The wonderful world of polyketides. This one helps you “go”. Ansamycin antibiotics are produced by cultures of Amycolatopsis mediterranei Rifamycin SV (below ) is an anti-tuberculosis drug that works against Gram-positive bacteria by inhibiting bacterial RNA synthesis - it binds to
This one helps you “go”
Ansamycin antibiotics are produced by cultures
Rifamycin SV (below ) is an anti-tuberculosis drug
that works against Gram-positive bacteria by
inhibiting bacterial RNA synthesis - it binds to
DNA-dependent bacterial RNA polymerase.
From Senna leaf and fruit, Cassia angustifolia (Leguminosae/Fabaceae). Senna is a stimulant laxative that acts on the wall of the large intestine, increasing
Organisms that produce polyketides make highly reactive poly-β-keto chains, which must be stabilized by association with groups on the enzyme surface until chain assembly is complete and then cyclizations occur.
Polyketide formation: folding is the key to ring formation:
Aldol or Claisen reaction forms the ring
Enolization produces phenol
rings can result from
formation of a depside occurs through esterification of two
phenolic acid units
A depside from
Turner, et al, 2007
1. chain folds in half
2. aldol condensation, dehydration, enolization
sequence forms the rings
3. oxidation of hydroxyl groups occurs after
“Emetics” or laxatives found in Senna (Cassia angustifolia), Cascara (Rhamnuspurshianus)
“Sennosides” have sugars
attached to the ring skeleton
Assembly of hypericin (St. John’s Wort – Hypericumperforatum)
Senna (Cassia angustifolia)
oxygenated C and
prior to cyclization
Radical coupling often joins phenolicrings. Ex: griseofulvin, an
Produced by cultures of Penicilliumgriseofulvumand is effective for difficult skin infections.
It’s absorbed from the gut and concentrated in keratin, so it is used orally to control dermatophytes. Works by disruption of the mitotic spindle, inhibiting fungal mitosis.
Oxidative cleavage, lactone and acetal formation results in major skeletal modifications
Patulin is a potent carcinogen produced by Penicilliumpatulum, a
common contaminant on apples.
Products made from contaminated fruit may contain dangerous levels
of patulin, so juices, etc. are routinely screened for patulin content
(max of 50 μg kg−1).
contains urushiols – part fatty acid, part polyketide
oxidized to a quinone, which is the
produces allergic rxn.
The origins of aflatoxins(Aspergillusflavus & Aspergillusparasiticus)
Aflatoxin – producing fungi grow mainly on peanuts, corn, rice, pistachio nuts
Targets the liver, which becomes enlarged due to fat deposition, cell necrosis, etc.
Recent dog food contamination resulted in several pet deaths
Aflatoxin B1 is carcinogenic - after epoxidization by CYP450 it can intercalate DNA, causing mutations.
works by mimicking the
natural molecules that bind
to endogenous cannabinoid
CB1 in the brain (mood, memory
motor control, pain, appetite)
CB2 in immune/reproductive
alpha-linolenic acid (20%–25%)
Many plants produce a range of compounds having similar structures with a few
modifications in substituents, side chains, sugars attached.
Comparison of the relative bioactivities of these molecules allows determination
of which structural features are necessary for activity
Important for turning drug leads into synthetic derivatives with increased activity
Methylation using SAM is more common in fungi
Actinomycetes (e.g. Streptomyces)
are filamentous bacteria that
gain methyls by incorporation of propionate via methylmalonyl-CoA as a building block.
There are a wide variety of
macrolides produced by Streptomyces spp., most of which have some antibiotic activity.
Many are readily identified by names ending in “mycin”.
Note: Streptococcus are a separate genus
Tetracyclines: produced from polyketide chain through series of aldol condensations, enolizations, and oxidations, similar to biosynthesis of anthrones. They have broad-spectrum activity against a variety of Gram-positive and Gram-negative bacteria.
Bacterial resistance to tetracyclines has developed in pathogens such as Pneumococcus, Staphylococcus, Streptococcus, and E.coli. Mechanism of resistance: decreased cell permeability, and membrane-embedded transport proteins that export the tetracycline out of the cell before it can exert its effect. Still effective for infections caused by Chlamydia, Mycoplasma, Brucella, Rickettsia, and chronic bronchitis due to Haemophilusinfluenzae.
that cause fruit & root rot
Macrolide ring formation and modification:
The macrolide antibiotics are a large family of compounds, many with antibiotic activity,
- characterized by a macrocycliclactone ring (12, 14, or 16 membered)
- the poly-b-keto chain undergoes reductions, dehydrations, during chain extension, so the molecule will not undergo cyclizations to fully aromatic structure.
target Gram-positive bacteria
Mode of action: “hijacks”
replication by binding to 50S
subunit of bacterial ribosome,
blocking translocation of
growing peptidyl RNA
are used in building
Produced by Streptomycesambofaciens
Used to treat toxoplasmosis,
a feline disease caused by
to treat Candida
Works by binding
to ergosterol, a
sterol in the fungal
causing pores to
form, cells leak vital
Used to treat yeasts & Cryptococcus, and
also to reduce mold growth on surfaces
of the sponge (3 kg) and found to kill HCT-116 colon
cancer cells at sub uM concentrations.
IC50 = 8 ng/mL for (2)
Hurgholide A inhibited Candida at 31 ug/mL
How do they work?
These macrolides kill cells by disrupting the actin cytoskeleton.
One dimeric molecule binds simultaneously to two molecules of G-actin, forming a tertiary complex and inhibiting polymerization.
The Swinholides also cause the filamentous actin strands to break.
All caused loss of cellular microfilaments at nM concentrations.
Cells treated with swinholide I collapsed and formed neuron-like structures.
Compounds 2 & 3 were isolated
after several rounds of column chromatography in mg quantities.
Many marine toxins are complex polyethers with origins in the acetate pathway
The brevetoxins are potent
neurotoxins that bind to sodium channels , keeping them open.
Brevenal (below) is a functional
antagonist to brevetoxin, inhibiting its activity in all assays.
Brevenal reduces brevetoxin
binding to rat brain synaptosomes, blocks brevetoxin-induced
bronchoconstriction in sheep, and reduces brevetoxin toxicity in fish.
Biosynthetic studies have shown that fragments
from the citric acid cycle and a 4C starter unit from
mevalonate are involved in generating C skeleton.
Some of the methyls originate from methionine.
Kareniabrevisis a marine dinoflagellate known for production of several different families of bioactive ladder-frame polyether compounds. They contain similar trans-fused, ladder-shaped, cyclic ether ring systems; with ring sizes (5 to 9-membered rings), number of rings (4, 5, 6, 10, and 11), and side chains vary among the different families. Algal blooms by this organism cause
red tide in Florida.
sites as the toxins but do not cause
toxic effects at nM concentrations.