Polycyclic Tetramate Macrolactams—A Group of Natural Bioactive Metallophores

New infectious diseases and increase in drug-resistant microbial pathogens emphasize the need for antibiotics with novel mode-of-action. Tetramates represented by fungi-derived tenuazonic acid and bacterial polycyclic tetramate macrolactams (PTMs) are an important family of natural products with a b...

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Autores principales:	Ling Ding, Sheng-Da Zhang, Ahmad Kasem Haidar, Manila Bajimaya, Yaojie Guo, Thomas Ostenfeld Larsen, Lone Gram
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	tetramate Fenton chemistry metallophore PTM antibiotics Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/f16ea8e814ef46a6aa1ace9a24c45bc7
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spelling	oai:doaj.org-article:f16ea8e814ef46a6aa1ace9a24c45bc72021-11-12T05:02:47ZPolycyclic Tetramate Macrolactams—A Group of Natural Bioactive Metallophores2296-264610.3389/fchem.2021.772858https://doaj.org/article/f16ea8e814ef46a6aa1ace9a24c45bc72021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fchem.2021.772858/fullhttps://doaj.org/toc/2296-2646New infectious diseases and increase in drug-resistant microbial pathogens emphasize the need for antibiotics with novel mode-of-action. Tetramates represented by fungi-derived tenuazonic acid and bacterial polycyclic tetramate macrolactams (PTMs) are an important family of natural products with a broad spectrum of antimicrobial activities. Despite their potential application as new antibiotics, it remains unknown how PTMs function. In this study, genomic mining revealed that PTM biosynthetic gene clusters (BGCs) are widespread in both Gram-positive and Gram-negative bacteria, and we investigated a sponge endosymbiont Actinoalloteichus hymeniacidonis harboring a potential PTM-BGC. Xanthobaccin A that previously has only been isolated from a Gram-negative bacterium was obtained after a scale-up fermentation, isolation, and structure elucidation through mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. Xanthobaccin A as well as two previously reported tetramates, equisetin and ikarugamycin, exhibited antibacterial activities against Bacillus subtilis. In addition, these three tetramates were for the first time to be confirmed as metallophores and the stoichiometry of the complexes were shown to be Fe(III)(equisetin)3/Fe(III)(equisetin)2 and Fe(III)(ikarugamycin)2, respectively. Meanwhile, we found that all three tetramates could reduce ferric into ferrous iron, which triggers the Fenton chemistry reaction. Their antibacterial activity was reduced by adding the radical scavenger, vitamin C. Altogether, our work demonstrates that equisetin and PTMs can act as metallophores and their antimicrobial mechanism is possibly mediated through Fenton chemistry.Ling DingSheng-Da ZhangAhmad Kasem HaidarManila BajimayaYaojie GuoThomas Ostenfeld LarsenLone GramFrontiers Media S.A.articletetramateFenton chemistrymetallophorePTMantibioticsChemistryQD1-999ENFrontiers in Chemistry, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	tetramate Fenton chemistry metallophore PTM antibiotics Chemistry QD1-999
spellingShingle	tetramate Fenton chemistry metallophore PTM antibiotics Chemistry QD1-999 Ling Ding Sheng-Da Zhang Ahmad Kasem Haidar Manila Bajimaya Yaojie Guo Thomas Ostenfeld Larsen Lone Gram Polycyclic Tetramate Macrolactams—A Group of Natural Bioactive Metallophores
description	New infectious diseases and increase in drug-resistant microbial pathogens emphasize the need for antibiotics with novel mode-of-action. Tetramates represented by fungi-derived tenuazonic acid and bacterial polycyclic tetramate macrolactams (PTMs) are an important family of natural products with a broad spectrum of antimicrobial activities. Despite their potential application as new antibiotics, it remains unknown how PTMs function. In this study, genomic mining revealed that PTM biosynthetic gene clusters (BGCs) are widespread in both Gram-positive and Gram-negative bacteria, and we investigated a sponge endosymbiont Actinoalloteichus hymeniacidonis harboring a potential PTM-BGC. Xanthobaccin A that previously has only been isolated from a Gram-negative bacterium was obtained after a scale-up fermentation, isolation, and structure elucidation through mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. Xanthobaccin A as well as two previously reported tetramates, equisetin and ikarugamycin, exhibited antibacterial activities against Bacillus subtilis. In addition, these three tetramates were for the first time to be confirmed as metallophores and the stoichiometry of the complexes were shown to be Fe(III)(equisetin)3/Fe(III)(equisetin)2 and Fe(III)(ikarugamycin)2, respectively. Meanwhile, we found that all three tetramates could reduce ferric into ferrous iron, which triggers the Fenton chemistry reaction. Their antibacterial activity was reduced by adding the radical scavenger, vitamin C. Altogether, our work demonstrates that equisetin and PTMs can act as metallophores and their antimicrobial mechanism is possibly mediated through Fenton chemistry.
format	article
author	Ling Ding Sheng-Da Zhang Ahmad Kasem Haidar Manila Bajimaya Yaojie Guo Thomas Ostenfeld Larsen Lone Gram
author_facet	Ling Ding Sheng-Da Zhang Ahmad Kasem Haidar Manila Bajimaya Yaojie Guo Thomas Ostenfeld Larsen Lone Gram
author_sort	Ling Ding
title	Polycyclic Tetramate Macrolactams—A Group of Natural Bioactive Metallophores
title_short	Polycyclic Tetramate Macrolactams—A Group of Natural Bioactive Metallophores
title_full	Polycyclic Tetramate Macrolactams—A Group of Natural Bioactive Metallophores
title_fullStr	Polycyclic Tetramate Macrolactams—A Group of Natural Bioactive Metallophores
title_full_unstemmed	Polycyclic Tetramate Macrolactams—A Group of Natural Bioactive Metallophores
title_sort	polycyclic tetramate macrolactams—a group of natural bioactive metallophores
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/f16ea8e814ef46a6aa1ace9a24c45bc7
work_keys_str_mv	AT lingding polycyclictetramatemacrolactamsagroupofnaturalbioactivemetallophores AT shengdazhang polycyclictetramatemacrolactamsagroupofnaturalbioactivemetallophores AT ahmadkasemhaidar polycyclictetramatemacrolactamsagroupofnaturalbioactivemetallophores AT manilabajimaya polycyclictetramatemacrolactamsagroupofnaturalbioactivemetallophores AT yaojieguo polycyclictetramatemacrolactamsagroupofnaturalbioactivemetallophores AT thomasostenfeldlarsen polycyclictetramatemacrolactamsagroupofnaturalbioactivemetallophores AT lonegram polycyclictetramatemacrolactamsagroupofnaturalbioactivemetallophores
_version_	1718431203597484032

Polycyclic Tetramate Macrolactams—A Group of Natural Bioactive Metallophores

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