferred by the synthesis of secondary metabolites. ( I t often seems that they serve primarily to enrich pharmaceutical companies.) U n t i l recently, the idea that they conferred a competitive advantage upon the producing organism seemed reasonable, since most of the products that had been detected had a n t i b i o t i c a c t i v i t y . For many years, screening programs were directed toward the discovery of a n t i b a c t e r i a l and antifungal a n t i b i o t i c s . Now the screening of microorganisms has shifted toward the search for other types of a c t i v i t i e s . Perhaps the products that had been found are more the result of the assays employed than of their synthetic c a p a b i l i t i e s . The a b i l i t y to discover new types of fermentation products may be limited only by the ingenuity i n developing new and sensitive assays along with a certain luck i n selecting the proper microorganisms to t e s t . The future for the use of fermentation products i n agriculture holds much promise. Acknowledgment I wish to thank Dr. Robert Hamill of L i l l y Research Laborat o r i e s f o r providing unpublished information about the discovery and development of monensin.


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5. 6.

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8. 9. 10. 11. 12. 13.

14. 15.

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21.

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RECEIVED February 18, 1986


Agricultural Uses of Antibiotics - American Chemical Society

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