5.1 Polyketides: A Link between Evolution and Health€¦ · 5.1 Polyketides: Link between...

5.1 Polyketides: A Link between

Evolution and Health

RA Macahig

FM Dayrit

O

O OH O

O

OH

S

N

Epothilone B

5.1 Polyketides: Link between Evolution and Health (Dayrit) 2

• The polyketides provide a very interesting link between

evolution and health:

• Many polyketides are produced in abundance by

microorganisms principally as defense compounds against

other microorganisms. That is, they are antibiotics.

• The PKS system is modular, flexible and diverse. This

characteristic is consistent with its role as a defense system

that is constantly evolving.

• Humans have depended on certain microorganisms to

produce antibiotics.

• Antibiotic resistance is also a natural evolutionary response

of microorganisms. Because of this, there is a continuing

need to develop polyketide antibiotics.

Introduction


• There are about 10,000 known microbial polyketides,

from which numerous pharmaceutical products in many

therapeutic areas have been derived, including:

adriamycin (doxorubicin), erythromycin, rapamycin,

tetracycline, lovastatin and many others.

• This discussion is divided into the following sections:

1.Evolutionary link between fats and polyketides

2. Overview: Polyketide antibiotics

3. Macrocyclic lactone antibiotics

4.Tetracycline antibiotics

5. Antibiotic resistance

Introduction


Evolutionary

symbiosis

Link between

FAS and PKS?

1. Evolutionary link between fats and polyketides


Organization of the most abundant large multimodular PKS gene cluster in metagenomic libraries from (bacteria associated with) D. dissoluta. The module and color-coded domain structure of the PKS genes is shown at the top, and the predicted polyketide product – a branched fatty acid – is shown at the bottom. (The biological activity of this compound and its role in the sponge-bacteria symbiosis is unknown.)


Bacteria were long believed to be unable to produce polyunsaturated fatty acids, which were previously ascribed exclusively to Eukaryotes. The discovery of PUFAs and bacterial polyketide synthases (PKS) in marine bacteria has caused scientists to revisit this dogma.

Both PKS and FAS use the same core of enzymatic activities and precursors (acetyl-CoA, malonyl-CoA), and ACP as a covalent attachment site for the growing carbon chain. It is believed that the FAS and PKS biosynthetic pathways are evolutionarily connected but probably diverged at an early stage during evolution.


Scheme of possible biosynthetic pathways of fatty acyl chains in piezophilic bacterial membrane lipids. The saturated and monounsaturated fatty acids are synthesized by the FAS pathway. The PUFAs in piezophilic bacteria are probably synthesized via the PKS pathway which may be unique to marine bacteria.

DH, dehydrase ER, enoyl reductase KR, 3-ketoacyl reductase KS, 3-ketoacylsynthase


2. Overview: Polyketide antibiotics Because their evolutionary pressures and strategies are

different, the various microorganisms produce different types

of defensive secondary metabolites. Polyketides are in bold

face.

Organism Activity Examples

Bacteria Antibiotics Streptozotocin, azaserin, daunomycin,

adriamycin, mitomycin C, bleomycin,

amphotericin, nystatin, rapamycin

Fungi Mycotoxins Aflatoxin, sterigmatocystins, ochratoxin

A, patulin, griseofulvin, illudin, ergot

alkaloids

Algae Toxins Brevetoxin, ciguatoxin, laulimalide,


3. Macrocyclic lactone antibiotics

This schematic picture of the ribosome illustrates how it helps attach messenger

RNA (mRNA) and begin the process of translation to make a polypeptide chain.

Macrolides inhibit protein synthesis in bacteria by binding to a

subunit of the bacterial ribosome (50S). Macrolides prevent

peptidyltransferase from adding the peptidyl attached to tRNA

to the next amino acid, as well as inhibiting ribosomal

translocation. The action of macrolides is mainly bacteriostatic,

but it can also be bactericidal in high concentrations.


Rapamycin (also known as sirolimus)

was first discovered in the bacterium

Streptomyces hygroscopicus, and was

originally developed as an antifungal

agent. It is currently being used as an

immunosuppresant drug used to prevent

rejection in organ transplantation,

especially kidney transplants. It is

marketed as Rapamune® by Wyeth.

HO

H3CO

ON

OH

H3C

OH3C

O

O

O

O

H3CHO

O

OCH3

H3CO

CH3

CH3

CH3

H3C

Rapamycin

Filipin was isolated by chemists at

the Upjohn company in 1955 from

the mycelium and culture filtrates of

a previously unknown actinomycete,

Streptomyces filipinensis, that was

discovered in a soil sample collected

in the Philippines. (From: Wikipedia)


Erythromycin has an antimicrobial spectrum

comparable to penicillin, and is often used for

people who have an allergy to penicillins. This

macrocyclic compound contains a 14-membered

lactone ring with ten asymmetric centers and

two sugars (L-cladinose and D-desosamine). It

is produced from a strain of the actinomycete

Saccharopolyspora erythraea. (From: Wikipedia)

Epothilone B was isolated from soil

bacteria collected from southern Africa

in 1987. Large quantities of the lactone

produced by fermentation have been

chemically modified to yield semi-

synthetic analogues which are being

tested against Taxol-resistant cancers. (C&EN, May 13, 2002)

O

O OH O

O

OH

S

N

Epothilone B


Brefeldin A is produced by the fungus, Eupenicillium

brefeldianum. Although initially used as a broad-

spectrum antibiotic, it is now used as a research tool

for the study of protein transport. BFA inhibits the

transport of proteins from ER to Golgi which leads to

a rapid accumulation of proteins within the ER and

collapse of the Golgi stacks; prolonged exposure can

induce apoptosis.

Nargenicin was isolated from Nocardia

argentinensis. It is a tricyclic lactone with

a unique ether bridge. Nargenicin is

effective against Staphylococcus aureus, a

methicillin resistance bacterium. It has also

been shown to induce cell differentiation

and be used as a possible treatment for

neoplastic diseases. (From: Wikipedia)


OH

OH

HO

S-ACP

O

"Diels-Alder"

OH

O

S-ACPOH

H H

HOH

O

OOH

H H

HOH

O

OOH

O H

OH

OH

OCH3

O

N

H

Nargenicin

Nargenicin biosynthesis


4. Tetracycline antibiotics

Tetracyclines are a group of broad-spectrum antibiotics

whose general usefulness has been reduced due to

bacterial resistance. Tetracycline antibiotics bind to the

bacterial 30S ribosomal subunit in the mRNA translation

complex. This inhibits the binding of aminoacyl-tRNA to

the mRNA-ribosome complex.

Macrolides

Tetracyclines


Next to the penicillins, the tetracylines are

the second most important class of

antibacterial metabolites. These are

produced by various Streptomyces spp. and

have the characteristic four linear fused

rings.

Aureomycin

The tetracycline to be discovered in the 1940s was aureomycin. It

was obtained from Streptomyces aureofaciens, a fungus-like, soil-

dwelling bacterium which was golden-colored (hence the name).

H2N

OHOHOO

HO

O

NH

OH

OHH

OH

Oxytetracycline (Tetracycline) was the

second tetracycline to be discovered. It is a

broad spectrum antibiotic; however, some

strains of bacteria have developed resistance

to this antibiotic.


Doxorubicin (adriamycin or

hydroxyldaunorubicin) is an anthracycline

(tetracyclic compound) produced by

Streptomyces species. It interferes with

DNA replication by binding to the

topoisomerase II enzyme, which is

supposed to unwind DNA for transcription.

Doxorubicin is used today in

chemotherapy, in particular for breast and

lung cancer. Doxorubicin is given as a

liposome-encapsulated dosage form

(Doxil® from J&J), which reduces its

cardiotoxicity.

Doxorubicin

OCH3

O

O

OH

OH O

O

OH

OHO

H3C

HONH2


5. Antibiotic Resistance

I eat BULLETS

for breakfast!!!


Percentage of bacteria

resistant to 18

antibiotics. Antibiotics are

color-coded by class.

Among these antibiotics

tested, only the quinolones are

related to the polyketides.

Quinolones block DNA

replication by intercalation.

Tetracyclines are quinolones.


Bacteria have evolved diverse mechanisms of resistance to

antimicrobial agents:

1. Control of uptake and efflux of drugs

2. Modification and detoxification of drugs

3. Alteration or protection of the target sites

4. Acquisition of heterologous resistance genes from external

sources.

5. Mutations in chromosomal genes, e.g, in the 23S rRNA

gene, which inhibit the binding of antibiotics to the

ribosome

In a colony of bacteria living in the

presence of a tetracycline antibiotic

in natural environments, it was

found that individuals that are

sensitive to the antibiotic can co-

exist with those that are resistant;

however, theory says that only

resistant bacteria should survive.

Tetracycline naturally decays in the soil into a number of products:

the stereoisomer epitetracycline (ETC); together with dehydration

products anhydrotetracycline (ATC) and anhydroepitetracycline

(AETC). In the presence of the decay products, the sensitive strain

outcompetes the resistant strain. The precise molecular mechanism

by which degradation products invert selection for resistance is not

understood. (http://www.rsc.org/chemistryworld/News/2010/January/10011001.asp)

Antibiotic decay products reverse resistance


Dr. Henry M. Sobell

http://members.localnet.com/~sobell/homepage.html

Actinomycin-b-DNA Complex

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