In addition to the screening programs for antibacterial activity, the
pharmaceutical industry has extended these programs to other disease
areas.
Microorganisms are a prolific source of structurally diverse
bioactive metabolites and have yielded some of the most important
products of the pharmaceutical industry. Microbial secondary metabolites
are now being used for applications other than antibacterial,
antifungal and antiviral infections. For example, immunosuppressants
have revolutionized medicine by facilitating organ transplantation.44
Other applications include antitumor drugs, enzyme inhibitors, gastrointestinal
motor stimulator agents, hypocholesterolemic drugs,
ruminant growth stimulants, insecticides, herbicides, coccidiostats,
antiparasitics vs coccidia, helminths and other pharmacological activities.
Further applications are possible in various areas of pharmacology
and agriculture, developments catalyzed by the use of simple
enzyme assays for screening before testing in intact animals or in
the field.
Antitumor drugs
In the year 2000, approximately 10 million new cases of cancer were
diagnosed in the world, resulting in 6 million cancer-related deaths.
The tumor types with the highest incidence were lung (12.3%), breast
(10.4%) and colorectal (9.4%).
Microbial metabolites are among the most important of the cancer
chemotherapeutic agents. They started to appear around 1940 with
the discovery of actinomycin and since then many compounds with
anticancer properties have been isolated from natural sources. More
than 60% of the current compounds with antineoplasic activity were
originally isolated as natural products or are their derivatives. Among
the approved products deserving special attention are actinomycin D,
anthracyclines (daunorubicin, doxorubicin, epirubicin, pirirubicin
and valrubicin), bleomycin, mitosanes (mitomycin C), anthracenones
(mithramycin, streptozotocin and pentostatin), enediynes (calcheamycin),
taxol and epothilones.
Actinomycin D is the oldest microbial metabolite used in cancer
therapy. Its relative, actinomycin A, was the first antibiotic isolated
from actinomycetes. The latter was obtained from Actinomyces antibioticus
(now Streptomyces antibioticus) by Waksman and Woodruff.46
As it binds DNA at the transcription initiation complex, it prevents
elongation by RNA polymerase. This property, however, confers some
human toxicity and it has been used primarily as an investigative tool
in the development of molecular biology. Despite the toxicity,
however, it has served well against Wilms tumor in children.
The anthracyclines are some of the most effective antitumor
compounds developed, and are effective against more types of cancer
than any other class of chemotherapy agents. They are used to treat a
wide range of cancers, including leukemias, lymphomas, and breast,
uterine, ovarian and lung cancers. Anthracyclines act by intercalating
DNA strands, which result in a complex formation that inhibits the
synthesis of DNA and RNA. It also triggers DNA cleavage by
topoisomerase II, resulting in mechanisms that lead to cell death.
In their cytotoxic effects, the binding to cell membranes and plasma
proteins plays an important role. Their main adverse effects are heart
damage (cardiotoxicity), which considerably limits their usefulness,
and vomiting. The first anthracycline discovered was daunorubicin
(daunomycin) in 1966, which is produced naturally by Streptomyces
peucetius. Doxorubicin (adriamycin) was developed in 1967. Another
anthracycline is epirubicin. This compound, approved by the FDA in
1999, is favored over doxorubicin in some chemotherapy regimens as
it appears to cause fewer side effects. Epirubicin has a different spatial
orientation of the hydroxyl group at the 4¢ carbon of the sugar, which
may account for its faster elimination and reduced toxicity. Epirubicin
is primarily used against breast and ovarian cancer, gastric cancer, lung
cancer and lymphomas. Valrubicin is a semisynthetic analog of
doxorubicin approved as a chemotherapeutic drug in 1999 and used
to treat bladder cancer.
Bleomycin is a non-ribosomal glycopeptide microbial metabolite
produced as a family of structurally related compounds by the
bacterium Streptomyces verticillus. First reported by Umezawa et al.48
in 1966, bleomycin obtained FDA approval in 1973. When used as an
anticancer agent (inducing DNA strand breaks), the chemotherapeutic
forms are primarily bleomycins A2 and B2.
Mitosanes are composed of several mitomycins that are formed
during the cultivation of Streptomyces caespitosus. Although the
mitosanes are excellent antitumor agents, they have limited utility
owing to their toxicity. Mitomycin C was approved by the FDA in
1974, showing activity against several types of cancer (lung, breast,
bladder, anal, colorectal, head and neck), including melanomas and
gastric or pancreatic neoplasms.Recently, mitomycin dimers have
been explored as potential alternatives for lowering toxicity and
increasing efficiency.
Mithramycin (plicamycin) is an antitumor aromatic polyketide
produced by Streptomyces argillaceous that shows antibacterial and
antitumor activity.It is one of the older chemotherapy drugs used in
the treatment of testicular cancer, disseminated neoplasms and hypercalcemia.
It binds to G-C-rich DNA sequences, inhibiting the binding
of transcription factors such as Sp1, which is believed to affect
neuronal survival/death pathways. It may also indirectly regulate
gene transcription by altering histone methylation. With repeated
use, organotoxicity (kidney, liver and hematopoietic system) can
become a problem.
Streptozotocin is a microbial metabolite with antitumor properties,
produced by Streptomyces achromogenes. Chemically, it is a glucosamine-
nitroso-urea compound. As with other alkylating agents in the
nitroso-urea class, it is toxic to cells by causing damage to DNA,
although other mechanisms may also contribute. The compound is
selectively toxic to the b-cells of the pancreatic islets. It is similar
enough to glucose to be transported into the cell by the glucose
transport protein of these cells, but it is not recognized by the other
glucose transporters.
In 1982, FDA granted approval for streptozotocin as
a treatment for pancreatic islet cell cancer.
Pentostatin (deoxycoformycin) is an anticancer chemotherapeutic
drug produced by S. antibioticus. It is classified as a purine analog,
which mimics the nucleoside adenosine and thus tightly binds and
inhibits adenosine deaminase (Ki of 2.5 10 12M). It interferes with
the cell’s ability to process DNA.53 Pentostatin is commonly used to
treat hairy cell leukemia, acute lymphocytic leukemia, prolymphocytic
leukemia (B- and T-cell origin), T-cell leukemia and lymphoma.
However, it can cause kidney, liver, lung and neurological toxicity.54
The FDA granted approval for pentostatin in 1993.
Calicheamicins are highly potent antitumor microbial metabolites
of the enediyne family produced by Micromonospora echinospora.
Their antitumor activity is apparently due to the cleavage of double-
stranded DNA.55 They are highly toxic, but it was possible to
introduce one such compound into the clinic by attaching it to an
antibody that delivered it to certain cancer types selectively. This
ingenious idea of the Wyeth Laboratories avoided the side effects of
calicheamicin. In this regard, gemtuzumab is effective against acute
myelogenous leukemia (AML). Calicheamicin is bound to a monoclonal
antibody against a transmembrane receptor (CD33) expressed
on cells of monocytic/myeloid lineage. CD33 is expressed in most
leukemic blast cells, but in normal hematopoietic cells the intensity
diminishes with maturation. It was approved by the FDA for use in
patients over the age of 60 years with relapsed AML who are not
considered candidates for standard chemotherapy.56
A successful non-actinomycete molecule is taxol (paclitaxel), which
was first isolated from the Pacific yew tree, Taxus brevifolia, but is also
produced by the endophytic fungi Taxomyces andreanae and Nodulisporium
sylviforme. This compound inhibits rapidly dividing mammalian
cancer cells by promoting tubulin polymerization and interfering
with normal microtubule breakdown during cell division. The drug
also inhibits several fungi (Pythium, Phytophthora and Aphanomyces)
by the same mechanism. In 1992, taxol was approved for refractory
ovarian cancer, and today it is used against breast and advanced
forms of Kaposi’s sarcoma.58 A new formulation is available in
which paclitaxel is bound to albumin. Taxol sales amounted
to US$1.6 billion in 2006 for Bristol Myers-Squibb, representing 10%
of the company’s pharmaceutical sales and its third largest selling
product. Currently, taxol production uses plant cell fermentation
technology.
The epothilones (a name derived from its molecular features:
epoxide, thiazole and ketone) are macrolides originally isolated from
the broth of the soil myxobacterium Sorangium cellulosum as weak
agents against rust fungi.59 They were identified as microtubulestabilizing
drugs, acting in a similar manner to taxol.60,61 However,
they are generally 5–25 times more potent than taxol in inhibiting cell
growth in cultures. Five analogs are now undergoing investigation as
candidate anticancer drugs, and their preclinical studies have indicated
a broad spectrum of antitumor activity, including taxol-resistant
tumor cells. With the best currently available therapies, the median
survival time for patients with metastatic breast cancer is only 2–3
years, and many patients develop resistance to taxanes or other
chemotherapy drugs. One epothilone, ixabepilone, was approved in
October 2007 by the FDA for use in the treatment of aggressive
metastatic or locally advanced breast cancer no longer responding to
currently available chemotherapies. In tumor cells, p-glycoprotein
reduces intracellular antitumor drug concentrations, thereby limiting
access of chemotherapeutic substrates to the site of action. The
epothilones are attractive because they are active against p-glycoprotein-
producing tumors and have good solubility.
Epothilone B is a 16-membered polyketide macrolactone with a methylthiazole group
connected to the macrocycle by an olefinic bond.
Testicular cancer is the most common cancer diagnosis in men
between the ages of 15 and 35 years, with approximately 8000 cases
detected in the United States annually. The majority (95%) of
testicular neoplasms are germ cell tumors, which are relatively
uncommon carcinomas, accounting for only 1% of all male malignancies.
Remarkable progress has been made in the medical treatment
of advanced testicular cancer, with a substantial increase in cure rates
from approximately 5% in the early 1970s to almost 90% today.64,65
This cure rate is the highest of any solid tumor, and improved survival
is primarily due to effective chemotherapy. A major advance in
chemotherapy for testicular germ cell tumors was the introduction
of cisplatin in the mid-1970s. Two chemotherapy regimens are
effective for patients with a good testicular germ cell tumor prognosis:
four cycles of etoposide and cisplatin or three cycles of bleomycin,
etoposide and cisplatin. Of the latter three agents, bleomycin and
etoposide are natural products.
Enzyme inhibitors
Enzyme inhibitors have received increasing attention as useful tools,
not only for the study of enzyme structures and reaction mechanisms
but also for potential utilization in medicine and agriculture. Several
enzyme inhibitors with various industrial uses have been isolated from
microbes.67 The most important are (1) clavulanic acid, the inhibitor
of b-lactamases discussed above in the section ‘Moves against
antibiotic resistance development in bacteria,’ and the statins, hypocholesterolemic
drugs presented below in the section ‘Hypocholesterolemic
drugs.’ Some of the common targets for other inhibitors are
glucosidases, amylases, lipases, proteases and xanthine oxidase (XO).
Acarbose is a pseudotetrasaccharide made by Actinoplanes sp. SE50.
It contains an aminocyclitol moiety, valienamine, which inhibits
intestinal a-glucosidase and sucrase. This results in a decrease in
starch breakdown in the intestine, which is useful in combating
diabetes in humans.
Amylase inhibitors are useful for the control of carbohydratedependent
diseases, such as diabetes, obesity and hyperlipemia.
Amylase inhibitors are also known as starch blockers because they
contain substances that prevent dietary starches from being absorbed
by the body. The inhibitors may also be useful for weight loss, as some
versions of amylase inhibitors do show potential for reducing carbohydrate
absorption in humans.
The use of amylase inhibitors for
the treatment of rumen acidosis has also been reported.73 Examples of
microbial a-amylase inhibitors are paim, obtained from culture
filtrates of Streptomyces corchorushii,74 and TAI-A, TAI-B, oligosaccharide
compounds from Streptomyces calvus TM-521.
Lipstatin is a pancreatic lipase inhibitor produced by Streptomyces
toxytricini that is used to combat obesity and diabetes. It interferes
with the gastrointestinal absorption of fat.76 The commercial product
is tetrahydrolipstatin, which is also known as orlistat.
In the pathogenic processes of some diseases, such as emphysema,
arthritis, pancreatitis, cancer and AIDS, protease inhibitors are potentially
powerful tools for inactivating target proteases. Examples of
microbial products include antipain, produced by Streptomyces yokosukaensis,
leupeptin from Streptomyces roseochromogenes and chymostatin
from Streptomyces hygroscopicus. Leupeptin is produced by
more than 17 species of actinomycetes.
XO catalyzes the oxidation of hypoxanthine to uric acid through
xanthine. An excessive accumulation of uric acid in the blood, called
hyperuricemia, causes gout. The inhibitors of XO decrease the uric
acid levels, which result in an antihyperuricemic effect. A potent
Microbial drug discovery
inhibitor of XO, hydroxyakalone, was purified from the fermentation
broth of Agrobacterium aurantiacum sp. nov., a marine bacterial
strain.
Fungal products are also used as enzyme inhibitors against cancer,
diabetes, poisonings, Alzheimer’s disease, etc. The enzymes inhibited
include acetylcholinesterase, protein kinase, tyrosine kinase, glycosidases
and others.
pharmaceutical industry has extended these programs to other disease
areas.
Microorganisms are a prolific source of structurally diverse
bioactive metabolites and have yielded some of the most important
products of the pharmaceutical industry. Microbial secondary metabolites
are now being used for applications other than antibacterial,
antifungal and antiviral infections. For example, immunosuppressants
have revolutionized medicine by facilitating organ transplantation.44
Other applications include antitumor drugs, enzyme inhibitors, gastrointestinal
motor stimulator agents, hypocholesterolemic drugs,
ruminant growth stimulants, insecticides, herbicides, coccidiostats,
antiparasitics vs coccidia, helminths and other pharmacological activities.
Further applications are possible in various areas of pharmacology
and agriculture, developments catalyzed by the use of simple
enzyme assays for screening before testing in intact animals or in
the field.
Antitumor drugs
In the year 2000, approximately 10 million new cases of cancer were
diagnosed in the world, resulting in 6 million cancer-related deaths.
The tumor types with the highest incidence were lung (12.3%), breast
(10.4%) and colorectal (9.4%).
Microbial metabolites are among the most important of the cancer
chemotherapeutic agents. They started to appear around 1940 with
the discovery of actinomycin and since then many compounds with
anticancer properties have been isolated from natural sources. More
than 60% of the current compounds with antineoplasic activity were
originally isolated as natural products or are their derivatives. Among
the approved products deserving special attention are actinomycin D,
anthracyclines (daunorubicin, doxorubicin, epirubicin, pirirubicin
and valrubicin), bleomycin, mitosanes (mitomycin C), anthracenones
(mithramycin, streptozotocin and pentostatin), enediynes (calcheamycin),
taxol and epothilones.
Actinomycin D is the oldest microbial metabolite used in cancer
therapy. Its relative, actinomycin A, was the first antibiotic isolated
from actinomycetes. The latter was obtained from Actinomyces antibioticus
(now Streptomyces antibioticus) by Waksman and Woodruff.46
As it binds DNA at the transcription initiation complex, it prevents
elongation by RNA polymerase. This property, however, confers some
human toxicity and it has been used primarily as an investigative tool
in the development of molecular biology. Despite the toxicity,
however, it has served well against Wilms tumor in children.
The anthracyclines are some of the most effective antitumor
compounds developed, and are effective against more types of cancer
than any other class of chemotherapy agents. They are used to treat a
wide range of cancers, including leukemias, lymphomas, and breast,
uterine, ovarian and lung cancers. Anthracyclines act by intercalating
DNA strands, which result in a complex formation that inhibits the
synthesis of DNA and RNA. It also triggers DNA cleavage by
topoisomerase II, resulting in mechanisms that lead to cell death.
In their cytotoxic effects, the binding to cell membranes and plasma
proteins plays an important role. Their main adverse effects are heart
damage (cardiotoxicity), which considerably limits their usefulness,
and vomiting. The first anthracycline discovered was daunorubicin
(daunomycin) in 1966, which is produced naturally by Streptomyces
peucetius. Doxorubicin (adriamycin) was developed in 1967. Another
anthracycline is epirubicin. This compound, approved by the FDA in
1999, is favored over doxorubicin in some chemotherapy regimens as
it appears to cause fewer side effects. Epirubicin has a different spatial
orientation of the hydroxyl group at the 4¢ carbon of the sugar, which
may account for its faster elimination and reduced toxicity. Epirubicin
is primarily used against breast and ovarian cancer, gastric cancer, lung
cancer and lymphomas. Valrubicin is a semisynthetic analog of
doxorubicin approved as a chemotherapeutic drug in 1999 and used
to treat bladder cancer.
Bleomycin is a non-ribosomal glycopeptide microbial metabolite
produced as a family of structurally related compounds by the
bacterium Streptomyces verticillus. First reported by Umezawa et al.48
in 1966, bleomycin obtained FDA approval in 1973. When used as an
anticancer agent (inducing DNA strand breaks), the chemotherapeutic
forms are primarily bleomycins A2 and B2.
Mitosanes are composed of several mitomycins that are formed
during the cultivation of Streptomyces caespitosus. Although the
mitosanes are excellent antitumor agents, they have limited utility
owing to their toxicity. Mitomycin C was approved by the FDA in
1974, showing activity against several types of cancer (lung, breast,
bladder, anal, colorectal, head and neck), including melanomas and
gastric or pancreatic neoplasms.Recently, mitomycin dimers have
been explored as potential alternatives for lowering toxicity and
increasing efficiency.
Mithramycin (plicamycin) is an antitumor aromatic polyketide
produced by Streptomyces argillaceous that shows antibacterial and
antitumor activity.It is one of the older chemotherapy drugs used in
the treatment of testicular cancer, disseminated neoplasms and hypercalcemia.
It binds to G-C-rich DNA sequences, inhibiting the binding
of transcription factors such as Sp1, which is believed to affect
neuronal survival/death pathways. It may also indirectly regulate
gene transcription by altering histone methylation. With repeated
use, organotoxicity (kidney, liver and hematopoietic system) can
become a problem.
Streptozotocin is a microbial metabolite with antitumor properties,
produced by Streptomyces achromogenes. Chemically, it is a glucosamine-
nitroso-urea compound. As with other alkylating agents in the
nitroso-urea class, it is toxic to cells by causing damage to DNA,
although other mechanisms may also contribute. The compound is
selectively toxic to the b-cells of the pancreatic islets. It is similar
enough to glucose to be transported into the cell by the glucose
transport protein of these cells, but it is not recognized by the other
glucose transporters.
In 1982, FDA granted approval for streptozotocin as
a treatment for pancreatic islet cell cancer.
Pentostatin (deoxycoformycin) is an anticancer chemotherapeutic
drug produced by S. antibioticus. It is classified as a purine analog,
which mimics the nucleoside adenosine and thus tightly binds and
inhibits adenosine deaminase (Ki of 2.5 10 12M). It interferes with
the cell’s ability to process DNA.53 Pentostatin is commonly used to
treat hairy cell leukemia, acute lymphocytic leukemia, prolymphocytic
leukemia (B- and T-cell origin), T-cell leukemia and lymphoma.
However, it can cause kidney, liver, lung and neurological toxicity.54
The FDA granted approval for pentostatin in 1993.
Calicheamicins are highly potent antitumor microbial metabolites
of the enediyne family produced by Micromonospora echinospora.
Their antitumor activity is apparently due to the cleavage of double-
stranded DNA.55 They are highly toxic, but it was possible to
introduce one such compound into the clinic by attaching it to an
antibody that delivered it to certain cancer types selectively. This
ingenious idea of the Wyeth Laboratories avoided the side effects of
calicheamicin. In this regard, gemtuzumab is effective against acute
myelogenous leukemia (AML). Calicheamicin is bound to a monoclonal
antibody against a transmembrane receptor (CD33) expressed
on cells of monocytic/myeloid lineage. CD33 is expressed in most
leukemic blast cells, but in normal hematopoietic cells the intensity
diminishes with maturation. It was approved by the FDA for use in
patients over the age of 60 years with relapsed AML who are not
considered candidates for standard chemotherapy.56
A successful non-actinomycete molecule is taxol (paclitaxel), which
was first isolated from the Pacific yew tree, Taxus brevifolia, but is also
produced by the endophytic fungi Taxomyces andreanae and Nodulisporium
sylviforme. This compound inhibits rapidly dividing mammalian
cancer cells by promoting tubulin polymerization and interfering
with normal microtubule breakdown during cell division. The drug
also inhibits several fungi (Pythium, Phytophthora and Aphanomyces)
by the same mechanism. In 1992, taxol was approved for refractory
ovarian cancer, and today it is used against breast and advanced
forms of Kaposi’s sarcoma.58 A new formulation is available in
which paclitaxel is bound to albumin. Taxol sales amounted
to US$1.6 billion in 2006 for Bristol Myers-Squibb, representing 10%
of the company’s pharmaceutical sales and its third largest selling
product. Currently, taxol production uses plant cell fermentation
technology.
The epothilones (a name derived from its molecular features:
epoxide, thiazole and ketone) are macrolides originally isolated from
the broth of the soil myxobacterium Sorangium cellulosum as weak
agents against rust fungi.59 They were identified as microtubulestabilizing
drugs, acting in a similar manner to taxol.60,61 However,
they are generally 5–25 times more potent than taxol in inhibiting cell
growth in cultures. Five analogs are now undergoing investigation as
candidate anticancer drugs, and their preclinical studies have indicated
a broad spectrum of antitumor activity, including taxol-resistant
tumor cells. With the best currently available therapies, the median
survival time for patients with metastatic breast cancer is only 2–3
years, and many patients develop resistance to taxanes or other
chemotherapy drugs. One epothilone, ixabepilone, was approved in
October 2007 by the FDA for use in the treatment of aggressive
metastatic or locally advanced breast cancer no longer responding to
currently available chemotherapies. In tumor cells, p-glycoprotein
reduces intracellular antitumor drug concentrations, thereby limiting
access of chemotherapeutic substrates to the site of action. The
epothilones are attractive because they are active against p-glycoprotein-
producing tumors and have good solubility.
Epothilone B is a 16-membered polyketide macrolactone with a methylthiazole group
connected to the macrocycle by an olefinic bond.
Testicular cancer is the most common cancer diagnosis in men
between the ages of 15 and 35 years, with approximately 8000 cases
detected in the United States annually. The majority (95%) of
testicular neoplasms are germ cell tumors, which are relatively
uncommon carcinomas, accounting for only 1% of all male malignancies.
Remarkable progress has been made in the medical treatment
of advanced testicular cancer, with a substantial increase in cure rates
from approximately 5% in the early 1970s to almost 90% today.64,65
This cure rate is the highest of any solid tumor, and improved survival
is primarily due to effective chemotherapy. A major advance in
chemotherapy for testicular germ cell tumors was the introduction
of cisplatin in the mid-1970s. Two chemotherapy regimens are
effective for patients with a good testicular germ cell tumor prognosis:
four cycles of etoposide and cisplatin or three cycles of bleomycin,
etoposide and cisplatin. Of the latter three agents, bleomycin and
etoposide are natural products.
Enzyme inhibitors
Enzyme inhibitors have received increasing attention as useful tools,
not only for the study of enzyme structures and reaction mechanisms
but also for potential utilization in medicine and agriculture. Several
enzyme inhibitors with various industrial uses have been isolated from
microbes.67 The most important are (1) clavulanic acid, the inhibitor
of b-lactamases discussed above in the section ‘Moves against
antibiotic resistance development in bacteria,’ and the statins, hypocholesterolemic
drugs presented below in the section ‘Hypocholesterolemic
drugs.’ Some of the common targets for other inhibitors are
glucosidases, amylases, lipases, proteases and xanthine oxidase (XO).
Acarbose is a pseudotetrasaccharide made by Actinoplanes sp. SE50.
It contains an aminocyclitol moiety, valienamine, which inhibits
intestinal a-glucosidase and sucrase. This results in a decrease in
starch breakdown in the intestine, which is useful in combating
diabetes in humans.
Amylase inhibitors are useful for the control of carbohydratedependent
diseases, such as diabetes, obesity and hyperlipemia.
Amylase inhibitors are also known as starch blockers because they
contain substances that prevent dietary starches from being absorbed
by the body. The inhibitors may also be useful for weight loss, as some
versions of amylase inhibitors do show potential for reducing carbohydrate
absorption in humans.
The use of amylase inhibitors for
the treatment of rumen acidosis has also been reported.73 Examples of
microbial a-amylase inhibitors are paim, obtained from culture
filtrates of Streptomyces corchorushii,74 and TAI-A, TAI-B, oligosaccharide
compounds from Streptomyces calvus TM-521.
Lipstatin is a pancreatic lipase inhibitor produced by Streptomyces
toxytricini that is used to combat obesity and diabetes. It interferes
with the gastrointestinal absorption of fat.76 The commercial product
is tetrahydrolipstatin, which is also known as orlistat.
In the pathogenic processes of some diseases, such as emphysema,
arthritis, pancreatitis, cancer and AIDS, protease inhibitors are potentially
powerful tools for inactivating target proteases. Examples of
microbial products include antipain, produced by Streptomyces yokosukaensis,
leupeptin from Streptomyces roseochromogenes and chymostatin
from Streptomyces hygroscopicus. Leupeptin is produced by
more than 17 species of actinomycetes.
XO catalyzes the oxidation of hypoxanthine to uric acid through
xanthine. An excessive accumulation of uric acid in the blood, called
hyperuricemia, causes gout. The inhibitors of XO decrease the uric
acid levels, which result in an antihyperuricemic effect. A potent
Microbial drug discovery
inhibitor of XO, hydroxyakalone, was purified from the fermentation
broth of Agrobacterium aurantiacum sp. nov., a marine bacterial
strain.
Fungal products are also used as enzyme inhibitors against cancer,
diabetes, poisonings, Alzheimer’s disease, etc. The enzymes inhibited
include acetylcholinesterase, protein kinase, tyrosine kinase, glycosidases
and others.
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