Herbicides are chemicals marketed to inhibit or interrupt normal
plant growth and development. They are widely used in agriculture,
industry and urban areas for weed management. Approximately
30 000 kinds of weeds are widely distributed in the world; yield losses
caused by 1800 kinds of weeds are approximately 9.7% of total crop
production every year.98 Herbicides provide cost-effective weed control
with a minimum of labor. Most are used on crops planted in large
acreages, such as soy, cotton, corn and canola. There are numerous
classes of herbicides with different modes of action, as well as different
potentials for adverse effects on health and the environment. Over the
past century, chemical herbicides, used to control various weeds, may
have caused many serious side effects, such as injured crops, threat to
the applicator and others exposed to the chemicals, herbicide-resistant
weed populations, reduction of soil and water quality, herbicide
residues and detrimental effects on non-target organisms.100 For
example, alachlor and atrazine were reported to cause cancer in
animal tests. With increasing global environmental consciousness,
bioherbicides, which are highly effective for weed control and environmentally
friendly as well, are very attractive both for research and
for application. Microbial herbicides can be divided into microbial
preparations (microorganisms that control weeds) and microbially
derived herbicides.
The first microbial herbicide was independently discovered in
Germany and Japan. In 1972, the ZaЁhner group in Germany isolated
phosphinothricin tripeptide, a peptide antibiotic consisting of two
molecules of L-alanine and one molecule of the unusual amino acid
L-phosphinothricin; that is, N(4[hydroxyl(methyl)phosphinoyl]homoalanyl)
alanylalanine. They isolated it from Streptomyces viridochromogenes
as a broad-spectrum antibacterial including activity against
Botrytis cinerea. In Japan, it was discovered at the Meiji Seiki
laboratories in 1973 from S. hygroscopicus and named bialaphos.102
The bioactive L-phosphinothricin is a structural analog of glutamic
acid, acting as a competitive inhibitor of glutamine synthetase, and has
bactericidal (Gram-positive and Gram-negative bacteria), fungicidal
(B. cinerea) and herbicidal properties. Glufosinate (DL-phosphinothricin)
(without Ala-Ala) was developed as a herbicide. Therefore, the
agent acts as a herbicide with or without Ala-Ala. Bialaphos has no
influence on microorganisms in the soil and is easily degraded in the
environment, having a half-life of only 2 h. This low level of environmental
impact is of great interest to environmentalists.
Antiparasitics and ruminant growth stimulants
In 2006, the global animal health market was valued at US$16 billion,
of which 29% was derived from parasiticides. Parasites are organisms
that inhabit the body and benefit from a prolonged, close association
with the host. Antiparasitics are compounds that inhibit the growth or
reproduction of a parasite; some antiparasitics directly kill parasites. In
general, parasites are much smaller than their hosts, show a high
degree of specialization for their mode of life and reproduce more
quickly and in greater numbers than their hosts. Classic examples of
parasitism include the interactions between vertebrate hosts and such
diverse animals as tapeworms, flukes, Plasmodium species and fleas.
Parasitic infections can cause potentially serious health problems
and even kill the host. Parasites mainly enter the body through
the mouth, usually through ingestion of tainted food or drink. This
is a very common problem in tropical areas, but is not limited to
those regions. There are 3200 varieties of parasites in four major
categories: Protozoa, Trematoda, Cestoda and Nematoda. The major
groups include protozoans (organisms having only one cell) and
parasitic worms (helminths). Each of these can infect the digestive
tract, and sometimes two or more can cause infection at the same
time. The WHO reported that approximately 25% of the world’s
population is infected with roundworms. In addition, a major
agricultural problem has been the infection of farm animals by worms.
The predominant type of antiparasitic screening effort over the
years was the testing of synthetic compounds against nematodes, and
some commercial products did result. Certain antibiotics were also
shown to possess antihelmintic activity against nematodes or cestodes,
but these failed to compete with the synthetic compounds. Although
Merck had earlier developed a commercially useful synthetic product,
thiabendazole, they had enough foresight to examine microbial
broths for antihelmintic activity, and found a non-toxic fermentation
broth that killed the intestinal nematode Nematosporoides dubius in
mice. The Streptomyces avermitilis culture, isolated by OЇ mura and
coworkers at the Kitasato Institute in Japan, produced a family of
secondary metabolites (eight compounds) with both antihelmintic
and insecticidal activities. These compounds, named ‘avermectins,’
are pentacyclic, 16-membered macrocyclic lactones, that harbor a
disaccharide of the methylated sugar, oleandrose, with exceptional
activity against parasites, especially Nemathelminthes (nematodes)
and arthropod parasites (10 times higher than any known synthetic
antihelmintic agent). Surprisingly, avermectins lack activity against
bacteria and fungi, do not inhibit protein synthesis and are
not ionophores. Instead, they interfere with neurotransmission in
many invertebrates, causing paralysis and death by neuromuscular
attacks.
The annual market for avermectins surpasses US$1 billion. They are
used against both nematode and arthropod parasites in sheep, cattle,
dogs, horses and swine. A semisynthetic derivative, 22,23-dihydroavermectin
B1 (‘ivermectin’) is 1000 times more active than thiabendazole
and is a commercial veterinary product. The efficacy of
ivermectin has made it a promising candidate for the control of
human onchocerciasis and human strongyloidiasis. Another avermectin,
called doramectin (or cyclohexyl avermectin B1), produced by
‘mutational biosynthesis’ was commercialized for use by food animals.
107 A semisynthetic monosaccharide derivative of doramectin
called selamectin is the most recently commercialized avermectin, and
is active against heartworms (Dirofilaria immitis) and fleas in companion
animals. Although the macrocyclic backbone of each of these
molecules (ivermectin, doramectin and selamectin) is identical, there
are different substitutions at pharmacologically relevant sites such as
C-5, C-13, C-22,23 and C-25.108 The avermectins are closely related to
the milbemycins, a group of non-glycosidated macrolides produced by
S. hygroscopicus subsp. Aureolacrimosus. These compounds possess
activity against worms and insects.
Coccidiostats are used for the prevention of coccidiosis in both
extensively and intensively reared poultry. Coccidiosis is the name
given to a common intestinal disease caused by the invading protozoan
parasites of the genus Eimeria that affects several different animal
species (cattle, dogs, cats, poultry, etc.). The major damage is caused
by the rapid multiplication of the parasite in the intestinal wall and the
subsequent rupture of the cells of the intestinal lining, leading to high
mortality and severe loss of productivity. Coccidia are obligate
intracellular parasites that show host specificity; only cattle coccidia
will cause disease in cattle; other species-specific coccidia will not.
For many years, synthetic compounds were used to combat
coccidiosis in poultry; however, resistance developed rapidly. A solution
came on the scene with the discovery of the narrow-spectrum
polyether antibiotic monensin, which had extreme potency against the
coccidian. Made by Streptomyces cinnamonensis, monensin led the
way for additional microbial ionophoric antibiotics, such as lasalocid,
narasin and salinomycin. All are produced by various Streptomyces
species. They form complexes with the polar cations K+, Na+, Ca2+
and Mg2+, severely affecting the osmotic balance in the parasitic cells
and thus causing their death. The widespread use of anticoccidials
has revolutionized the poultry industry by reducing the mortality and
production losses caused by coccidiosis. Of great interest was another
extremely valuable application of monensin; that is, growth promotion
in ruminants. Synthetic chemicals had been tested for years to
inhibit wasteful methane production by cattle and sheep and increase
fatty acid formation (especially propionate) to improve feed efficiency;
however, they failed. The solution was monensin, which became a
major success as a ruminant growth enhancer.
For more than 40 years, certain antibiotics have been used in foodanimal
production to enhance feed utilization and weight gain.112
From a production standpoint, feed antibiotics have been consistently
shown to improve animal weight gain and feed efficiency, especially in
younger animals. These responses are probably derived from an
inhibitory effect on the normal microbiota, which can lead to reduced
intestinal inflammation and improved nutrient utilization.113 Pigs
in the USA are exposed to a great variety of antibiotics. These include
b-lactam antibiotics (including penicillins), lincosamides and macrolides
(including erythromycin and tetracyclines). All these groups have
members that are used to treat infections in humans. In addition,
bacitracin, flavophospholipol, pleuromutilins, quinoxalines and virginiamycin
are utilized as growth stimulants. Flavophospholipol and
virginiamycin are also used as growth promoters in poultry.
As described above, cattle are also exposed to ionophores such as
monensin to promote growth. The Animal Health Institute of
America114 has estimated that without the use of growth-promoting
antibiotics, the USA would require an additional 452 million chickens,
23 million more cattle and 12 million more pigs to reach the levels of
production attained by the current practices.
Considering that animal health research and the development of
new anti-infective product discovery have decreased, the discovery of
new antibiotics has decreased over the past 15 years, with few new
drug approvals.115 Therefore, it will be incumbent on veterinary
practitioners to use the existing products in a responsible manner to
ensure their longevity. It remains to be seen what effects the dearth of
new antibiotics for veterinary medicine will have on the future
practice of veterinary medicine, production agriculture, food safety
and public health.
Since the 1999 EU decision to prohibit antibiotic use for foodanimal
growth promotion, four antibiotic growth promoters have
been banned, including the macrolide drugs tylosin and spiramycin.
117 Although macrolides are no longer formally used as ‘growth
promoters,’ their use under veterinary prescription has risen from 23
tons in 1998 to 55 tons in 2001, which suggests that more of them are
being used now than before the prohibition.
plant growth and development. They are widely used in agriculture,
industry and urban areas for weed management. Approximately
30 000 kinds of weeds are widely distributed in the world; yield losses
caused by 1800 kinds of weeds are approximately 9.7% of total crop
production every year.98 Herbicides provide cost-effective weed control
with a minimum of labor. Most are used on crops planted in large
acreages, such as soy, cotton, corn and canola. There are numerous
classes of herbicides with different modes of action, as well as different
potentials for adverse effects on health and the environment. Over the
past century, chemical herbicides, used to control various weeds, may
have caused many serious side effects, such as injured crops, threat to
the applicator and others exposed to the chemicals, herbicide-resistant
weed populations, reduction of soil and water quality, herbicide
residues and detrimental effects on non-target organisms.100 For
example, alachlor and atrazine were reported to cause cancer in
animal tests. With increasing global environmental consciousness,
bioherbicides, which are highly effective for weed control and environmentally
friendly as well, are very attractive both for research and
for application. Microbial herbicides can be divided into microbial
preparations (microorganisms that control weeds) and microbially
derived herbicides.
The first microbial herbicide was independently discovered in
Germany and Japan. In 1972, the ZaЁhner group in Germany isolated
phosphinothricin tripeptide, a peptide antibiotic consisting of two
molecules of L-alanine and one molecule of the unusual amino acid
L-phosphinothricin; that is, N(4[hydroxyl(methyl)phosphinoyl]homoalanyl)
alanylalanine. They isolated it from Streptomyces viridochromogenes
as a broad-spectrum antibacterial including activity against
Botrytis cinerea. In Japan, it was discovered at the Meiji Seiki
laboratories in 1973 from S. hygroscopicus and named bialaphos.102
The bioactive L-phosphinothricin is a structural analog of glutamic
acid, acting as a competitive inhibitor of glutamine synthetase, and has
bactericidal (Gram-positive and Gram-negative bacteria), fungicidal
(B. cinerea) and herbicidal properties. Glufosinate (DL-phosphinothricin)
(without Ala-Ala) was developed as a herbicide. Therefore, the
agent acts as a herbicide with or without Ala-Ala. Bialaphos has no
influence on microorganisms in the soil and is easily degraded in the
environment, having a half-life of only 2 h. This low level of environmental
impact is of great interest to environmentalists.
Antiparasitics and ruminant growth stimulants
In 2006, the global animal health market was valued at US$16 billion,
of which 29% was derived from parasiticides. Parasites are organisms
that inhabit the body and benefit from a prolonged, close association
with the host. Antiparasitics are compounds that inhibit the growth or
reproduction of a parasite; some antiparasitics directly kill parasites. In
general, parasites are much smaller than their hosts, show a high
degree of specialization for their mode of life and reproduce more
quickly and in greater numbers than their hosts. Classic examples of
parasitism include the interactions between vertebrate hosts and such
diverse animals as tapeworms, flukes, Plasmodium species and fleas.
Parasitic infections can cause potentially serious health problems
and even kill the host. Parasites mainly enter the body through
the mouth, usually through ingestion of tainted food or drink. This
is a very common problem in tropical areas, but is not limited to
those regions. There are 3200 varieties of parasites in four major
categories: Protozoa, Trematoda, Cestoda and Nematoda. The major
groups include protozoans (organisms having only one cell) and
parasitic worms (helminths). Each of these can infect the digestive
tract, and sometimes two or more can cause infection at the same
time. The WHO reported that approximately 25% of the world’s
population is infected with roundworms. In addition, a major
agricultural problem has been the infection of farm animals by worms.
The predominant type of antiparasitic screening effort over the
years was the testing of synthetic compounds against nematodes, and
some commercial products did result. Certain antibiotics were also
shown to possess antihelmintic activity against nematodes or cestodes,
but these failed to compete with the synthetic compounds. Although
Merck had earlier developed a commercially useful synthetic product,
thiabendazole, they had enough foresight to examine microbial
broths for antihelmintic activity, and found a non-toxic fermentation
broth that killed the intestinal nematode Nematosporoides dubius in
mice. The Streptomyces avermitilis culture, isolated by OЇ mura and
coworkers at the Kitasato Institute in Japan, produced a family of
secondary metabolites (eight compounds) with both antihelmintic
and insecticidal activities. These compounds, named ‘avermectins,’
are pentacyclic, 16-membered macrocyclic lactones, that harbor a
disaccharide of the methylated sugar, oleandrose, with exceptional
activity against parasites, especially Nemathelminthes (nematodes)
and arthropod parasites (10 times higher than any known synthetic
antihelmintic agent). Surprisingly, avermectins lack activity against
bacteria and fungi, do not inhibit protein synthesis and are
not ionophores. Instead, they interfere with neurotransmission in
many invertebrates, causing paralysis and death by neuromuscular
attacks.
The annual market for avermectins surpasses US$1 billion. They are
used against both nematode and arthropod parasites in sheep, cattle,
dogs, horses and swine. A semisynthetic derivative, 22,23-dihydroavermectin
B1 (‘ivermectin’) is 1000 times more active than thiabendazole
and is a commercial veterinary product. The efficacy of
ivermectin has made it a promising candidate for the control of
human onchocerciasis and human strongyloidiasis. Another avermectin,
called doramectin (or cyclohexyl avermectin B1), produced by
‘mutational biosynthesis’ was commercialized for use by food animals.
107 A semisynthetic monosaccharide derivative of doramectin
called selamectin is the most recently commercialized avermectin, and
is active against heartworms (Dirofilaria immitis) and fleas in companion
animals. Although the macrocyclic backbone of each of these
molecules (ivermectin, doramectin and selamectin) is identical, there
are different substitutions at pharmacologically relevant sites such as
C-5, C-13, C-22,23 and C-25.108 The avermectins are closely related to
the milbemycins, a group of non-glycosidated macrolides produced by
S. hygroscopicus subsp. Aureolacrimosus. These compounds possess
activity against worms and insects.
Coccidiostats are used for the prevention of coccidiosis in both
extensively and intensively reared poultry. Coccidiosis is the name
given to a common intestinal disease caused by the invading protozoan
parasites of the genus Eimeria that affects several different animal
species (cattle, dogs, cats, poultry, etc.). The major damage is caused
by the rapid multiplication of the parasite in the intestinal wall and the
subsequent rupture of the cells of the intestinal lining, leading to high
mortality and severe loss of productivity. Coccidia are obligate
intracellular parasites that show host specificity; only cattle coccidia
will cause disease in cattle; other species-specific coccidia will not.
For many years, synthetic compounds were used to combat
coccidiosis in poultry; however, resistance developed rapidly. A solution
came on the scene with the discovery of the narrow-spectrum
polyether antibiotic monensin, which had extreme potency against the
coccidian. Made by Streptomyces cinnamonensis, monensin led the
way for additional microbial ionophoric antibiotics, such as lasalocid,
narasin and salinomycin. All are produced by various Streptomyces
species. They form complexes with the polar cations K+, Na+, Ca2+
and Mg2+, severely affecting the osmotic balance in the parasitic cells
and thus causing their death. The widespread use of anticoccidials
has revolutionized the poultry industry by reducing the mortality and
production losses caused by coccidiosis. Of great interest was another
extremely valuable application of monensin; that is, growth promotion
in ruminants. Synthetic chemicals had been tested for years to
inhibit wasteful methane production by cattle and sheep and increase
fatty acid formation (especially propionate) to improve feed efficiency;
however, they failed. The solution was monensin, which became a
major success as a ruminant growth enhancer.
For more than 40 years, certain antibiotics have been used in foodanimal
production to enhance feed utilization and weight gain.112
From a production standpoint, feed antibiotics have been consistently
shown to improve animal weight gain and feed efficiency, especially in
younger animals. These responses are probably derived from an
inhibitory effect on the normal microbiota, which can lead to reduced
intestinal inflammation and improved nutrient utilization.113 Pigs
in the USA are exposed to a great variety of antibiotics. These include
b-lactam antibiotics (including penicillins), lincosamides and macrolides
(including erythromycin and tetracyclines). All these groups have
members that are used to treat infections in humans. In addition,
bacitracin, flavophospholipol, pleuromutilins, quinoxalines and virginiamycin
are utilized as growth stimulants. Flavophospholipol and
virginiamycin are also used as growth promoters in poultry.
As described above, cattle are also exposed to ionophores such as
monensin to promote growth. The Animal Health Institute of
America114 has estimated that without the use of growth-promoting
antibiotics, the USA would require an additional 452 million chickens,
23 million more cattle and 12 million more pigs to reach the levels of
production attained by the current practices.
Considering that animal health research and the development of
new anti-infective product discovery have decreased, the discovery of
new antibiotics has decreased over the past 15 years, with few new
drug approvals.115 Therefore, it will be incumbent on veterinary
practitioners to use the existing products in a responsible manner to
ensure their longevity. It remains to be seen what effects the dearth of
new antibiotics for veterinary medicine will have on the future
practice of veterinary medicine, production agriculture, food safety
and public health.
Since the 1999 EU decision to prohibit antibiotic use for foodanimal
growth promotion, four antibiotic growth promoters have
been banned, including the macrolide drugs tylosin and spiramycin.
117 Although macrolides are no longer formally used as ‘growth
promoters,’ their use under veterinary prescription has risen from 23
tons in 1998 to 55 tons in 2001, which suggests that more of them are
being used now than before the prohibition.
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