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3 Echinocandins, Pneumocandin and Papulacandin

3 Echinocandins, Pneumocandin and Papulacandin

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4



S.M. Mandal et al.



Table 1.1 Natural strobilurins with their respective structure

Natural

isolated

Strobilurin

General

structure



Strobilurin A



Structure



Substitution in

R1 and R2



Name of the

fungus



HÀ in both R1

and R2



Strobilurus

tenacellus



Anke et al. (1977),

Balba (2007), and

Schramm et al. (1978)



Strobilurus

tenacellus



Anke et al. (1977),

Balba (2007), and

Schramm et al. (1978)



Xerula

sp. (agaricales)



Balba (2007) and Anke

et al. (1983)



Cyphellopsis

anomala



Balba (2007) and

Weber et al. (1990b)



Crepidotus

fulvotomentosus.



Weber et al. (1990a)



Strobilurin B

in R1 and ClÀ in

R2



Strobilurin C



Reference



in R1 and ClÀ in

R2

Strobilurin D



in R1 and



in R2

Strobilurin E



(continued)



1



Fungi Fights Fungi: Tip-off in Antifungal Chemotherapy



5



Table 1.1 (continued)

Natural

isolated

Strobilurin

Strobilurin F



Structure



Substitution in

R1 and R2

ÀOH in R1 and



Name of the

fungus

Cyphellopsis

anomala and

Bolinea lutea. I.



Reference

Balba (2007), Weber

et al. (1990b),

Fredenhagen

et al. (1990a, b)



in R2



Strobilurin G



Strobilurin H



in R2

ÀOH in R1 and

ÀH in R2



from each other (Fig. 1.2). Several unusual

amino

acids

like

dihydroxyornithine,

4-hydroxyproline, dihydrooxy homotyrosine

and 3-hydroxy-4-methylproline, as well as two

threonine component of hexapeptide nucleus are

reported (Kurtz and Rex 2001).

In 1977, a new antifungal antibiotic,

Aculeacin is isolated from the mycelial cake of

Aspergillus

aculeatus

M-4214

(Mizuno

et al. 1977b). Subsequently, another six new

antibiotics were isolated as the minor

components related to aculeacin A from the

same culture named as aculeacins B, C, D, E, F

and G. The structure of Aculeacin is similar to

echinocandin B but differs in the acyl moiety.

Their acyl moiety is either the myristoyl

(aculacin Aα–Dα) or palmytoyl (aculacin Aγ–

Dγ)

group.

Physicochemical

properties

aculeacins B, C, D, E, F and G were analogous

to those of aculeacin A and they all showed



Bolinea lutea. I.



Balba (2007), Weber

et al. (1990a), and

Fredenhagen

et al. (1990a, b)



Bolinea lutea. I.



Balba (2007), and

Fredenhagen

et al. (1990a b)



significant activity against fungi (Satoi

et al. 1977).

Pneumocandin is another fungi-mediated

antifungal compound. Pneumocandin has a sulfate moiety in the molecule and is differentiated

from echinocandins by their structural difference

(Fig. 1.2). The first member of pneumocandin

class was pneumocandin B0 and was isolated

from Glarea lozoyensis in 1985 at CIBE, a subsidiary of Merck located in Madrid, Spain. Subsequently, pneumocandin Ao was also reported

from same culture by the same research group

(Schwartz et al. 1989, 1992). Pneumocandin Ao

is less haemolytic than other member of naturally

occurring echinocandins (Boeck et al. 1989),

whereas pneumocandin Bo appears to be the

most potent glucan synthase inhibitor compared

to other pneumocandin and in vitro and in vivo.

Pneumocandin Bo differs from pneumocandin

Ao only by the absence of a methyl on one of



6



S.M. Mandal et al.



Table 1.2 Natural Echinocandin with fungal in origin

Echinocandins

Echinocandin A

Echinocandin B



Fungus origin

Aspergillus nidulans

A. rugulosus

Aspergillus nidulans, A. rugulosus

A. nidulans var. roseus A. rugulosus



Reference

Geiser et al. (2007)

Nyfeler and Keller (1974),

Geiser et al. (2007), and

Traber et al. (1979)



Echinocandin c



A. rugulosus



Traber et al. (1979)



Echinocandin d



A. rugulosus



Traber et al. (1979)



Aculeacin A–G



Aspergillus aculeatus, A. japonicus

var. aculeatus



Mizoguchi et al. (1977a),

Mizuno et al. (1977a),

Satoi et al. (1977), and

Hino et al. (2001)



Mulundocandin

deoxymulundocandin



Aspergillus sydowi



Roy et al. (1987),

Mukhopadhyay

et al. (1992), and Hawser

et al. (1999)



Cryptocandin



Cryptosporiopsis quercina



Strobel et al. (1999)



“Catechol-sulfate” echinocandins

(have thesame peptide nucleus as

echinocandin B but an N-palmitoyl

side chain (FR901379, FR901381-82,

FR190293, FR209602-4, FR220897,

FR220899, FR227673)

Pneumocandin A–E



Coleophoma empetri, Coleophoma

crateriformis



Iwamoto et al. (1994), and

Kanasaki et al. (2006a, b,

c)



Glarea lozoyensis, Pezicula

carpinea, Cryptosporiopsis

G. lozoyensis, Pezicula carpinea,

Cryptosporiopsis sp., Aspergillus

aculeatus



Satoi et al. (1977),

Schwartz et al. (1989,

1992), Nobel et al. (1991),

Morris et al. (1994), Bills

et al. (1999), Mizoguchi

et al. (1977)



Sporiofungin A–C



Cryptosporiopsis sp.



Tscherter and Dreyfuss

(1982)



WF11899s



Coleophoma empetri



Hino et al. (2001)



WF738s



Coleophoma crateriformis



Hino et al. (2001)



WF14573s



Coleophoma empetri



Hino et al. (2001)



WF16616



Tolypocladium parasiticum



Hino et al. (2001)



WF22210



Chalara sp.



Hino et al. (2001)



Aculeacin A–G



A aculeatus, Aspergillus japonicus

var. aculeatus



Mizuno et al. (1977a, b),

Satoi et al. (1977), Hino

et al. (2001)



1



Fungi Fights Fungi: Tip-off in Antifungal Chemotherapy



Echinocandin



R



R1



Echinocandin B



linoleoyl



OH



Echinocandin C



linoleoyl



H



Echinocandin D



linoleoyl



H



Aculeacin Ay



palmitoyl



OH



Mulundocandin



12-methylmyristoyl



sporiofungin A



R2



7



R3



R4



R5



R6



R7



R8



OH



OH



CH3



CH3



OH



OH



CH3



CH3



H



OH



-



H



OH



H



H



CH3



CH3



H



OH



OH



OH



CH3



CH3



H



OH



OH



OH



OH



H



H



H



OH



10,12-dimethylmyristoyl



OH



OH



OH



CH2CONH2



H



H



OH



Pneumocandin Ao



10,12-dimethylmyristoyl



OH



OH



OH



CONH2



CH3



H



OH



CH3



Pneumocandin Bo



10,12-dimethylmyristoyl



OH



OH



OH



CONH2



CH3



OH



OH



H



Lipopeptide family



Pneumocandin Co



OH



OH



OH



CONH2



-



OH



OH



H



WF11899A



palmitoyl



OH



OH



OH



CONH2



CH3



OSO3H



OH



H



L693, 989



10,12-dimethylmyristoyl



OH



OH



OH



CONH2



CH3



-



OPO(OH)2



H



L 705, 589



10,12-dimethylmyristoyl



OH



OCH2CH2NH2



OH



CONH2



CH3



-



OH



H



L 731, 373



10,12-dimethylmyristoyl



OH



OH



OH



CH2NH2



CH3



-



OH



H



L733, 560



10,12-dimethylmyristoyl



OH



OCH2CH2NH2



OH



CH2NH2



CH3



-



OH



H



Fig. 1.2 Structure of echinocandin compounds. Structural skeleton (above picture) with variable functional groups

(listed at lower side)



the proline ring (Lora´nd and Kocsis 2007)

(Lorand). Both the drug shows low water solubility that makes it difficult to formulate.

Pneumocandin Co is another structural isomer

of pneumocandin Bo with a hydroxyl group at

the c-4 of proline. Pneumocandin Do possess

hydroxyl group at both c-3 and c-4 of proline.

Pneumocandin Eo has no hydroxyl groups on the

proline at position 1. Sporiofungin is another

echinocandins type of antifungal antibiotic

isolated from Coleophoma empetri. Three

sporiofungin antibiotics exist in the form of

Sporiofungin A, B and C. This compound poses

potent antifungal action against Candida.

Sporiofungins do not contain Thr but they have

3R-hydroxyl-L-Gln, and L-Ser residues at position 5 and 2, respectively. Besides the

3R-hydroxyl-LGln moiety, they also have a



10,12-dimethylmyristoyl acyl group, similar to

pneumocandins (Emri et al. 2013). Eli Lilly

Company has it under clinical trials by the

name LY-303366.

Mulundocandins a lipopeptide antibiotic

belonging to the echinocandin class. The first

report of isolation was done in 1987 from Aspergillus sydowi strain no. Y-30462 (Roy

et al. 1987). This compound has 10,12dimethylmyristoyl acyl moiety and they contain

L-Ser (instead of LThr) at position 5 from the

N-terminus Orn (Mukhopadhyay et al. 1992)..

Pneumocandins differ from mulundocandins by

the

3R-hydroxyl-L-Gln

at

position

5 (Mukhopadhyay et al. 1992). This group of

antifungal agent shows broad spectrum activity

against Candida albicans (MIC range

0.5–4.0 μg/ml), C. glabrata (2.0–4.0 μg/ml) and



8



S.M. Mandal et al.



C. tropicalis (1.0–8.0 μg/ml) (Mizuno

et al. 1977b).

Cryptocandin is also a similar class of

echinocandin. It was extracted from the strain

of Cryptosporiopsis cf.quercina, isolated from

an endophyte of Tripterigeum wilfordii stems

(Strobel et al. 1999). More related compound

like WF11899A came to discovery from fungal

endophytes. This compound possess sulphate

group at the para or meta position of the

homotyrosine in the hexapeptide ring. This compound offers minimal inhibitory concentration

values of 0.03–0.07 μg/ml against Candida

albicans, Trichophyton mentagrophytes and

Trichophyton rubrum. It contains palmitoyl moiety and also Gln residue at position 5 which

makes the difference from echinocandin B.

Catechol-sulfate echinocandins are the fungal

metabolites having antifungal activity and have

drawn a remarkable attention nowadays. Their

acyl-moiety is palmitoyl. They have a catecholsulfate core in the homoTyr residue and contain

3R-hydroxyl-L-Gln at position 5. In some cases,

the second amino acid was L-Thr and the others

are L-Ser (Kanasaki et al. 2006b, c). They also

show some heterogeneity (both meta and para

positions may occur) in the position of sulfate

group (Emri et al. 2013). Several synthetic

analogues are reported as FR901379,

FR901381-82,

FR190293,

FR209602-4,

FR220897, FR220899, FR227673, etc.



1.4



Fungi-Derived Antifungal

Compounds Having Anticancer

Activities



1.4.1



Polyketides



Polyketides represent one of the major classes of

natural products known to have members

possessing both anti-cancer and antifungal

activities were shown in Table 1.3. Some wellknown fungal polyketides e.g compactin and

lovastatin having anticancer activity belong to

the statin family (Qiao et al. 2007; Chamilos

et al. 2006; Macreadie et al. 2006). A

dicyclohexene ring system linked to a side



chain with a closed lactone ring or an open acid

form constitutes the basic structure of statin.

Small antifungal polyketides, brefeldin A and

terrain were isolated from P. brefeldianum and

A. terreus, respectively (Betina et al. 1962; Singleton et al. 1958; Ghisalberti and Narbey 1990;

Raistrick and Smith 1935). Griseofulvin, another

famous

polyketide

isolated

from

P. griseofulvum, described earlier in details,

exhibits both anticancer and antifungal activities.

One of the antifungal γ-pyrones, 3-Omethylfunicone, produced by Talaromyces

pinophilus was also seen to have anticancer

activity (Hector 2005). Nowadays, several allied

azaphilones

belonging

to

antifungal

chaetomugilin family were isolated from

Chaetomium globosum (Buommino et al. 2007;

Baroni et al. 2009). The hypocrellins of the

perylenequinone family was isolated from

Hypocrella bambusae, and one of the potent analog hypocrellin D showed both antifungal and

anticancer properties (Cai et al. 2011).



1.4.2



Terpenes



Wortmannin, produced by T. wortmannii, is an

antifungal compound capable of inhibiting the

activity of leukemia HL-60 and K-562

(OH et al. 2001). The fungal genera Bipolaris,

Aspergillus, Sarocladium and Drechslera are the

known sources of sesterterpenes including

ophiobolins (Table 1.4). In addition to anticancer

activity, the ophiobolin family also shows antifungal activity against a wide range of fungi

(Li et al. 1995; Krizsa´n et al. 2010). The isolation

of taxol from the bark of Taxus brevifolia and

identification of taxol as one of the most efficacious drug against cancer followed by the high

demand of raw material led to the search for an

alternative producer strain. The fungus

Taxomyces andreanea and P. raistrickii

produces taxol (Visalakchi and Muthumary

2010; Niedens et al. 2013). Terrecyclic acid A

is an example of another sesquiterpene, isolated

from A. terreus, which exhibit both antifungal

and anticancer activities (Nakagawa and Hirota

1982). Among the several trichothecenes, AETD



1



Fungi Fights Fungi: Tip-off in Antifungal Chemotherapy



9



Table 1.3 Polyketides having both anticancer and antifungal actvities

Producer organism

Talaromyces pinophilus (Penicillium

pinophilum)



Compound

3-Omethylfunicone



P. brefeldianum



Brefeldin A



Chaetomium globosum



11epichaetomugilin

I



P. griseofulvum



Griseofulvin



Hypocrella bambusae



Hypocrellin D



Structure



(continued)



10



S.M. Mandal et al.



Table 1.3 (continued)

Producer organism

P. solitum; P. citrinum



Compound

Compactin



Aspergillus terreus Monascus sp.



Lovastatin



A. terreus



Terrein



has also characteristic cytotoxic activity against

both fungi and cancer cell lines (Woloshuk and

Shim 2013). Another terpene, wentilactones,

isolated from the marine alga-derived endophytic

fungus, Aspergillus wentii, has shown potential

antifungal activity beside its anticancer property

(Sun et al. 2012).



1.5



Fungal Nitrogenous

Compounds Including

Non-ribosomal Peptides (NRPs)



A large group of natural products constituted

nitrogen containing compounds of fungal origin



Structure



that integrate amino acid building blocks into

often complex heteroaromatic compounds such

as

diketopiperazines,

quinazolines

and

benzodiazepines known to have biological

activities (Table 1.5). These compounds contain

primary, secondary or tertiary amine

functionalities and because of their basic nature

are often called as alkaloids. However,

compounds only containing amide bonds, that

are essentially neutral, are also referred to as

alkaloids.

Several

nitrogen

containing

compounds are produced biochemically with

the aid of non-ribosomal peptide synthases called

non-ribosomal peptides (NRPs) even though they

are also called alkaloids. Xanthocillin X, an



1



Fungi Fights Fungi: Tip-off in Antifungal Chemotherapy



11



Table 1.4 Terpenes having both anticancer and antifungal activities

Producer

organism

T. wortmannii



Compound

Wortamannin



Bipolaris sp.

A. calidoustas

A. ustus



Ophiobolin A



Taxomyces

andreanea



Taxol



A. terreus



Fusarium spp.



A. wentii



Terrecyclic acid A



4-Acetyl-12,13-epoxy-9-trichothecene-3,15diol [AETD]



Wentilactones



Structure



12



S.M. Mandal et al.



Table 1.5 Fungal nitrogenous compounds including non-ribosomal peptides (NRPs) having both anticancer and

antifungal activities

Producer organism

A. fumigatus



Compound

(Diketopiperazines with a disulfide

bridge) Gliotoxin



Emericella striata



(Diketopiperazines with a disulfide

bridge) Emestrin A



A. fumigates

A. fischeri



(Tryptophan/proline diketopiperazines)

Fumitremorgin C



P. chrysogenum



Xanthocillin X



Purpureocillium

lilacinum



(Peptide) Leucinostatin A



Structure



1



Fungi Fights Fungi: Tip-off in Antifungal Chemotherapy



antifungal

compound,

produced

by

P. chrysogenum was also found to inhibit several

cancer cell lines (Frisvad et al. 2004). Diketopiperazines are basically cyclic dipeptides that are

reported to inhibit cell cycle at G2/M phase

(Borthwick 2012). The fumitremorgin group of

compounds among tryptophan/proline diketopiperazines is produced by A. fumigatus and

A. fischeri (Abraham and Arfmann 1990).

Fumitremorgin C, a potent antifungal compound,

was also found active against human carcinoma

cell lines (Zhao et al. 2002). Among another

group of diketopiperazines containing a

di-sulfide bridge in the diketopiperazine ring,

antifungal

compounds,

gliotoxin

and

emestrin A, were shown to be potent inhibitor

of human cancer cell lines (Seya et al. 1986;

Finefield et al. 2012). The peptide

leucinostatin A, isolated from Purpureocillium

lilacinum, was found to be active against a number of fungi and Gram-positive bacteria as well

as several cancer cell lines (Arai et al. 1973;

Kawada et al. 2010).



1.6



Antifungal Metabolites from

Coprophilous Fungi



Coprophilus fungi are the type of saprobic fungi

prefer to grow on animal dung shares a lot of

fruitful metabolites having antifungal activity

and may lead some new in near future. They

have been generally isolated from animal dung

particularly from herbivorous mammals. The

interference competition among coprophilous

fungi in dung environment offers the production

of secondary metabolites by one species that

deter the growth of competitors (Bills and Gloer

2013). Here are some of the coprophilous fungi

with their antifungal metabolites (Table 1.6).



1.7



13



Mechanism of Antifungal

Action



Antifungal drug from natural or synthetic in origin share some common strategies which facilitate to inhibit the fungal cells. Very often the

strategies are cell wall biosynthesis, sphingolipid

synthesis, protein synthesis, electron transport,

membrane integrity, etc. Fungal cell wall composition varies among species to species but

three major polymeric components are glucan,

chitin and mannoproteins. Finding inhibitors of

such polymeric components are the prime objective of cell wall biosynthesis inhibition (Oxford

and Raistrick 1939). Sphingolipids and their

metabolites are present in relatively small proportion modulate various cellular events including proliferation, differentiation and apoptosis

(Brian and Curtis 1946). Inhibition of

sphingolipid synthesis results in disturbance in

fungal growth and subsequent cell death (Brian

1949; Grove and McGowan 1947; Brian and

Curtis 1949).

Apparently, the similarity in human and fungal sphingolipid biosynthetic pathway may seem

that it is difficult to develop a controlling point.

But major enzymatic deviations like serine

palmitoyltranferase, ceramide synthase and IPC

synthase from mammalian system make this as

active target of sphingolipid synthesis. Although

protein synthesis is the primary and most important choice of bacterial inactivation, fungal and

mammalian protein synthesis machinery is

almost same which makes it difficult to target

(Brian and Curtis 1949). Several approaches are

made to overcome such problems. Membrane

integrity and electron transport are the targets of

several antifungal agents. Compounds that target

membrane integrity bind with the common fungal sterols, causing membrane permeability and

leakage of cytoplasmic content yielding cell



14



S.M. Mandal et al.



Table 1.6 Other antifungal compounds from fungi special focus to coprophilous fungi

Name of the compound

Appenolides A–C

Apiosporamide



Name of the fungus

Podospora appendiculata

Apiospora montagnei



Year

1993

1994



Coniochaeta saccardoi.

Sporormiella teretispora

Petriella sordida

Polytolypa hystricis

Cercophora areolata

Podospora anserina

Cercophora sordarioides



1995

1995

1995

1995

1996

1997

1997



References

Wang et al. (1993)

Alfatafta

et al. (1994)

Wang et al. (1995a)

Wang et al. (1995b)

Lee et al. (1995)

Gamble et al. (1995)

Whyte et al. (1996)

Wang et al. (1997)

Whyte et al. (1997)



Ascodesmis sphaerospora

Sporormiella vexans



1998

1999



Hein et al. (1998)

Soman et al. (1999)



Bombardioidea anartia

Lasiosphaeriaceae pleiospora

Nigrosabulum globosum



2001

2001

2001



Hein et al. (2001)

Odds (2001)

Che et al. (2001)



Podospora decipiens.



2002



Terpenoid



Podosordaria tulasnei



2004



Peptide and

Terpenoid



Stilbella erythrocephala



2006



Che and Gloer

(2002)

Ridderbusch

et al. (2004)

Lehr et al. (2006)



Shikimate



Gymnoascus reessii

Pestalotiopsis adusta

Hawaiian fungicolous fungus



2005

2008

2007

2008

1995



australifungin



Polyketide-TCAamino acid

Polyketide



Endophytic fungus, Edenia

gomezpompae.

S. intermedia, and L. elatius

Sporormiella australis



1995



Sporminarins A and B



Polyketide



Sporormiella minimoides



2006



Similins A and B



Polyketide



Sporormiella similis



1992



Marine isolate of the fungus,

Stilbella aciculosa



2001



Coniochaetones A and B:

Terezines A–D

Petriellin A

Polytolypin

Cercophorins A–C:

Anserinones A and B

Coniochaetones and

Cerdarin

Arugosin F:

Sporovexins A–C

Bombardolides

Sordarins

Pseudodestruxins A, B and

Ascochlorin

Decipinin A and

decipienolides A and B

Tulasnein and podospirone

Antiamoebins, myrocin B

Others

Gymnoascolides A–C

Pestalachlorides A–C

Solanapyrone analogues

Naphthoquinone

spiroketal

zaragozic acids



Fusidic acid



Biosynthetic family

Polyketide

Polyketide-amino

acid

Polyketide antifungal

Peptide

Peptide

Terpenoid

Polyketide

Polyketide

Both polyketide

Polyketide

Mixed preussomerin

analog

Modified polyketide

Terpenoid glycoside

Peptide and

Terpenoid/polyketide

Benzopyrans.



Solanapyrone

Naphthoquinone



death (Fig. 1.3). Mitochondrial electron transport

is now used as a target to fungal control.

Compounds (UK2A, UK3A) are structurally

related to actinomycin A, with nine member

dilactone ring offers broad spectrum antifungal

activities (Brian and Curtis 1955; Brian 1949;

Araujo et al. 1990).



1.8



Clark et al. (2005)

Li et al. (2008)

Schmidt and Gloer

(2007)

Macı´as-Rubalcava

et al. (2008)

Bergstrom

et al. (1995)

Mandala

et al. (1995)

Mudur and Gloer

(2006)

Weber and Swenson

(1992)

Kuznetsova

et al. (2001)



Advancement

of Biosynthesized Antifungal

Agents



Fungal origin requires critical care in producing

compound in a large scale that includes from

designing bioreactor to finding optimum



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