Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction

Abstract Candida spp. are leading causes of opportunistic mycoses, including life-threatening hospital-borne infections, and novel antifungals, preferably aiming targets that have not been used before, are constantly needed. Hydrazone- and guanidine-containing molecules have shown a wide range of bi...
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Autor*in:	Lazić, Jelena [verfasserIn] Ajdačić, Vladimir Vojnovic, Sandra Zlatović, Mario Pekmezovic, Marina Mogavero, Selene Opsenica, Igor Nikodinovic-Runic, Jasmina

Format:	Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	Antifungal activity spp. Bis-guanylhydrazone DNA interaction ROS generation Synergy

Anmerkung:	© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Übergeordnetes Werk:	Enthalten in: Applied microbiology and biotechnology - Springer Berlin Heidelberg, 1984, 102(2018), 4 vom: 12. Jan., Seite 1889-1901
Übergeordnetes Werk:	volume:102 ; year:2018 ; number:4 ; day:12 ; month:01 ; pages:1889-1901

Links:	Volltext

DOI / URN:	10.1007/s00253-018-8749-3

Katalog-ID:	OLC2050790511

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520			\|a Abstract Candida spp. are leading causes of opportunistic mycoses, including life-threatening hospital-borne infections, and novel antifungals, preferably aiming targets that have not been used before, are constantly needed. Hydrazone- and guanidine-containing molecules have shown a wide range of biological activities, including recently described excellent antifungal properties. In this study, four bis-guanylhydrazone derivatives (BG1–4) were generated following a previously developed synthetic route. Anti-Candida (two C. albicans, C. glabrata, and C. parapsilosis) minimal inhibitory concentrations (MICs) of bis-guanylhydrazones were between 2 and 15.6 μg/mL. They were also effective against preformed 48-h-old C. albicans biofilms. In vitro DNA interaction, circular dichroism, and molecular docking analysis showed the great ability of these compounds to bind fungal DNA. Competition with DNA-binding stain, exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane, and activation of metacaspases were shown for BG3. This pro-apoptotic effect of BG3 was only partially due to the accumulation of reactive oxygen species in C. albicans, as only twofold MIC and higher concentrations of BG3 caused depolarization of mitochondrial membrane which was accompanied by the decrease of the activity of fungal mitochondrial dehydrogenases, while the activity of oxidative stress response enzymes glutathione reductase and catalase was not significantly affected. BG3 showed synergistic activity with amphotericin B with a fractional inhibitory concentration index of 0.5. It also exerted low cytotoxicity and the ability to inhibit epithelial cell (TR146) invasion and damage by virulent C. albicans SC5314. With further developments, BG3 may further progress in the antifungal pipeline as a DNA-targeting agent.
650		4	\|a Antifungal activity
650		4	\|a spp.
650		4	\|a Bis-guanylhydrazone
650		4	\|a DNA interaction
650		4	\|a ROS generation
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700	1		\|a Ajdačić, Vladimir \|4 aut
700	1		\|a Vojnovic, Sandra \|4 aut
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700	1		\|a Mogavero, Selene \|4 aut
700	1		\|a Opsenica, Igor \|4 aut
700	1		\|a Nikodinovic-Runic, Jasmina \|0 (orcid)0000-0002-2553-977X \|4 aut
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allfields	10.1007/s00253-018-8749-3 doi (DE-627)OLC2050790511 (DE-He213)s00253-018-8749-3-p DE-627 ger DE-627 rakwb eng 570 VZ 12 ssgn BIODIV DE-30 fid Lazić, Jelena verfasserin aut Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction 2018 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Candida spp. are leading causes of opportunistic mycoses, including life-threatening hospital-borne infections, and novel antifungals, preferably aiming targets that have not been used before, are constantly needed. Hydrazone- and guanidine-containing molecules have shown a wide range of biological activities, including recently described excellent antifungal properties. In this study, four bis-guanylhydrazone derivatives (BG1–4) were generated following a previously developed synthetic route. Anti-Candida (two C. albicans, C. glabrata, and C. parapsilosis) minimal inhibitory concentrations (MICs) of bis-guanylhydrazones were between 2 and 15.6 μg/mL. They were also effective against preformed 48-h-old C. albicans biofilms. In vitro DNA interaction, circular dichroism, and molecular docking analysis showed the great ability of these compounds to bind fungal DNA. Competition with DNA-binding stain, exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane, and activation of metacaspases were shown for BG3. This pro-apoptotic effect of BG3 was only partially due to the accumulation of reactive oxygen species in C. albicans, as only twofold MIC and higher concentrations of BG3 caused depolarization of mitochondrial membrane which was accompanied by the decrease of the activity of fungal mitochondrial dehydrogenases, while the activity of oxidative stress response enzymes glutathione reductase and catalase was not significantly affected. BG3 showed synergistic activity with amphotericin B with a fractional inhibitory concentration index of 0.5. It also exerted low cytotoxicity and the ability to inhibit epithelial cell (TR146) invasion and damage by virulent C. albicans SC5314. With further developments, BG3 may further progress in the antifungal pipeline as a DNA-targeting agent. Antifungal activity spp. Bis-guanylhydrazone DNA interaction ROS generation Synergy Ajdačić, Vladimir aut Vojnovic, Sandra aut Zlatović, Mario aut Pekmezovic, Marina aut Mogavero, Selene aut Opsenica, Igor aut Nikodinovic-Runic, Jasmina (orcid)0000-0002-2553-977X aut Enthalten in Applied microbiology and biotechnology Springer Berlin Heidelberg, 1984 102(2018), 4 vom: 12. Jan., Seite 1889-1901 (DE-627)129942634 (DE-600)392453-1 (DE-576)015507750 0175-7598 nnns volume:102 year:2018 number:4 day:12 month:01 pages:1889-1901 https://doi.org/10.1007/s00253-018-8749-3 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-TEC SSG-OLC-CHE SSG-OLC-PHA SSG-OLC-DE-84 GBV_ILN_70 GBV_ILN_130 GBV_ILN_267 GBV_ILN_2018 GBV_ILN_4012 GBV_ILN_4277 GBV_ILN_4305 AR 102 2018 4 12 01 1889-1901
spelling	10.1007/s00253-018-8749-3 doi (DE-627)OLC2050790511 (DE-He213)s00253-018-8749-3-p DE-627 ger DE-627 rakwb eng 570 VZ 12 ssgn BIODIV DE-30 fid Lazić, Jelena verfasserin aut Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction 2018 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Candida spp. are leading causes of opportunistic mycoses, including life-threatening hospital-borne infections, and novel antifungals, preferably aiming targets that have not been used before, are constantly needed. Hydrazone- and guanidine-containing molecules have shown a wide range of biological activities, including recently described excellent antifungal properties. In this study, four bis-guanylhydrazone derivatives (BG1–4) were generated following a previously developed synthetic route. Anti-Candida (two C. albicans, C. glabrata, and C. parapsilosis) minimal inhibitory concentrations (MICs) of bis-guanylhydrazones were between 2 and 15.6 μg/mL. They were also effective against preformed 48-h-old C. albicans biofilms. In vitro DNA interaction, circular dichroism, and molecular docking analysis showed the great ability of these compounds to bind fungal DNA. Competition with DNA-binding stain, exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane, and activation of metacaspases were shown for BG3. This pro-apoptotic effect of BG3 was only partially due to the accumulation of reactive oxygen species in C. albicans, as only twofold MIC and higher concentrations of BG3 caused depolarization of mitochondrial membrane which was accompanied by the decrease of the activity of fungal mitochondrial dehydrogenases, while the activity of oxidative stress response enzymes glutathione reductase and catalase was not significantly affected. BG3 showed synergistic activity with amphotericin B with a fractional inhibitory concentration index of 0.5. It also exerted low cytotoxicity and the ability to inhibit epithelial cell (TR146) invasion and damage by virulent C. albicans SC5314. With further developments, BG3 may further progress in the antifungal pipeline as a DNA-targeting agent. Antifungal activity spp. Bis-guanylhydrazone DNA interaction ROS generation Synergy Ajdačić, Vladimir aut Vojnovic, Sandra aut Zlatović, Mario aut Pekmezovic, Marina aut Mogavero, Selene aut Opsenica, Igor aut Nikodinovic-Runic, Jasmina (orcid)0000-0002-2553-977X aut Enthalten in Applied microbiology and biotechnology Springer Berlin Heidelberg, 1984 102(2018), 4 vom: 12. Jan., Seite 1889-1901 (DE-627)129942634 (DE-600)392453-1 (DE-576)015507750 0175-7598 nnns volume:102 year:2018 number:4 day:12 month:01 pages:1889-1901 https://doi.org/10.1007/s00253-018-8749-3 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-TEC SSG-OLC-CHE SSG-OLC-PHA SSG-OLC-DE-84 GBV_ILN_70 GBV_ILN_130 GBV_ILN_267 GBV_ILN_2018 GBV_ILN_4012 GBV_ILN_4277 GBV_ILN_4305 AR 102 2018 4 12 01 1889-1901
allfields_unstemmed	10.1007/s00253-018-8749-3 doi (DE-627)OLC2050790511 (DE-He213)s00253-018-8749-3-p DE-627 ger DE-627 rakwb eng 570 VZ 12 ssgn BIODIV DE-30 fid Lazić, Jelena verfasserin aut Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction 2018 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Candida spp. are leading causes of opportunistic mycoses, including life-threatening hospital-borne infections, and novel antifungals, preferably aiming targets that have not been used before, are constantly needed. Hydrazone- and guanidine-containing molecules have shown a wide range of biological activities, including recently described excellent antifungal properties. In this study, four bis-guanylhydrazone derivatives (BG1–4) were generated following a previously developed synthetic route. Anti-Candida (two C. albicans, C. glabrata, and C. parapsilosis) minimal inhibitory concentrations (MICs) of bis-guanylhydrazones were between 2 and 15.6 μg/mL. They were also effective against preformed 48-h-old C. albicans biofilms. In vitro DNA interaction, circular dichroism, and molecular docking analysis showed the great ability of these compounds to bind fungal DNA. Competition with DNA-binding stain, exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane, and activation of metacaspases were shown for BG3. This pro-apoptotic effect of BG3 was only partially due to the accumulation of reactive oxygen species in C. albicans, as only twofold MIC and higher concentrations of BG3 caused depolarization of mitochondrial membrane which was accompanied by the decrease of the activity of fungal mitochondrial dehydrogenases, while the activity of oxidative stress response enzymes glutathione reductase and catalase was not significantly affected. BG3 showed synergistic activity with amphotericin B with a fractional inhibitory concentration index of 0.5. It also exerted low cytotoxicity and the ability to inhibit epithelial cell (TR146) invasion and damage by virulent C. albicans SC5314. With further developments, BG3 may further progress in the antifungal pipeline as a DNA-targeting agent. Antifungal activity spp. Bis-guanylhydrazone DNA interaction ROS generation Synergy Ajdačić, Vladimir aut Vojnovic, Sandra aut Zlatović, Mario aut Pekmezovic, Marina aut Mogavero, Selene aut Opsenica, Igor aut Nikodinovic-Runic, Jasmina (orcid)0000-0002-2553-977X aut Enthalten in Applied microbiology and biotechnology Springer Berlin Heidelberg, 1984 102(2018), 4 vom: 12. Jan., Seite 1889-1901 (DE-627)129942634 (DE-600)392453-1 (DE-576)015507750 0175-7598 nnns volume:102 year:2018 number:4 day:12 month:01 pages:1889-1901 https://doi.org/10.1007/s00253-018-8749-3 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-TEC SSG-OLC-CHE SSG-OLC-PHA SSG-OLC-DE-84 GBV_ILN_70 GBV_ILN_130 GBV_ILN_267 GBV_ILN_2018 GBV_ILN_4012 GBV_ILN_4277 GBV_ILN_4305 AR 102 2018 4 12 01 1889-1901
allfieldsGer	10.1007/s00253-018-8749-3 doi (DE-627)OLC2050790511 (DE-He213)s00253-018-8749-3-p DE-627 ger DE-627 rakwb eng 570 VZ 12 ssgn BIODIV DE-30 fid Lazić, Jelena verfasserin aut Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction 2018 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Candida spp. are leading causes of opportunistic mycoses, including life-threatening hospital-borne infections, and novel antifungals, preferably aiming targets that have not been used before, are constantly needed. Hydrazone- and guanidine-containing molecules have shown a wide range of biological activities, including recently described excellent antifungal properties. In this study, four bis-guanylhydrazone derivatives (BG1–4) were generated following a previously developed synthetic route. Anti-Candida (two C. albicans, C. glabrata, and C. parapsilosis) minimal inhibitory concentrations (MICs) of bis-guanylhydrazones were between 2 and 15.6 μg/mL. They were also effective against preformed 48-h-old C. albicans biofilms. In vitro DNA interaction, circular dichroism, and molecular docking analysis showed the great ability of these compounds to bind fungal DNA. Competition with DNA-binding stain, exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane, and activation of metacaspases were shown for BG3. This pro-apoptotic effect of BG3 was only partially due to the accumulation of reactive oxygen species in C. albicans, as only twofold MIC and higher concentrations of BG3 caused depolarization of mitochondrial membrane which was accompanied by the decrease of the activity of fungal mitochondrial dehydrogenases, while the activity of oxidative stress response enzymes glutathione reductase and catalase was not significantly affected. BG3 showed synergistic activity with amphotericin B with a fractional inhibitory concentration index of 0.5. It also exerted low cytotoxicity and the ability to inhibit epithelial cell (TR146) invasion and damage by virulent C. albicans SC5314. With further developments, BG3 may further progress in the antifungal pipeline as a DNA-targeting agent. Antifungal activity spp. Bis-guanylhydrazone DNA interaction ROS generation Synergy Ajdačić, Vladimir aut Vojnovic, Sandra aut Zlatović, Mario aut Pekmezovic, Marina aut Mogavero, Selene aut Opsenica, Igor aut Nikodinovic-Runic, Jasmina (orcid)0000-0002-2553-977X aut Enthalten in Applied microbiology and biotechnology Springer Berlin Heidelberg, 1984 102(2018), 4 vom: 12. Jan., Seite 1889-1901 (DE-627)129942634 (DE-600)392453-1 (DE-576)015507750 0175-7598 nnns volume:102 year:2018 number:4 day:12 month:01 pages:1889-1901 https://doi.org/10.1007/s00253-018-8749-3 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-TEC SSG-OLC-CHE SSG-OLC-PHA SSG-OLC-DE-84 GBV_ILN_70 GBV_ILN_130 GBV_ILN_267 GBV_ILN_2018 GBV_ILN_4012 GBV_ILN_4277 GBV_ILN_4305 AR 102 2018 4 12 01 1889-1901
allfieldsSound	10.1007/s00253-018-8749-3 doi (DE-627)OLC2050790511 (DE-He213)s00253-018-8749-3-p DE-627 ger DE-627 rakwb eng 570 VZ 12 ssgn BIODIV DE-30 fid Lazić, Jelena verfasserin aut Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction 2018 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Candida spp. are leading causes of opportunistic mycoses, including life-threatening hospital-borne infections, and novel antifungals, preferably aiming targets that have not been used before, are constantly needed. Hydrazone- and guanidine-containing molecules have shown a wide range of biological activities, including recently described excellent antifungal properties. In this study, four bis-guanylhydrazone derivatives (BG1–4) were generated following a previously developed synthetic route. Anti-Candida (two C. albicans, C. glabrata, and C. parapsilosis) minimal inhibitory concentrations (MICs) of bis-guanylhydrazones were between 2 and 15.6 μg/mL. They were also effective against preformed 48-h-old C. albicans biofilms. In vitro DNA interaction, circular dichroism, and molecular docking analysis showed the great ability of these compounds to bind fungal DNA. Competition with DNA-binding stain, exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane, and activation of metacaspases were shown for BG3. This pro-apoptotic effect of BG3 was only partially due to the accumulation of reactive oxygen species in C. albicans, as only twofold MIC and higher concentrations of BG3 caused depolarization of mitochondrial membrane which was accompanied by the decrease of the activity of fungal mitochondrial dehydrogenases, while the activity of oxidative stress response enzymes glutathione reductase and catalase was not significantly affected. BG3 showed synergistic activity with amphotericin B with a fractional inhibitory concentration index of 0.5. It also exerted low cytotoxicity and the ability to inhibit epithelial cell (TR146) invasion and damage by virulent C. albicans SC5314. With further developments, BG3 may further progress in the antifungal pipeline as a DNA-targeting agent. Antifungal activity spp. Bis-guanylhydrazone DNA interaction ROS generation Synergy Ajdačić, Vladimir aut Vojnovic, Sandra aut Zlatović, Mario aut Pekmezovic, Marina aut Mogavero, Selene aut Opsenica, Igor aut Nikodinovic-Runic, Jasmina (orcid)0000-0002-2553-977X aut Enthalten in Applied microbiology and biotechnology Springer Berlin Heidelberg, 1984 102(2018), 4 vom: 12. Jan., Seite 1889-1901 (DE-627)129942634 (DE-600)392453-1 (DE-576)015507750 0175-7598 nnns volume:102 year:2018 number:4 day:12 month:01 pages:1889-1901 https://doi.org/10.1007/s00253-018-8749-3 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-TEC SSG-OLC-CHE SSG-OLC-PHA SSG-OLC-DE-84 GBV_ILN_70 GBV_ILN_130 GBV_ILN_267 GBV_ILN_2018 GBV_ILN_4012 GBV_ILN_4277 GBV_ILN_4305 AR 102 2018 4 12 01 1889-1901
language	English
source	Enthalten in Applied microbiology and biotechnology 102(2018), 4 vom: 12. Jan., Seite 1889-1901 volume:102 year:2018 number:4 day:12 month:01 pages:1889-1901
sourceStr	Enthalten in Applied microbiology and biotechnology 102(2018), 4 vom: 12. Jan., Seite 1889-1901 volume:102 year:2018 number:4 day:12 month:01 pages:1889-1901
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topic_facet	Antifungal activity spp. Bis-guanylhydrazone DNA interaction ROS generation Synergy
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author	Lazić, Jelena
spellingShingle	Lazić, Jelena ddc 570 ssgn 12 fid BIODIV misc Antifungal activity misc spp. misc Bis-guanylhydrazone misc DNA interaction misc ROS generation misc Synergy Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction
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topic_title	570 VZ 12 ssgn BIODIV DE-30 fid Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction Antifungal activity spp Bis-guanylhydrazone DNA interaction ROS generation Synergy
topic	ddc 570 ssgn 12 fid BIODIV misc Antifungal activity misc spp. misc Bis-guanylhydrazone misc DNA interaction misc ROS generation misc Synergy
topic_unstemmed	ddc 570 ssgn 12 fid BIODIV misc Antifungal activity misc spp. misc Bis-guanylhydrazone misc DNA interaction misc ROS generation misc Synergy
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title	Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction
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title_full	Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction
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author_browse	Lazić, Jelena Ajdačić, Vladimir Vojnovic, Sandra Zlatović, Mario Pekmezovic, Marina Mogavero, Selene Opsenica, Igor Nikodinovic-Runic, Jasmina
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title_sort	bis-guanylhydrazones as efficient anti-candida compounds through dna interaction
title_auth	Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction
abstract	Abstract Candida spp. are leading causes of opportunistic mycoses, including life-threatening hospital-borne infections, and novel antifungals, preferably aiming targets that have not been used before, are constantly needed. Hydrazone- and guanidine-containing molecules have shown a wide range of biological activities, including recently described excellent antifungal properties. In this study, four bis-guanylhydrazone derivatives (BG1–4) were generated following a previously developed synthetic route. Anti-Candida (two C. albicans, C. glabrata, and C. parapsilosis) minimal inhibitory concentrations (MICs) of bis-guanylhydrazones were between 2 and 15.6 μg/mL. They were also effective against preformed 48-h-old C. albicans biofilms. In vitro DNA interaction, circular dichroism, and molecular docking analysis showed the great ability of these compounds to bind fungal DNA. Competition with DNA-binding stain, exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane, and activation of metacaspases were shown for BG3. This pro-apoptotic effect of BG3 was only partially due to the accumulation of reactive oxygen species in C. albicans, as only twofold MIC and higher concentrations of BG3 caused depolarization of mitochondrial membrane which was accompanied by the decrease of the activity of fungal mitochondrial dehydrogenases, while the activity of oxidative stress response enzymes glutathione reductase and catalase was not significantly affected. BG3 showed synergistic activity with amphotericin B with a fractional inhibitory concentration index of 0.5. It also exerted low cytotoxicity and the ability to inhibit epithelial cell (TR146) invasion and damage by virulent C. albicans SC5314. With further developments, BG3 may further progress in the antifungal pipeline as a DNA-targeting agent. © Springer-Verlag GmbH Germany, part of Springer Nature 2018
abstractGer	Abstract Candida spp. are leading causes of opportunistic mycoses, including life-threatening hospital-borne infections, and novel antifungals, preferably aiming targets that have not been used before, are constantly needed. Hydrazone- and guanidine-containing molecules have shown a wide range of biological activities, including recently described excellent antifungal properties. In this study, four bis-guanylhydrazone derivatives (BG1–4) were generated following a previously developed synthetic route. Anti-Candida (two C. albicans, C. glabrata, and C. parapsilosis) minimal inhibitory concentrations (MICs) of bis-guanylhydrazones were between 2 and 15.6 μg/mL. They were also effective against preformed 48-h-old C. albicans biofilms. In vitro DNA interaction, circular dichroism, and molecular docking analysis showed the great ability of these compounds to bind fungal DNA. Competition with DNA-binding stain, exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane, and activation of metacaspases were shown for BG3. This pro-apoptotic effect of BG3 was only partially due to the accumulation of reactive oxygen species in C. albicans, as only twofold MIC and higher concentrations of BG3 caused depolarization of mitochondrial membrane which was accompanied by the decrease of the activity of fungal mitochondrial dehydrogenases, while the activity of oxidative stress response enzymes glutathione reductase and catalase was not significantly affected. BG3 showed synergistic activity with amphotericin B with a fractional inhibitory concentration index of 0.5. It also exerted low cytotoxicity and the ability to inhibit epithelial cell (TR146) invasion and damage by virulent C. albicans SC5314. With further developments, BG3 may further progress in the antifungal pipeline as a DNA-targeting agent. © Springer-Verlag GmbH Germany, part of Springer Nature 2018
abstract_unstemmed	Abstract Candida spp. are leading causes of opportunistic mycoses, including life-threatening hospital-borne infections, and novel antifungals, preferably aiming targets that have not been used before, are constantly needed. Hydrazone- and guanidine-containing molecules have shown a wide range of biological activities, including recently described excellent antifungal properties. In this study, four bis-guanylhydrazone derivatives (BG1–4) were generated following a previously developed synthetic route. Anti-Candida (two C. albicans, C. glabrata, and C. parapsilosis) minimal inhibitory concentrations (MICs) of bis-guanylhydrazones were between 2 and 15.6 μg/mL. They were also effective against preformed 48-h-old C. albicans biofilms. In vitro DNA interaction, circular dichroism, and molecular docking analysis showed the great ability of these compounds to bind fungal DNA. Competition with DNA-binding stain, exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane, and activation of metacaspases were shown for BG3. This pro-apoptotic effect of BG3 was only partially due to the accumulation of reactive oxygen species in C. albicans, as only twofold MIC and higher concentrations of BG3 caused depolarization of mitochondrial membrane which was accompanied by the decrease of the activity of fungal mitochondrial dehydrogenases, while the activity of oxidative stress response enzymes glutathione reductase and catalase was not significantly affected. BG3 showed synergistic activity with amphotericin B with a fractional inhibitory concentration index of 0.5. It also exerted low cytotoxicity and the ability to inhibit epithelial cell (TR146) invasion and damage by virulent C. albicans SC5314. With further developments, BG3 may further progress in the antifungal pipeline as a DNA-targeting agent. © Springer-Verlag GmbH Germany, part of Springer Nature 2018
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title_short	Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction
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author2	Ajdačić, Vladimir Vojnovic, Sandra Zlatović, Mario Pekmezovic, Marina Mogavero, Selene Opsenica, Igor Nikodinovic-Runic, Jasmina
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