¹Department of Biotechnology, Sreenidhi Institute of Science and Technology, Ghatkesar, Hyderabad–501301, India

²Department of Biotechnology, Centurion University of Technology and Management, Bhubaneswar–752050 India

Corresponding author Email: mishra.bishwambhar@gmail.com

Article Publishing History

Introduction

Many research advances have been made in medicine at present. Be it in the treatment of HIV-AIDS, cancer, or organ transplantation, the success rates have increased drastically over past 50 years. Even though success rates have been increased, many patients are left with compromised immune systems (Wisplinghoff et al., 2004). The Patients, receiving chemotherapy, organ transplantation, use of prosthetic Devices and vascular catheters, dialysis etc., are easily susceptible to manybacterial, viral and fungal infections (Spellberg et al., 2008). Even though fungal species are serious pathogens, they get lesser attention when compared to bacterial and viral infections as, the frequency of occurrence of fungal infections has been comparatively less to bacterial and viral infections (Georgopapadakou et al., 1996; Wisplinghoff et al., 2004; Porto et al., 2012). Human fungal infections, caused by Aspergillus fumigatus, Cryptococcusneoformans, Candida albicans, are increasing in a number ofimmune-compromised patients (Blanco et al., 2008). Fungal pathogens such as Candida species and Aspergillus species are more common and account up to 19% of cases (Schelenz et al., 2009). C. albicans is known as major fungal pathogen and is 4^th most common cause of nosocomial infections (Banerjee et al., 1991; Beck-Sague et al., 1993; Wisplinghoff et al., 2004; Xiao et al., 2013; Chen et al., 2016; Ageitos et al., 2017; Bondaryk et al., 2017).

Only a limited number of antifungal drugs are available such as echinocandins, polyenes etc., (Gupte et al., 2002). Amphotericin B, which was discovered in 1956, is still used for treatment many fungal infections. Just like bacterial resistance, fungal pathogens have also developed resistance in past 20 years. (Gold et al., 2002; Georgopapadakou et al., 1996). The fact that fungal and bacterial infections are different and bacterial infections are treated more easily is because, fungal cells are eukaryotic and bacterial cells are prokaryotic. The main concern in treating fungal infections is that any chemical substance that is successful in damaging the eukaryotic cell wall of fungi may also cause possible damage to human cells, unlike antibiotics, which won’t have any effect on humans. Any chemical substance that is toxic to fungus may also be toxic to humans (Mohammad et al., 2015). Therefore, there is need to discover new biochemical targets in fungi. Antifungal peptides are treatment alternatives, derived from natural sources and are effective against fungal infections, thus, safe for immune compromised patients (Gold et al., 2002; Ravi et al., 2011; Thakur et al., 2012; Jia et al., 2016; Wang et al., 2016; Veltri et al., 2017).

Antifungal peptides from natural sources are much cheaper than commercial antifungal drugs and are also better alternative to combat resistance. Antifungal peptides are cationic biomolecules with weight around 1.3 kDa to 30 kDa (Mohammad et al., 2015). Antifungal peptides are classified into two types based on their mode of action. First group are, lytic peptides, (Rees et al., 1997; Shai et al., 1995). These peptides are amphipathic in nature (contain a positive and a neutral charge) and disrupt the membrane structure by fixing onto its surface (Leuschner et al., 2004; Shai et al., 1995). The second group of peptides act by inhibiting the synthesis of cell wall or essential cell wall components such as glucan, chitin (Fernández et al., 2004; Lata et al., 2010; Joseph et al., 2012; Liu et al., 2016; Bondaryk et al., 2017).

Sources Of Antifungal Peptides

Bacterial Peptides Iturins

Iturin was one of first antifungal peptides, ever isolated. It is produced by different strains of Bacillus subtilis (Georgopapadakou et al., 1996). They are cyclic lipopeptides and act by disrupting the cell membrane of fungi, hence leaking its vital ions (XinZhao et al., 2013; Lemaitre et al., 1997). Iturin A, of iturin family, was observed to inhibit A. flavus and F. moniliforme growth and had Minimal inhibitory concentration (MIC) of 22.0 μg/ml against Saccharomyces cerevisiae. It was found to be effective against dermatomycoses. (De Lucca et al., 1999). But iturin A was also observed to be hemolytic. Bacillomycin F, another family member of iturin, is known to inhibit strains such as Byssochlamys fulva, A.niger, C.albicans, and F.oxysporumand had MIC of 40.0μg/ml for A.niger (De Lucca et al., 1999). Bacillomycin D produced by Bacillus amyloliquefaciens was found to be effective against a plant pathogenic fungi Fusarium graminearum and Candida species. MIC of (12.5-25) μg/ml was observed against various Candida species (Tabbene et al., 2015; Qin Gu et al., 2017).

Syringomycins: Syringomycins are produced by Pseudomonas syringae are small cyclic lipodepsipeptides with ergosterol as a binding site in yeast. The most prevalent of Syringomycinsis syringomycin-E (SE) which was found to be lethal to many strains such as A. flavus, A. fumigatus, A.niger, F. moniliforme and F. oxysporum showing LD95 of 1.9 μg/ml. it showed MIC of (0.8–12.5) μg/ml against C. neoformans (De Lucca et al., 1999). Syringotoxin B, syringostantin A which were lipodepsinonapeptides were found to be effective against Candida, Cryptococcus, and Aspergillus species. Syringostantin A had MIC of 5.0μg/ml against A. fumigatus. Syringotoxin B had MIC of 3.2μg/ml against C. albicans (Sorensen et al., 1996; Zhao et al., 2013; Chereddy et al., 2014; Deslouches et al., 2015; Gao et al., 2016; Kubicek-Sutherland et al., 2017).

Pseudomycins: Pseudomycins, another family, structurally related to syringomycins also have antifungal activity against wide ranges of species. Existing as pseudomycins (A, B, and C), these have shown antifungal activity against Ceratocystis ulmi, C. Albicans, Rynchosporium secalis,Rhizoctonia solani,Sclerotiniasclerotiorum Verticillium albo-atrum, Verticillium dahliae, Thielaviopis basicola, F. oxysporum, F. culmorum. The MIC of pseudomycin A, against C. neoformans was 1.56 μg/ml whereas 3.12 μg/ml was observed against C. albicans (De Lucca et al., 1999).

Plant Peptides: Large number of antifungal peptides are identified from plant sources, but only few were tested and found to be effective.

Plant defensins

Plant defensins are eight disulfide-linked cysteines with a single helix and triple-stranded b-sheet (Bruix et al., 1995). Ib-AMP₃, isolated from Impatiens balsamina, was observed to be lethal against germinated conidia of A. flavus by 42%, where as it was non-lethal against non-germinated conidia.It had MIC of 50.0μg/ml against F. moniliforme (De Lucca et al., 1999; Asano et al.,
2013).

Cyclopeptides: Cyclopeptides from different species of Rhamnaceae family were observed to have antifungal activities. Frangufoline, from barks of Rhamnus frangula were observed to have anti-bacterial and anti-fungal properties. It showed MIC of 5.0 μg/ml for A. niger. Nummularine (B, K, R, and S), from stem barks of Ziziphus nummularia, Rugosanine (A and B) from stem barks of Ziziphus rugosa and abyssenine-C from stem barks of Ziziphus abyssinica, were all observed to have antifungal properties against A. niger with MIC of 5 μg/ml. However, they were observed to be well effective against A. niger but not against C. albicans and their mechanism of action was also unknown (Gournelis et al., 1997; De Lucca 2000; Tan et al., 2006).

Lipid transfer proteins and other peptides: ACE-AMP1 is a lipid transfer protein, produced by seeds of Allium cepa which was observed to be effective against F. oxysporum with MIC of 10.0 μg/ml (Cammue et al., 1995; De Lucca 2000). Apart from the above antifungal peptides, some other peptides include, Chitinases and glucanases, which hydrolyze chitin, glucan, and the essential cell wall components of fungi. Prematins, members of PR-5 protein family, act by permeabilizing fungal membranes. Similarly, Thionins inhibit by permeabilizing fungal membranes and were found to be effective against F. graminearum and F. sporotrichioides (Velazhahan et al., 2001; Asano et al., 2013).

Fungal Peptides: Antifungal peptides from fungi are more active than those compared to bacteria and plants. Echinocandins are lipopeptides which inhibit 1,3-â-glucan synthase (Gregory et al., 2007). Glucan is the major component of cell wall of fungi and inhibition of glucan may result in osmotic instability and in cell lysis. (Lee et al., 1995; Gregory et al., 2007; Osorio et al., 2015; Liu et al., 2016). The MIC90 value of echinocandins was found to be ≤2 μg/mL against Candida spp (Zaas et al., 2005). A-192411.29 had anti- fungicidal activity against C. albicans, C. tropicalis and C. glabrata (Vazquez et al., 2005; Kaconis et al., 2011; Chu et al., 2013). But, the echinocandins do not show any antifungal activity against Cryptococcus spp, Trichosporon spp, Fusarium spp, zygomycetes (Zaas et al., 2005; Kazemzadeh-Narbat et al., 2010). They also, do not affect human cells, as human cells do not contain 1,3-â-D-glucan. However, echinocandins are labeled category C and are toxic to embryos (Gregory et al., 2007; Lakshmaiah Narayana et al., 2014).

Table 1: Antifungal peptides from bacterial sources
Peptide name	Family/group	Structure	source	Fungal species effected	Typical target organism	Mode of action	In vitro MIC (μg/ml)	Reference
Bacillomycin F	Iturins	lipopeptide	B. subtilis.	Byssochlamys fulva, A. niger, C.albicans, and F.oxysporum	A. niger	lysis	40	(De Lucca et al., 1999; Bionda et al., 2016)
iturin A	Iturins	lipopeptide	Bacillus amyloliquefaciens	A. flavus, F. moniliforme, S. cerevisiae	S. cerevisiae	lysis	22.0	(Georgopapadakou et al., 1996; De Lucca et al., 1999; Brandenburg et al., 2015)
bacillomycin D	Iturins	lipopeptide	Bacillus amyloliquefaciens	F. graminearum and Candida species.	Candida species	lysis	12.50-25.0	(Tabbene et al., 2015; Qin Gu et al., 2017,)
syringomycin-E (SE)	Syringomycins	lipodepsipeptide	Pseudomonas syringae	A. flavus, A. fumigatus, A.niger, F. moniliforme and F. oxysporum	C. neoformans	lysis	0.8–12.5	(De Lucca et al., 1999; Falciani et al., 2014)
syringostantin A	Syringomycins	lipodepsinonapeptides	Pseudomonas syringae	Candida, Cryptococcus, and Aspergillus species	A. fumigatus	lysis	5.0	(Sorensen et al., 1996; Falciani et al., 2014)
Syringotoxin B	Syringomycins	Lipodepsinonapeptide	Pseudomonas syringae	Candida, Cryptococcus, and Aspergillus species.	C. albicans	lysis	3.2	(Sorensen et al., 1996; Lyu et al., 2016)
pseudomycin A	Pseudomycins	lipodepsinonapeptides	Pseudomonas syringae	C. albicans, F. oxysporum , F. culmorum, C. neoformans	C. albicans	lysis	3.12	(De Lucca et al., 1999; Brunetti et al., 2016)

Micafungin from Coleophoma empedra, caspofungin from Glarea lozoyensis and anidulafungin from A. nidulans of echinocandin family have been approved so far (Murdoch et al., 2004; Montgomery et al., 2013). Of these, anidulafungin displays least MIC values followed by micafungin and caspofungin being most. This was observed against Candida spp. (Zaas et al., 2005; Mojsoska et al., 2015). Caspofungin, also known as (MK-0991) is a second generation pneumocandin from Glarea lozoyensis (Abruzzo et al., 1997; Groll et al., 1999; López-Garcia et al. 2005; Popovic et al., 2012 ). It was fungicidal against C.albicans and C. parapsilosis (Bartizal et al., 1997; Kuhn et al., 2002; Deresinski et al., 2003; Ordonez et al., 2014 ). It was observed be effective against hyphal tips A. fumigatus although not completely lethal (Krishnan et al., 2005). It was also lethal against several molds such as Alternaria sp., Curvularia sp., Acremonium sp., Bipolaris sp., and Trichodermasp (Kahn et al., 2006). Micafungin also known as FK463 had antifungal activity against disseminated candidiasis and aspergillosis (Petraitiset al., 2000; Lakshmaiah Narayana et al., 2015).

Table 2: Antifungal peptides from plant sources
Peptide name	Family/group	No. of amino acids	source	Target organism	In vitro MIC (μg/ml)	Reference
Ib-AMP3	Plant defensins	20	Impatiens balsamina	F. moniliforme	50.0	(De Lucca et al., 1999; Asano et al., 2013)
Frangufoline	Cyclopeptides	*534	Rhamnus frangula	A. niger	5.0	(Gournelis et al., 1997; De Lucca 2000; Tanet al., 2006; Choe et al., 2015)
Rugosanine A	Cyclopeptides	*585	Ziziphus rugosa	A. niger	5.0	(Gournelis et al., 1997; De Lucca 2000; Tanet al., 2006; Cole et al., 2016)
Nummularine	Cyclopeptides	*587	Ziziphus nummularia	A. niger	5.0	(Gournelis et al., 1997; De Lucca 2000; Tanet al., 2006; Dobson et al., 2014)
ACE-AMP1	Lipid transfer proteins	93	Allium cepa L	F. oxysporum	10.0	(De Lucca 2000; Dutta et al., 2015)

The optimal concentration of FR463 at single infusion was observed to be 2.5-25 mg (Azuma et al., 1998; Pettengell et al., 1999; Kasetty et al., 2015; Kang et al., 2017). Anidulafungin (V-echinocandin), previously known as LY303366 is a semisynthetic echinocandin currently used as antifungal drug (Krause et al., 2004; Harder et al., 2013; Kang et al., 2017).It is a lipopeptide produced by A. nidulans, (Lei et al., 2013) and acts by inhibiting glucan synthase (Denning et al., 1997; Anunthawan et al., 2015). It was observed to be effective against Candidemia and other Candida infections and esophageal candidiasis. MIC of (0.5 to 4.0) μg/ml was observed in Candida spp. However, Anidulafungin displays low MICs against strains of C. parapsilosis and is not effective inactive against C. neoformans and Blastomyces dermatitidis (De Lucca et al., 1999; Ghannoum et al., 2005; Ben Lagha et al., 2017).

Echinocandin B from A. nidulans and A. rugulosus was effective against C. albicans with MIC of 0.625 μg/ml. Cilofungin (LY121019), isolated from Aspergillus spp. had MIC of 0.62 μg/ml. Amino-lipopeptides such as Trichopolyns from Trichoderma polysporum have MIC of (0.78 – 6.25) μg/ml for C. albicans. Other families of potent antifungal peptides include the leucinostatins and helioferins families also consist of antifungal poperties, but, where toxic, hemolytic to mammalian cells in vitro (De Lucca 2000; Lei et al., 2013; Osorio et al., 2015; Chen et al., 2016; Ageitos et al., 2017).

Table 3: Antifungal peptides from fungal sources
Peptide name	Structure	source	Typical target organism	Mode of action	In vitro MIC (μg/ml)	Reference
Caspofungin	lipopeptide	G.lozoyensis	Candida spp	glucan synthesis	8 – 64	(Bartizalet al.,1997;Groll et al., 1999; Kuhn et al., 2002;Deresinski et al.,2003; Porto et al., 2012)
Anidulafungin (LY303366)	Lipopeptide	A. nidulans	Candida spp	glucan synthesis	0.5 – 4.0	(Lucca et al., 1999; Denning et al., 1997; Ghannoum et al., 2005; De Lei et al., 2013)
Cilofungin (LY121019)	Lipopeptide	A. nidulans	C. albicans	Glucan synthesis	0.62	(De Lucca 2000; Joseph et al., 2012)
Echinocandin B	Lipopeptide	A. nidulans	C. albicans	Glucan synthesis	0.625	(De Lucca 2000; Veltri et al., 2017)
Aculeacin	Lipopeptide	A. aculeatus	C. albicans	Glucan synthesis	0.2	(De Lucca et al., 1999; Chen et al., 2016)
Trichopolyn	Amino- lipopeptide	Trichoderma polysporum	C. albicans	Unknown	0.8	(De Lucca 2000; Liu et al., 2016)
Leucinostatin	Amino- lipopeptide	Penicillium lilacinum	C. neoformans	Unknown	0.5	(De Lucca 2000; Zhao et al., 2013 )

Insect Peptides: Cecropins

Cecropins (A and B) are linear lytic peptides, made up of an 11- amino acid sequence, produced in hemolymph giant silk moth, Hyalopora cecropia. Cecropin B was observed lethal against F. oxysporum (approximately 95%), A. fumigatus 9.5 μg/ml (De Lucca et al., 1998; Nappi et al., 2001). cecropin A was observed to be more fungicidal at neutral pH and was more affective against Fusarium moniliforme and Fusarium oxysporum with total killing of 12.4 μg/ml (De Lucca et al.,1998).

Table 4: Antifungal peptides from insect sources
Peptide name	Family/group	No. of amino acids	source	Typical Target organism	Mode of action	In vitro MIC (μg/ml)	Reference
Cecropin A	Cecropins	37	Hyalopora cecropia	F. oxysporum,	lysis	12.4	(De Lucca et al.,1998; Joseph et al., 2012)
Cecropin B	Cecropins	35	Hyalopora cecropia	A. fumigatus	lysis	9.5	(Nappi et al., 2001; Xiao et al., 2013)
Drosomycin	Cysteine-rich peptides	44	Drosophila melanogaster and Podisus maculiveris	F.oxysporum	lysis	5.9	(De Lucca, 2000; Veltri et al., 2017)
Thanatin	Cysteine-rich peptides	21	Podisus maculiveris	F. oxysporum	Unknown	5.0	(Bulet et al., 2005; Wang et al., 2015)
Heliomicins	Insect Defensins	44	Heliothis virescens	C. neoformans	Unknown	12.0	Nappi et al., 2001; De Lucca 2000; Zhao et al., 2013; Ageitos et al., 2017)

Drosomycin: Drosomycin is a Cysteine-rich peptide containing 44 amino acid with a twisted three-stranded sheet structure steadied by disulfide bonds. It is isolated from Drosophila melanogaster and Podisus maculiveris and was found to be effective against F.oxysporum with MIC value of 5.9 μg/ml (De Lucca, 2000 ).

Glycin-rich peptides

Antifungal peptides, such as holotricin-3, and tenecin-3 are glycine-rich peptides isolated from insects (Nappi et al., 2001). Tenecin-3 was studied to be effective against C. albicans (Ganz, 2003). Holotricin-3, was isolated from larval hemolymph of Holotrichia diomphalia, and was observed to inhibit C. albicans growth (Lee et al., 1995).

Table 5: Antifungal peptides from amphibian sources
Peptide name	No. of amino acids	source	Typical Target organism	Mode of action	In vitro MIC (μg/ml)	Reference
Magainin 2	23	Xenopus laevis	C. albicans	Lysis	80.0	(Zasloff et al., 2002; Bondaryk et al., 2017)
Dermaseptin b	27	Phyllomedusa sauvagii	C. neoformans	Lysis	60.0	(Landon et al., 1997; Brandenburg et al., 2015)
Dermaseptin s	34	P. sauvagii	C. neoformans	Lysis	5.0	(Landon et al., 1997; Brunetti et al., 2016)
Skin-PYY (SPYY)	36	P. bicolor	A. fumigatus	Membrane permiation	80.0	(Vouldoukis et al., 1996; Brunetti et al., 2016)
Brevinin-2R	24	Rana ridibunda	C. albicans	—	3.0	(Conlon et al., 2003; Anunthawan et al., 2015 )

Thanatin:Thanatin is another non-hemolytic Cysteine-rich peptide containing 21 amino acid residues and is smaller compared to drosomycin. It was affective against many strains such as Trichoderma viride, Alternaria brassicola, Neurospora crassa, Botrytis cinerea, and Fusarium culmorum, A. fumigatusT. mentagrophytes and F. oxysporum (Fehlbaum et al., 1996; Bulet et al., 2005). MIC of 5.0 μg/ml was observed against F. oxysporum. However Thanatin was not effective against yeast (Mandard et al., 1998).

Heliomicin: Heliomicin from Heliothis virescens (tobacco budworm), was observed to have antifungal activity against C. neoformans, with MIC of 12.0 μg/ml (De Lucca 2000; Nappi et al., 2001).

Amphibian Peptides: Magainins: Magainins was the first among the antifungal peptides from amphibian sources. They are amphiphilic, non-hemolytic and are produced by Xenopus laevis (African clawed frog). Magainin 2 inhibited C. albicans growth and had MIC of 80.0 μg/ml (De Lucca et al., 1999; Zasloff et al., 2002).

Dermaseptins: Dermaseptins are linear, lytic,peptides produced by Phyllomedusa sauvagii (South American arboreal frog). Dermaseptin was lethal towards for A. flavus, A. fumigatus, and F. oxysporum, with LD50 values observed as 3 μM, 0.5 μM, and 0.8 μM, respectively (Landon et al., 1997). Dermaseptin b was effective against yeasts and some filamentous fungi such as C. neoformansand had MIC value of 60.0μg/ml. Dermaseptin s had MIC of 5.0μg/mlfor C. neoformans. (De Lucca et al., 1999).

Skin-PYY (SPYY): Skin-PYY (SPYY), is an antifungal compound produced by Phyllomedusa bicolor (South American tree frog). It was observed to inhibit C. neoformans, C. albicans, and A. fumigatus and had MIC values of 20 μg/ml, 15 μg/ml, and 80 μg/ml, respectively (Vouldoukis et al., 1996).

Brevinin: Brevinin-2R isolated from skin of Rana ridibunda (red frog). It is non-hemolytic, 24 amino acid peptide with á-helical conformation. It was observed to have MIC of 3.0 μg/ml against C. albicans (Conlon et al., 2003).

Future Prospects

Emerging fungal resistance to conventional therapies necessitates the development of novel antifungal strategies. In this context, Anti-fungal peptides draw the attention as alternative potential antifungal agents (Brunetti et al., 2016). These peptides are relatively safe, tolerated and highly effective. As per the information available in the literatures, only few antifungal peptides are used in antifungal therapy (Brandenburg et al., 2015). There are various problems addressed which is limiting the uses of these peptides, such as low bioavailability, hemolytic activity, instability, high cost of production, possible aggregation, loss of activity in high salt concentrations, poor ability to cross physiological barriers (Chen et al., 2016; Ageitos et al., 2017).

Due to these effects, the therapeutic use of antifungal peptides is significantly decreased now a day. However, the utilization of these peptides could be enhanced by chemical optimization and new delivery strategies. With the advancement of new research strategies, the wide variety of natural antimicrobial peptides should be characterized both structurally and functionally for making them extremely promising source of ideas in design the novel antifungal peptides. In particular, application of dendrimers as scaffolds for assembling well defined macromolecular polyvalent molecules or synthesis de novo of per se active linear and branched peptide mimics makes them extremely promising for use as new generation antifungal peptides.As found in several studies, the modes of antifungal action must be well understood (Deslouches et al., 2015; Gao et al., 2016; Kubicek-Sutherland et al., 2017). Hopefully, all these efforts will result in the development of a novel class of antifungal agents to their full potential.

Conclusion

Antifungal peptides are excellent models for drug discovery exhibiting unique characteristics such as low level of resistance reaching the absent, high specificity, broad spectrum, and unique mode of action. Despite the distinctiveness, only few examples of antifungal peptides have successfully reached the market.

Acknowledgements

All the authors want to acknowledge Sreenidhi Institute of Science and Technology, Hyderabad and Centurion University, Bhubaneswar for providing digital library to explore the information to execute this work.

References

Ageitos, J. M., Sánchez-Pérez, A., Calo-Mata, P., and Villa, T. G. (2017). Antimicrobial peptides (AMPs): ancient compounds that represent novel weapons in the fight against bacteria. Biochem. Pharmacol. 133, 117–138. doi: 10.1016/j.bcp.2016.09.018

Anunthawan, T., De La Fuente-Nunez, C., Hancock, R. E., and Klaynongsruang, S. (2015). Cationic amphipathic peptides KT2 and RT2 are taken up into bacterial cells and kill planktonic and biofilm bacteria. Biochim. Biophys. Acta 1848, 1352–1358. doi: 10.1016/j.bbamem.2015.02.021

Asano T, Miwa A, Maeda K, Kimura M, Nishiuchi T (2013). The Secreted Antifungal Protein Thionin 2.4 in Arabidopsis thaliana suppresses the Toxicity of a Fungal Fruit Body Lectin from Fusarium graminearum. PLoS Pathog 9(8): e1003581. https://doi.org/10.1371/journal.ppat.1003581

Bartizal K, Gill CJ, Abruzzo GK, et al.. (1997). In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872) Antimicrob Agents Chemother.; 41:2326–32.

Ben Lagha, A., Haas, B., Gottschalk, M., and Grenier, D. (2017). Antimicrobial potential of bacteriocins in poultry and swine production. Vet. Res. 48:22. doi: 10.1186/s13567-017-0425-6

Bionda, N., Fleeman, R. M., De La Fuente-Núñez, C., Rodriguez, M. C., Reffuveille, F., Shaw, L. N., et al.. (2016). Identification of novel cyclic lipopeptides from a positional scanning combinatorial library with enhanced antibacterial and antibiofilm activities. Eur. J. Med. Chem. 108, 354–363. doi: 10.1016/j.ejmech.2015.11.032

Blanco, J. L., and M. E. Garcia (2008). Immune response to fungal infections. Vet. Immunol. Immunopathol. 125:47–70. doi: 10.1016/j.vetimm.2008.04.020

Bondaryk, M., Staniszewska, M., Zielinska, P., and Urbanczyk-Lipkowska, Z. (2017). Natural antimicrobial peptides as inspiration for design of a new generation antifungal compounds. J. Fungi 3:46. doi: 10.3390/jof3030046

Brandenburg, K., and Schürholz, T. (2015). Lack of new antiinfective agents: passing into the pre-antibiotic age? World J. Biol. Chem. 6, 71–77. doi: 10.4331/wjbc.v6.i3.71

Bruix, M., C. Gonzales, J. Santoro, F. Soriano, A. Rocher, E. Mendez, and M. Rico (1995). 1HNMR studies on the structure of a new thionin from barely endosperm. Biopolymers 36:751–763. https://doi.org/10.1002/bip.360360608.

Brunetti, J., Falciani, C., Roscia, G., Pollini, S., Bindi, S., Scali, S., et al.. (2016). In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate. Sci. Rep. 6:26077. doi: 10.1038/srep26077

Bulet P, Stocklin R (2005). Insect antimicrobial peptides: structures, properties and gene regulation. Protein and Peptide Letters; 12:3-11. DOI: 10.2174/0929866053406011.

Cammue, B. P. A., K. Thevissen, M. Hendricks, K. Eggermont, I. J. Goderis, P. Proost, J. Van Damme, R. W. Osborn, F. Guerbette, J.-C. Kader, and W. F. Broekaert. (1995). A potent antimicrobial protein from onion seeds showing sequence homology to plant lipid transfer protein. Plant Pathol; 109:445–455. https://doi.org/10.1104/pp.109.2.445.

Chen, W., Ding, H. & Feng, P (2016) iACP: a sequence-based tool for identifying anticancer peptides. Oncotarget. 7, 16895–16909.

Chereddy, K. K., Her, C. H., Comune, M., Moia, C., Lopes, A., Porporato, P. E., et al.. (2014). PLGA nanoparticles loaded with host defense peptide LL37 promote wound healing. J. Control. Release 194, 138–147. doi: 10.1016/j.jconrel.2014.08.016

Choe, H., Narayanan, A. S., Gandhi, D. A., Weinberg, A., Marcus, R. E., Lee, Z., et al.. (2015). Immunomodulatory peptide IDR-1018 decreases implant infection and preserves osseointegration. Clin. Orthop. Relat. Res. 473, 2898–2907. doi: 10.1007/s11999-015-4301-2

Chu, H. L., Yu, H. Y., Yip, B. S., Chih, Y. H., Liang, C. W., Cheng, H. T., et al.. (2013). Boosting salt resistance of short antimicrobial peptides. Antimicrob. Agents Chemother. 57, 4050–4052. doi: 10.1128/AAC.00252-13

Cole, J. N., and Nizet, V. (2016). Bacterial evasion of host antimicrobial peptide defenses. Microbiol. Spectr. 4:VMBF-0006-2015. doi: 10.1128/microbiolspec.VMBF-0006-2015

Conlon JM, Sonnevend A, Patel M, Davidson C, Nielsen PF, Pál T, Rollins-Smith LA. (2003). Isolation of peptides of the brevinin-1 family with potent candidacidal activity from the skin secretions of the frog Rana boylii. J Pept Res. 2003 Nov; 62(5):207-13. DOI: 10.1034/j.1399-3011.2003.00090.x

De Lucca A, Bland J, Jacks T, Grimm C, Cleveland T, Walsh T. (1997). Fungicidal activity of cecropin A. Antimicrob Agents Chemother; 41: 481-483.

De Lucca A, Bland J, Jacks T, Grimm C, Walsh T. (1998). Fungicidal and binding properties of the natural peptides cecropin B and dermaseptin. Med Mycol;36(5):291-8. https://doi.org/10.1080/02681219880000461.

De Lucca A, Bland J, Vigo C, Jacks T, Peter J, Walsh T. (2000). D-cecropin B: proteolytic resistance, lethality for pathogenic fungi and binding properties. Medical Mycology; 38:301-308. https://doi.org/10.1080/714030954.

De Lucca A, Jacks T, Takemoto J, Vinyard B, Peter J, Navarro E, et al.. (1999). Fungal lethality, binding, and cytotoxicity of syringomycin-E. Antimicrobial agents and chemotherapy; 43:371-3.

De Lucca A. (2000). Antifungal peptides: potential candidates for the treatment of fungal infections. Expert opinion on investigational drugs; 9(2):273-299. http://dx.doi.org/10.1517/13543784.9.2.273

De Lucca, Thomas J. Walsh. (1999). Antifungal Peptides: Novel Therapeutic Compounds against Emerging Pathogens. Antimicrob Agents Chemother. 1999 Jan; 43(1): 1–11.

Denning DW. (1997). Echinocandins and pneumocandins – a new antifungal class with a novel mode of action. J Antimicrob Chemother. 40 (5): 611–614. https://doi.org/10.1093/jac/40.5.611.

Deresinski SC; Stevens DA. (2003). Caspofungin. Clin Infect Dis. 36 (11): 1445–1457. Doi:10.1086/375080.

Deslouches, B., Steckbeck, J. D., Craigo, J. K., Doi, Y., Burns, J. L., and Montelaro, R. C. (2015). Engineered cationic antimicrobial peptides to overcome multidrug resistance by ESKAPE pathogens. Antimicrob. Agents Chemother. 59, 1329–1333. doi: 10.1128/AAC.03937-14

Dobson, A. J., Purves, J., and Rolff, J. (2014). Increased survival of experimentally evolved antimicrobial peptide-resistant Staphylococcus aureus in an animal host. Evol. Appl. 7, 905–912. doi: 10.1111/eva.12184

Dutta, P., and Das, S. (2015). Mammalian antimicrobial peptides: promising therapeutic targets against infection and chronic inflammation. Curr. Top. Med. Chem. 16, 99–129. doi: 10.2174/1568026615666150703121819

Falciani, C., Lozzi, L., Scali, S., Brunetti, J., Bracci, L., and Pini, A. (2014). Site-specific pegylation of an antimicrobial peptide increases resistance to Pseudomonas aeruginosa elastase. Amino Acids 46, 1403–1407. doi: 10.1007/s00726-014-
1686-2

Fehlbaum P, Bulet P, Chernych S, et al. (1996). Structure-activity analysis of thanatin, a 21-residue inducible insect defense peptide with sequence homology to frog skin antimicrobial peptides. Proc Natl Acad Sci USA; 93: 1221-1225. https://doi.org/10.1073/pnas.93.3.1221.

Fernández‐Carneado J, Kogan MJ, Pujals S, Giralt E. (2004). Amphipathic peptides and drug delivery. Peptide Science; 76:196-203. https://doi.org/10.1002/bip.10585.

Ganz T. (2003) Defensins: antimicrobial peptides of innate immunity. Nature Reviews Immunology; 3:710-20. https://doi.org/10.1038/nri1180.

Gao, Y., Wu, D., Xi, X., Wu, Y., Ma, C., Zhou, M., et al.. (2016). Identification and characterisation of the antimicrobial peptide, phylloseptin-PT, from the skin secretion of Phyllomedusa tarsius, and comparison of activity with designed, cationicity-enhanced analogues and diastereomers. Molecules 21:E1667. doi: 10.3390/molecules21121667

Georgopapadakou N, Walsh T. (1996). Antifungal agents: chemotherapeutic targets and immunologic strategies. Antimicrob Agents Chemother; 40:279- 291.

Ghannoum MA, Chen A, Buhari M, et al.. (2005). Multi-echinocandin resistant Candida parapsilosis: an emerging pathogen [abstract M-722a]. Abstracts of the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16–19, 2005; Washington, DC: American Society for Microbiology.

Gold, W., H.A.Stout, J.F.Pagano, and R.Donovick. (2002). Amphotericins A and B, antifungal antibiotics produced by a Streptomycete. I. Invitrostudies, p.579–586.Antibiot.

Gournelis, D. C., G. G. Laskaris, and R. Verpoorte. (1997). Cyclopeptide alkaloids. Nat. Prod. Rep. 14:75–82. https://doi.org/10.1039/np9971400075.

Gregory Eschenauer,Daryl D DePestel,and Peggy L Carver. (2007). Comparison of echinocandin antifungals. Ther Clin Risk Manag. 2007 Mar; 3(1): 71–97. https://doi.org/10.2147/tcrm.2007.3.1.71.

Groll A, Walsh T. (1999). Preliminary evaluation of the antifungal echinocandin MK-0991. Current Opinions in Anti-infective Investigational Drugs; 1:334-335.

Gupte, M., P. Kulkarni, and B. N. Ganguli. (2002). Antifungal antibiotics. Appl. Microbiol. Biotechnol. 58:46–57. https://doi.org/10.1007/s002530100822.

Harder, J., Tsuruta, D., Murakami, M., and Kurokawa, I. (2013). What is the role of antimicrobial peptides (AMP) in acne vulgaris? Exp. Dermatol. 22, 386–391. doi: 10.1111/exd.12159

Jia, J., Liu, Z. & Xiao, X. pSuc-Lys: Predict lysine succinylation sites in proteins with PseAAC and ensemble random forest approach. J. Theor. Biol. 394, 223–230 (2016).

Joseph, S., Karnik, S., Nilawe, P., Jayaraman, V. K. & Idicula-Thomas, S(2012). ClassAMP: a prediction tool for classification of antimicrobial peptides. IEEE/ACM Trans. Comput. Biol. Bioinform. 9(5), 1535–1538

Kaconis, Y., Kowalski, I., Howe, J., Brauser, A., Richter, W., RazquinOlazaran, I., et al.(2011). Biophysical mechanisms of endotoxin neutralization by cationic amphiphilic peptides. Biophys. J. 100, 2652–2661. doi: 10.1016/j.bpj.2011.04.041

Kahn J N, Hsu M, Racine F, Giacobbe R, Motyl M (2006). Caspofungin susceptibility in Aspergillus and non-Aspergillus molds: inhibition of glucan synthase and reduction of ˜-D-1, 3 glucan levels in culture. Antimicrob Agents Chemother; 50:2214–16. https://doi.org/10.1128/aac.01610-05.

Kang, H. K., Kim, C., Seo, C. H., and Park, Y. (2017). The therapeutic applications of antimicrobial peptides (AMPs): a patent review. J. Microbiol. 55, 1–12. doi: 10.1007/s12275-017-6452-1

Kasetty, G., Kalle, M., Morgelin, M., Brune, J. C., and Schmidtchen, A. (2015). Anti-endotoxic and antibacterial effects of a dermal substitute coated with host defense peptides. Biomaterials 53, 415–425. doi: 10.1016/j.biomaterials.2015.02.111

Kazemzadeh-Narbat, M., Kindrachuk, J., Duan, K., Jenssen, H., Hancock, R. E., and Wang, R. (2010). Antimicrobial peptides on calcium phosphate-coated titanium for the prevention of implant-associated infections. Biomaterials 31, 9519–9526. doi: 10.1016/j.biomaterials.2010.08.035

Krause DS, Reinhardt J, Vazquez JA, Reboli A, Goldstein BP, Wible M, Henkel T. (2004). Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia. Antimicrob Agents Chemother.48 (6):2021–4. Doi: 10.1128/AAC.48.6.2021-2024.2004.

Krishnan S, Manavathu EK, Chandrasekar PH. (2005). A comparative study of fungicidal activities of voriconazole and amphotericin B against hyphae of Aspergillus fumigatus. J Antimicrob Chemother. J Antimicrob Chemother. 2005 Jun; 55(6):914-20. DOI: 10.1093/jac/dki100

Kubicek-Sutherland, J. Z., Lofton, H., Vestergaard, M., Hjort, K., Ingmer, H., and Andersson, D. I. (2017). Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides. J. Antimicrob. Chemother. 72, 115–127. doi: 10.1093/jac/dkw381

Kuhn DM, George T, Chandra J, Mukherjee P.K, Ghannoum M.A (2002). Antifungal susceptibility of Candida biofilms: unique efficacy of amphotericin B lipid formulations and echinocandins. Antimicrob Agents Chemother; 46:1773–80. https://doi.org/10.1128/aac.46.6.1773-1780.2002.

Lakshmaiah Narayana, J., and Chen, J. Y. (2015). Antimicrobial peptides: possible anti-infective agents. Peptides 72, 88–94. doi: 10.1016/j.peptides.2015.05.012

Lakshminarayanan, R., Liu, S., Li, J., Nandhakumar, M., Aung, T. T., Goh, E., et al. (2014). Synthetic multivalent antifungal peptides effective against fungi. PLoS ONE 9:e87730. doi: 10.1371/journal.pone.0087730

Landon C, Sodano P, Hetru C, Hoffman J, Ptak M. (1997). Solution structure of drosomycin, the first inducible antifungal protein from insects. Protein Sci; 6:1878-1884. https://doi.org/10.1002/pro.5560060908.

Lata, S., Mishra, N. K. & Raghava, G. P. S. (2010) AntiBP2: improved version of antibacterial peptide prediction. BMC Bioinform. 11 (Suppl 1),S19.

Lei Shao; Jian Li; Aijuan Liu; Qing Chang; Huimin Lin; Daijie Chen. (2013). Efficient Bioconversion of Echinocandin B to Its Nucleus by Overexpression of Deacylase Genes in Different Host Strains. Applied and Environmental Microbiology. 79 (4): 1126–1133. doi:10.1128/AEM.02792-12.

Lemaitre B, Reichhart J-M, Hoffmann JA. (1997). Drosophila host defense: differential induction of antimicrobial peptide genes after infection by various classes of microorganisms. Proceedings of the National Academy of Sciences; 94:14614-9. https://doi.org/10.1073/pnas.94.26.14614.

Leuschner C, Hansel W. (2004). Membrane disrupting lytic peptides for cancer treatments. Current pharmaceutical design; 10:2299-310. https://doi.org/10.2174/1381612043383971.

Liu, B. & Long, R(2016). iDHS-EL: Identifying DNase I hypersensi-tivesites by fusing three different modes of pseudo nucleotide composition into an en-semble learning framework. Bioinform. 32, 2411–2418.

Liu, Z., Xiao, X. & Yu, D. J (2016). pRNAm-PC: Predicting N-methyl-adenosine sites in RNA sequences via physical-chemical properties. Anal. Biochem. 497, 60–67.

López-Garcia, B., Lee, P. H., Yamasaki, K., and Gallo, R. L. (2005). Anti-fungal activity of cathelicidins and their potential role in Candida albicans skin infection. J. Invest. Dermatol. 125, 108–115. doi: 10.1111/j.0022-202X.2005.23713.x

Lyu, Y., Yang, Y., Lyu, X., Dong, N., and Shan, A. (2016). Antimicrobial activity, improved cell selectivity and mode of action of short PMAP36-derived peptides against bacteria and Candida. Sci. Rep. 6:27258. doi: 10.1038/srep27258

Mandard N, Sodano P, Labbe H, Bonmatin JM, Bulet P, Hetru C, et al.. (1998). Solution structure of thanatin, a potentbactericidal and fungicidal insect peptide, determined from proton two‐dimensional nuclear magnetic resonance data. European Journal of Biochemistry; 256:404-10. https://doi.org/10.1046/j.1432-1327.1998.2560404.x.

Mohammad Omer Faruck, Faridah yusof, Silvia Chowdhury. (2015).an overview of antifungal peptides derived from insect. Peptides. 18 Jun 2015; 80:80-88. https://doi.org/10.1016/j.peptides.2015.06.001.

Montgomery, C. P., Daniels, M. D., Zhao, F., Spellberg, B., Chong, A. S., and Daum, R. S. (2013). Local inflammation exacerbates the severity of Staphylococcus aureus skin infection. PLoS ONE 8:e69508. doi: 10.1371/journal.pone.0069508

Murdoch D, Plosker GL. (2004). Anidulafungin. Drugs; 64: 2249–58.https://doi.org/10.2165/00003495-200464190-00011.

Nappi A, Vass E. (2001). Cytotoxic reactions associated with insect immunity. Phylogenetic perspectives on the vertebrate immune system: Springer; 2001. p. 329-48. https://doi.org/10.1007/978-1-4615-1291-2_33.

Ordonez, S. R., Amarullah, I. H., Wubbolts, R. W., Veldhuizen, E. J., and Haagsman, H. P. (2014). Fungicidal mechanisms of cathelicidins LL-37 and CATH-2 revealed by live-cell imaging. Antimicrob. Agents Chemother. 58, 2240–2248. doi: 10.1128/AAC.01670-13

Osorio, D., Rondon-Villarreal, P. & Torres, R (2015). Peptides: A package for data mining of antimicrobial peptides. The R Journal. 7(1),4–14.

Pettengell K, Mynhardt J, Kluytis T, SoniP. (1999). A multicenter study to determine the minimal effective dose of FK 463 for the treatment of esophageal candidiasis in HIV-positive patients. Abstracts of the39th Interscience Conference on Antimicrobial Agents and Chemotherapy.San Francisco, CA 1999: 1421.

Pfaller MA, Boyken L, Hollis RJ, Messer SA, Tendolkar S, Diekema DJ (2005). In Vitro Activities of Anidulafungin against More than 2,500 Clinical Isolates of Candida spp., Including 315 Isolates Resistant to Fluconazole. J Clin Microbiol. 43 (11): 5425–7. Doi:10.1128/JCM.43.11.5425-5427.2005.

Pfaller MA, Diekema DJ, Boyken L, Messer SA, Tendolkar S, Hollis RJ, Goldstein BP. (2005). Effectiveness of anidulafungin in eradicating Candida species in invasive candidiasis. Antimicrob Agents Chemother. 49 (11): 4795–7. Doi: 10.1128/AAC.49.11.4795-4797.2005.

Popovic, S., Urban, E., Lukic, M., and Conlon, J. M. (2012). Peptides with antimicrobial and anti-inflammatory activities that have therapeutic potential for treatment of acne vulgaris. Peptides 34, 275–282. doi: 10.1016/j.peptides.2012.02.010

Porto, W. F., Souza, V. A., Nolasco, D. O. & Franco, O. L (2012). In silico identification of novel hevein-like peptide precursors. Peptides. 38, 127–136.

Qin Gu, Yang Yang, Qiming Yuan, Guangming Shi, Liming Wu, Zhiying Lou,Rong Huo, Huijun Wu, Rainer Borriss and Xuewen Gao. (2017). Bacillomycin D produced by Bacillus amyloliquefaciens is involved in the antagonistic interaction with the plant pathogenic fungus Fusarium graminearum. American Society for Microbiology.21 July 2017, doi: 10.1128/AEM.01075-17.

Ravi C, Jeyashree A, Devi KR. (2011). Antimicrobial peptides from insects: An overview. Research in Biotechnology. 2011; 2.

Rees JA, Moniatte M, Bulet P. (1997). Novel antibacterial peptides isolated from a European bumblebee, Bombus pascuorum (Hymenoptera, apoidea). Insect biochemistry and molecular biology; 27:413-22. ttps://doi.org/10.1016/s0965-1748(97)00013-1.

Schelenz S, Barnes R, Kibbler C, Jones B, Denning D. (2009). Standards of care for patients with invasive fungal infections within the United Kingdom: a national audit. Journal of Infection; 58:145-53. https://doi.org/10.1016/j.jinf.2008.12.006.

Shai, Y. (1995). Molecular recognition between membrane-spanning polypeptides. TIBS 20:460–464. https://doi.org/10.1016/s0968-0004(00)89101-x.

Sorensen, K. N., K.-H. Kim, and J. Y. Takemoto. (1996). In vitro antifungal and fungicidal activities and erythrocyte toxicities of cyclic lipodepsin peptides produced by Pseudomonas syringae pv. syringae. Antimicrob.Agents Chemother. 40:2710–2713.

Spellberg B, Guidos R, Gilbert D, Bradley J, Boucher HW, Scheld WM, et al.. (2008). The epidemic of antibiotic resistant infections: a call to action for the medical community from the Infectious Diseases Society of America. Clinical Infectious Diseases; 46:155-64. https://doi.org/10.1086/524891.

Tabbene Olfa, Di Grazia Antonio, Azaiez Sana, Ben Slimene Imen, Elkahoui Salem, Alfeddy Mohamed Najib, Casciaro Bruno, Luca Vincenzo, Limam Ferid, Mangoni Maria Luisa; Synergistic fungicidal activity of the lipopeptide bacillomycin D with amphotericin B against pathogenic Candida species, FEMS Yeast Research, Volume 15, Issue 4, 1 June 2015, fov022, https://doi.org/10.1093/femsyr/fov022.

Tan NH, Zhou J. (2006). Plant cyclopeptides. Chem Rev. 2006 Mar; 106(3):840-95. https://doi.org/10.1021/cr040699h.

Thakur, N., Qureshi, A. & Kumar, M (2012). AVP pred: collection and prediction of highly effective antiviral peptides. Nucl. Acids. Res. 40,W199–204.

Vazquez JA. (2005). Anidulafungin: A New Echinocandin with a Novel Profile, Clin Ther; 27(6):657-73. https://doi.org/10.1016/j.clinthera.2005.06.010.

Velazhahan, R., Radhajeyalakshmi, R., Thangavelu, S. Muthukrishnan.(2001). An Antifungal Protein Purified from Pearl Millet Seeds Shows Sequence Homology to Lipid Transfer Proteins. Biologia Plantarum; 44: 417. https://doi.org/10.1023/A:1012463315579

Veltri, D., Shehu, A. & Kamath, U (2017). Improving recognition of antimicrobial peptides and target selectivity through machine learning and genetic programming. IEEE/ACM Trans. Comput. Biol. Bioinform. 14(2):300-313. doi: 10.1109/TCBB.2015.2462364.

Vouldoukis I, Shai Y, Nicolas P, Mor A. (1996).Broad spectrum antibiotic activity of skin- PYY. FEBS Lett; 380: 237- 240. https://doi.org/10.1016/0014-5793(96)00050-6.

Wang, G., Li, X. & Wang, Z (2016). APD3: the antimicrobial peptide database as a tool for research and education. Nucl. Acids Res. 44(D1),D1087–1093.

Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. (2004). Nosocomial blood stream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clinical Infectious Diseases; 39:309-17. https://doi.org/10.1086/421946.

Xiao, X., Wang, P., Lin, W. Z., Jia, J. H. & Chou, K. C (2013). iAMP-2L: A two- level multi-label classifier for identifying antimicrobial peptides and their functional types. Anal. Biochem. 436(2), 168–177 .

XinZhao, Zhi-jiangZhou, YeHanZhan-zhongWang, JieFan, Hua-zhiXia. (2013). Isolation and identification of antifungal peptides from Bacillus BH072, a novel bacterium isolated from honey; [598-606]. https://doi.org/10.1016/j.micres.2013.03.001.

Zaas AK, Alexander BD. (2005). Echinocandins: role in antifungal therapy. Exp Opin Pharmacother. 2005; 6:1657–68. https://doi.org/10.1517/14656566.6.10.1657.

Zasloff M. (2002). Antimicrobial peptides of multicellular organisms. Nature. 2002; 415:38-95. https://doi.org/10.1038/41538

Zhao, X., Wu, H., Lu, H., Li, G. & Huang, Q (2013). LAMP: A database linking antimicrobial peptides. PLoS ONE. 8(6), e66557.