Antimicrobial Compounds from Endolichenic Fungi

Antimicrobial Compounds from Endolichenic Fungi: Comparison

Please note this is a comparison between Version 1 by Priyani Ashoka Paranagama and Version 2 by Peter Tang.

A lichen is a symbiotic relationship between a fungus and a photosynthetic organism, which is algae or cyanobacteria. Endolichenic fungi are a group of microfungi that resides asymptomatically within the thalli of lichens. Endolichenic fungi can be recognized as luxuriant metabolic artists that produce propitious bioactive secondary metabolites.

endolichenic fungi
antibacterial
antifungal
antiviral
antiplasmodial
secondary metabolites

1. Introduction

Thousands of microorganisms, including fungi and bacteria, often associate with living and dead plant tissues [1]. Oftentimes, the importance of these microorganisms is unobserved; only the saprotrophic and pathogenic relationships are being investigated, and are viewed as a troublesome group of organisms. However, there are groups of micro-organisms that are phyto-friendly and able to produce a plethora of secondary metabolites with significant biological activities that will aid them to adapt better to their surroundings ^[2][3][2,3].

Lichens are an amalgamation or a symbiotic partnership between a fungus and a photosynthetic organism. The heterotrophic fungal partner is termed as a “mycobiont”, while the photoautotrophic “photobiont”, could be either green algae or cyanobacteria ^[4][5][6][4,5,6]. As the mycobiont usually plays the more prominent member, lichens have traditionally exhibited characteristics similar to theirs. The two partners share water, nutrients and gases [6] and this mutualism allows the lichens to develop under extremely exceptional ecological conditions like deserts, rocky coasts, alpine zones and droughts ^[5][6][7][8][5,6,7,8]. Living under these unusual conditions enables lichens to give birth to a variety of luxurious compounds with complex structures and numerous bioactivities, making this a highly interesting stream for natural product chemists to pursue ^[8][9][10][8,9,10]. However, lichen flora is less abundant in the neighbourhood of urban and industrialized areas, as lichens are easily affected by air pollutants [11]. Lichens display a wide distribution of more than 20,000 different species worldwide [12], and have been utilized on various occasions in the past, such as in food, perfumes, dyes and as antidotes for folk medication ^[10][11][10,11].

2. Antimicrobial Compounds Extracted from Endolichenic Fungi

The need for new antimicrobial drugs is enhanced by the emergence of microbial resistance against almost all the currently available antibiotics and the sudden appearance of deadly viral infections ^[13][35]. Discovery of novel antimicrobial drugs was speculated as a solution to the growing threat of antibiotic-resistant microorganisms by the former secretary general of the United Nations, Ban Ki-Moon, at the UN General Assembly in 2016 ^[14][36].

The significant role of fungal species in producing antibiotics is elicited after the discovery of Penicillin G in 1928 [7]. Symbiotic fungal species like endophytic fungi are known to produce a plethora of antimicrobial compounds pertinent in therapeutics and agriculture ^[15][37]. Similar to other symbiotic fungi, ELF produces several secondary metabolites, which protect the lichen from biotic as well as abiotic stress ^[16][38]. ELF-derived antimicrobial compounds are one such group of metabolites essential to overcome the constant microbial threats faced by lichens. In some cases, extracts or natural products isolated from ELF show strong antimicrobial properties even though these bioactivities are not naturally observed within their ecological niche.

The discovery of many antimicrobial metabolites from ELF, establishes a hopeful satisfaction to the perpetual thirst for new antimicrobial drugs. However, these compounds might need further optimizations to modify their pharmacological and toxicological profiles. On the other hand, the development of synthetic pathways to produce these compounds, an industrial scale is essential to minimize the cost of production and minimize the environmental impacts. Thus, a detailed summary is provided here to describe the antimicrobial compounds isolated from ELF, including their sources, structures, activities and potencies in antimicrobial drug discovery.

Addressing the aforesaid requirement, Table 1 of this review provides an overview of antimicrobial secondary metabolites isolated from ELF, which includes 31 antibacterial compounds, 58 antifungal compounds, two antiviral compounds, and one antiplasmodial (antimalarial) compound. The structures of these compounds are given in the Figure 1. Most of the authors have either reported only the antimicrobial properties of the lichenic and endolichenic fungal extracts without isolation of the metabolites responsible for the relevant bioactivity or have not quantified it in the form of Minimum Inhibitory Concentration (MIC) or IC₅₀. However, only the endolichenic fungal secondary metabolites, whose antimicrobial properties are satisfactorily quantified, are summarized in this review. For ease of comparison, all of the antimicrobial potencies are presented in µg/mL and activities of the positive control are also given wherever available.

Figure 1. Structures of the antimicrobial compounds isolated from ELF.

Table 1. Antimicrobial Compounds Isolated from ELF.

Lichen	Scaffold					Compounds				Compound					Activity (µg/mL)			Positive Control			Activity (µg/mL)			Reference
Diorygma hieroglyphicum		Talaromyces funiculosus
							4, 9, 14, 15, 25	1		, 42,		Funiculosone	43, 44,		Escherichia coli		45,		IC₅₀ = 25			-			-	53, 54, 56, 57, 66, 67, 68, 69, 70, 71	^[17]	[39]
					Staphylococcus aureus			1				Funiculosone
						IC₅₀ = 58		1, 2, 3, 5, 8, 10, 18, 19, 20, 21, 30,		-		31, 55	-
			,	59			2		Mangrovamide J			Escherichia coli
							2		Mangrovamide J			IC₅₀ = 65		-			-
				24, 26, 33, 34, 35, 36, 37, 38, 39, 40, 41			Staphylococcus aureus
	IC₅₀ = 104				48, 49, 50, 51, 52		-		-
3		Ravenilin		Escherichia coli			IC₅₀ = 23		-			-
				Pseudomonas aeruginosa
							17,	IC₅₀ = 96			-		-
Staphylococcus aureus		IC₅₀ = 25		-			-
Everniastrum sp.		Ulocladium sp.		4			6-hydroxy-8-methoxy-3a-methyl-3a,9b-dihydro-3H-furo[3,2-c]isochromene-2,5-dione		Bacillus subtilis			IC₅₀ = 25.0		Gentamicin			IC₅₀ < 0.048		^[18]	[40]
				5			6-O-methylnorlichexanthone		Bacillus subtilis			IC₅₀ = 0.39
				6			Altenusin		Bacillus subtilis			IC₅₀ = 11.3
				7			Alterlactone		Bacillus subtilis			IC₅₀ = 11.8
				8			Griseoxanthone C		Bacillus subtilis			IC₅₀ = 0.35
				9			Isoaltenuene		Bacillus subtilis			IC₅₀ = 14.7
				10			Norlichexanthone		Bacillus subtilis			IC₅₀ = 0.58
				10			Norlichexanthone		Methicillin Resistant Staphylococcus aureus.			IC₅₀ = 5.4		Vancomycin			IC₅₀ < 1.03
				11			Tricycloalternarene 1b		Bacille Calmette-Guérin strain			MIC = 125		-			-		^[19]	[41]
		Ulocladium sp. (CHMCC 5507)		12			Ophiobolin P		Bacillus subtilis			MIC = 12.6		Gentamicin			MIC = 0.05		^[20]	[27]
				12			Ophiobolin P		Methicillin Resistant Staphylococcus aureus.			MIC = 25.1		Vancomycin			MIC = 1.0
				13			Ophiobolin T		Bacille Calmette-Guérin strain			MIC = 12.7		Hygromycin			MIC = 0.35
									Bacillus subtilis			MIC = 6.3		Gentamicin			MIC = 0.05
									Methicillin Resistant Staphylococcus aureus			MIC = 12.7		Vancomycin			MIC = 1.0
Parmelinella wallichiana		Nigrospora sphaerica		14			Alternariol		Bacillus subtilis			MIC = 31.2		Amikacin sulfate			MIC = 0.45		^[21]	[42]
									Escherichia coli			MIC = 62.5					MIC = 0.90
									Staphylococcus aureus			MIC = 62.5					MIC = 0.90
				15			Alternariol-9-methyl ether		Bacillus subtilis			MIC = 62.5					MIC = 0.45
								61	, 63			Pseudomonas				fluorescens					MIC = 31.2			MIC = 0.90
									Staphylococcus aureus			MIC = 62.5					MIC = 0.90
Parmotrema rampoddense		Fusarium	proliferatum			16		Acetyl tributyl citrate			Klebsiella pneumoniae		MIC = 125			-			-		^[22]	[43]
											Pseudomonas aeruginosa		MIC = 125			-			-
											Staphylococcus aureus		MIC = 125			-			-
						17		Fusarubin			Escherichia coli		MIC = 1.56			-			-
											Pseudomonas aeruginosa		MIC = 1.56			-			-
											Staphylococcus aureus		MIC = 1.56			-			-
Parmotrema ravum		Aspergillus niger		18			Asperpyrone A		Staphylococcus aureus MTCC 737			IC₅₀ = 112		-			-		^[23]	[44]
				19			Aurasperone A		Dickeya solani GBBC 1502			IC₅₀ = 63		-			-
									Listeria innocua LMG11387			IC₅₀ = 141		-			-
									Pectobacterium sp.			IC₅₀ = 76		-			-
									Pseudomonas aeruginosa MTCC 424			IC₅₀ = 160		-			-
									Pseudomonas syringae pv. Maculicola I11004			IC₅₀ = 80		-			-
									Staphylococcus aureus MTCC 737			IC₅₀ = 135		-			-
				20			Carbonarone A		Dickeya solani GBBC 1502			IC₅₀ = 88		-			-
				21			Fonsecinone A		Escherichia coli MTCC 443			IC₅₀ = 47		-			-
									Pseudomonas syringae pv. Maculicola I11004			IC₅₀ = 154		-			-
									Staphylococcus aureus MTCC 738			IC₅₀ = 120		-			-
				22			Pyrophen		Aeromonas hydrophila ATCC 7966			IC₅₀ = 78		-			-
									Listeria innocua LMG11387			IC₅₀ = 86		-			-
									Micrococcus luteus DPMB3			IC₅₀ = 63		-			-
Sticta fuliginosa		Xylariaceae sp. (CR1546C)		23			(R)-4,6,8-trihydroxy-3,4-dihydro-1(2H)-naphthalenone		Bacillus subtilis			IC₅₀ = 104.2		Streptomycin sulphate			IC₅₀ = 5.2		^[24]	[45]
				24			18-O-acetylambuic acid		Staphylococcus aureus ATCC 6538			IC₅₀ = 10.9		Antimicrobial peptide (AMP)			^[25]	[46]
				25			6,8-dihydroxy-(3R)-(2-oxopropyl)-3,4-dihydroisocoumarin		Bacillus subtilis			IC₅₀ = 106.4		Streptomycin sulphate			IC₅₀ = 5.2		^[24]	[45]
				26			Ambuic acid		Staphylococcus aureus ATCC 6538			IC₅₀ = 15.4		Antimicrobial peptide (AMP)			^[25]	[46]
Usnea sp.		Hypoxylon fuscum		27			16-α-D-mannopyranosyloxyisopimar-7-en-19-oic acid		Staphylococcus aureus CGMCC 1.2465			MIC = 46.4		Vancomycin Hydrochloride			MIC = 3.12		^[26]	[47]
				28			8-methoxy-1-naphthyl-β-glucopyranoside		Staphylococcus aureus CGMCC 1.2465			MIC = 30.1
				29			Phomol		Staphylococcus aureus CGMCC 1.2465			MIC = 21.1
-		Coniochaeta sp.		30			Coniothienol A		Enterococcus faecalis (CGMCC 1.2535)			IC₅₀ = 4.89		Ampicillin			IC₅₀ = 2.61		^[27]	[48]
				30			Coniothienol A		Enterococcus faecium (CGMCC 1.2025)			IC₅₀ = 2.00					IC₅₀ = 0.51
				31			Coniothiepinols A		Enterococcus faecalis (CGMCC 1.2535)			IC₅₀ = 11.51					IC₅₀ = 2.61
				31			Coniothiepinols A		Enterococcus faecium (CGMCC 1.2025)			IC₅₀ = 3.93					IC₅₀ = 0.51
Cetraria islandica		Myxotrichum sp.		32			Myxodiol A		Candida albicans SC 5314			MIC = 128		Fluconazole			MIC = 2		^[28]	[49]
		Pestalotiopsis sp.		33			Ambuic acid derivative 1		Fusarium oxysporum			MIC = 8		Ketoconazole			MIC = 8		^[29]	[50]
				34			Ambuic acid derivative 2

							23, 64		Fusarium oxysporum			MIC = 32					MIC = 8
				35			Ambuic acid derivative 4		Verticillium dahlia			MIC = 32					MIC = 1
				36			Ambuic acid derivative 5		Fusarium gramineum			MIC = 8					MIC = 8
									Fusarium oxysporum			MIC = 8					MIC = 8
									Verticillium dahlia			MIC = 16					MIC = 1
				37			Ambuic acid derivative 6		Fusarium gramineum			MIC = 8					MIC = 8
				38			Ambuic acid derivative 7		Rhizoctonia solani			MIC = 32					MIC = 8
				39			Ambuic acid derivative 8		Rhizoctonia solani			MIC = 32					MIC = 8
				40			Ambuic acid derivative 9		Fusarium gramineum			MIC = 32					MIC = 8
Fusarium oxysporum		MIC = 16		40			Ambuic acid derivative 9		MIC = 8
41		Ambuic acid derivative 11		Fusarium gramineum			MIC = 32		MIC = 8
Cetrelia sp.		Aspergillus sp. CPCC 400810		42			Isocoumarindole A		Candida albicans			MIC = 32.0		Caspofungin			MIC = 0.03		^[30]	[51]
Diorygma hieroglyphicum		Talaromyces funiculosus		1			Funiculosone		Candida albicans			IC₅₀ = 35		-			-		^[17]	[39]
Everniastrum sp.		Ulocladium sp.		43			7-hydroxy-3-(2-hydroxy-propyl)-5-methyl-isochromen-1-one		Candida albicans SC 5314			IC₅₀ = 45.4		Amphotericin B			IC₅₀ = 1.03		^[18]	[40]
				44			7-hydroxy-3,5-dimethyl-isochromen-1-one		Candida albicans SC 5314			IC₅₀ = 18.7					IC₅₀ = 1.03
				6			Altenusin		Aspergillus fumigatus			IC₅₀ = 57.5					IC₅₀ = 0.74
				8			Griseoxanthone C		Candida albicans SC 5314			IC₅₀ = 40.6					IC₅₀ = 1.03
				10			Norlichexanthone		Aspergillus fumigatus			IC₅₀ = 43.6					IC₅₀ = 0.74
				45			Rubralactone		Aspergillus fumigatus			IC₅₀ = 63.3					IC₅₀ = 0.74
				45			Rubralactone		Candida albicans SC 5314			IC₅₀ = 54.7					IC₅₀ = 1.03
Lethariella zahlbruckner		Tolypocladium cylindrosporum		46			Pyridoxatin		Candida albicans (Multiple strains)			MIC =	0.5 − 8.0			Fluconazole			MIC =		1.0 − 2.0		^[31]	[52]
									Candida glabrata (Multiple strains)			MIC =	1.0 − 8.0						MIC =		1.0 − 2.0
									Candida krusei (Multiple strains)			MIC =	1.0 − 4.0						MIC =		1.0 − 2.0
									Candida tropicalis CT2			MIC = 32		MIC = 2.0
Lobaria quercizans		Aspergillus versicolor		47			3,7-dihydroxy-1,9-dimethyldibenzofuran		Candida albicans			MIC = 64		Fluconazole			MIC = 2		^[32]	[53]
				48			Cordyol C		Candida albicans			MIC = 8
				49			Diorcinol D		Candida albicans			MIC = 8
				50			Diorcinol I		Candida albicans			MIC = 32
				51		Violaceol I		Candida albicans			MIC = 8
			,	65			52		Violaceol II			Candida albicans										MIC = 8
Parmelia sp.		Periconia sp.		53			3-(2-oxo-2H-pyran-6-yl)propanoic acid		Aspergillus niger			MIC = 31		Cycloheximide			MIC < 16		^[33]	[54]
				54			Pericocin A		Aspergillus niger			MIC = 31		Cycloheximide			MIC < 16
				55			Pericocin B		Aspergillus niger			MIC = 31
				56			Pericocin C		Aspergillus niger			MIC = 31
				57			Pericocin D		Aspergillus niger			MIC = 31
				58			Pericoterpenoid A		Aspergillus niger			MIC = 31							^[34]	[55]
		Tolypocladium sp. (4259a)		46			Pyridoxatin		Candida albicans			MIC = 0.5		-			-		^[35]	[56]
Parmelinella wallichiana		Nigrospora sphaerica		14			Alternariol		Candida albicans			MIC = 80.0		Ketoconazole			MIC = 1.90		^[21]	[42]
Parmotrema ravum		Aspergillus niger		59			Aspergyllone		Candida parapsilosis			IC₅₀ = 52		-			-		^[23]	[44]
				19			Aurasperone A		Candida krusei MTCC 9215			IC₅₀ = 373		-			-
				20			Carbonarone A		Candida albicans MTCC 227			IC₅₀ = 103		-			-
				20			Carbonarone A		Candida krusei MTCC 9215			IC₅₀ = 31		-			-
				22			Pyrophen		Candida albicans MTCC 227			IC₅₀ = 74		-			-
									Candida glabrata			IC₅₀ = 97		-			-
									Candida utilis IHEM 400			IC₅₀ = 62		-			-
Pseudosyphellaria sp.		Biatriospora sp.		60			2-acetonyl-3-methyl-5-hydroxy-7-methoxynaphthazarin		Candida albicans			MIC = 64		Fluconazole			MIC = 2		^[36]	[29]
				61			6-deoxy-7-O-demethyl-3,4-anhydrofusarubin		Candida albicans			MIC = 32
				62			Biatriosporin D		Candida albicans			MIC = 16
				63			Biatriosporin K		Candida albicans			MIC = 64
Sticta fuliginosa		Xylariaceae sp. (CR1546C)		64			(3R,4S)-3,4,8-trihydroxy-3,4-dihydro-1(2H)-naphthalenone		Candida albicans			IC₅₀ = 63.2		Amphotericin B			IC₅₀ = 1.3		^[24]	[45]
				65			(3S,4S)-3,4,6,8-tetrahydroxy-3,4-dihydro-1(2H)-naphthalenone		Candida albicans			IC₅₀ = 67.8
				23			(R)-4,6,8-trihydroxy-3,4-dihydro-1(2H)-naphthalenone		Candida albicans			IC₅₀ = 78.2
				66			2,4-dihydroxy-6-(2-oxopropyl)-benzoic acid		Candida albicans			IC₅₀ = 101.3
				67			5,6,8-trihydroxy-3(R)-methyl-3,4-dihydroisocoumarin		Candida albicans			IC₅₀ = 71.4
				68			6,8-dihydroxy-(3)-(2-oxopropyl)-isocoumarin		Candida albicans			IC₅₀ = 98.1
				25			6,8-dihydroxy-(3R)-(2-oxopropyl)-3,4-dihydroisocoumarin		Candida albicans			IC₅₀ = 71.2
				69			6,8-dihydroxy-3(R)-methyl-3,4-dihydroisocoumarin		Candida albicans			IC₅₀ = 65.1
				70			6,8-dihydroxy-3-[(2S)-2-hydroxypropyl]-isocoumarin		Candida albicans			IC₅₀ = 99.1
				71			6,8-dihydroxy-3-methylisocoumarin		Candida albicans			IC₅₀ = 67.2
Umbilicaria sp.		Floricola striata		72			Floricolin A		Candida albicans			MIC = 16		-			-		^[37]	[57]
				73			Floricolin B		Candida albicans			MIC = 8		-			-
				74			Floricolin C		Candida albicans			MIC = 8		-			-
				75			Floricolin D		Candida albicans			MIC = 64		-			-
				76			Terphenyl 2		Candida albicans			MIC = 64		-			-
Usnea baileyi		Xylaria venustula		77			N-dodecyldiethanolamine (DDE)		Candida albicans NCTC713			MIC = 5.5		-			-		^[38]^[39]	[33,58]
				78			Piliformic acid		Colletotrichum gloeosporioides			MIC = 625.2		Captan			MIC = 5000		^[38]^[40]	[33,59]
				78			Piliformic acid		Colletotrichum gloeosporioides			MIC = 625.2		Difenoconazole			MIC = 8.1		^[38]^[40]	[33,59]
-		Coniochaeta sp.		31			Coniothiepinols A		Fusarium oxysporum (CGMCC 3.2830)			IC₅₀ = 13.12		Carbendazim			IC₅₀ = 0.44		^[27]	[48]
Parmelinella wallichiana		Nigrospora sphaerica		14			Alternariol		Herpes Simplex Virus			IC₅₀ = 34.9		-			-		^[41]	[26]
Parmelinella wallichiana		Nigrospora sphaerica		15			Alternariol-9-methyl ether		Herpes Simplex Virus			IC₅₀ = 64.0		-			-		^[41]	[26]
Usnea baileyi		Xylaria venustula		79			Isoplysin A		Plasmodium falciparum			MIC = 0.97		-			-		^[38]^[42]	[33,60]

3. Structural Features Which Affect the Antimicrobial Activity of the Compounds

ELF are metabolically versatile organisms that can produce secondary metabolites belonging to different natural product classes. However, by observing the structures of the compounds isolated from ELF categorized above, some common scaffolds leading to distinct antimicrobial properties can be identified. Knowledge of the bioactivities of such chemical scaffolds plays an important role in rational drug discovery and in natural product-related research to make intelligent guesses about the potentials of isolated compounds. The presence of a large pool of data about the potencies of natural compounds or their synthetic or semi-synthetic derivatives with common scaffolds will be helpful in structure–activity relationship (SAR) studies. In order to facilitate such studies, we have summarized the structural scaffolds in Table 2 that can be identified commonly among the antimicrobial compounds isolated from ELF.

Table 2. Common structural scaffolds among the antimicrobial compounds isolated from ELF.