Indole Reverses Intrinsic Antibiotic Resistance by Activating a Novel Dual-Function Importer

ABSTRACT Bacterial antibiotic resistance modulation by small signaling molecules is an emerging mechanism that has been increasingly reported in recent years. Several studies indicate that indole, an interkingdom signaling molecule, increases bacterial antibiotic resistance. However, the mechanism t...

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Autores principales:	Yan Wang, Tian Tian, Jingjing Zhang, Xin Jin, Huan Yue, Xiao-Hua Zhang, Liangcheng Du, Fan Bai
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Lysobacter antibiotic resistance btuD indole vitamin B12 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a707a8111af24e03ba47f7b7550c2dd9
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spelling	oai:doaj.org-article:a707a8111af24e03ba47f7b7550c2dd92021-11-15T15:55:25ZIndole Reverses Intrinsic Antibiotic Resistance by Activating a Novel Dual-Function Importer10.1128/mBio.00676-192150-7511https://doaj.org/article/a707a8111af24e03ba47f7b7550c2dd92019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00676-19https://doaj.org/toc/2150-7511ABSTRACT Bacterial antibiotic resistance modulation by small signaling molecules is an emerging mechanism that has been increasingly reported in recent years. Several studies indicate that indole, an interkingdom signaling molecule, increases bacterial antibiotic resistance. However, the mechanism through which indole reduces antibiotic resistance is largely unknown. In this study, we demonstrated a novel mechanism for indole-mediated reversal of intrinsic antibiotic resistance in Lysobacter. This reversal was facilitated by a novel BtuD-associated dual-function importer that can transfer both vitamin B12 and antibiotics. Indole stimulated btuD overexpression and promoted efficient absorption of extracellular vitamin B12; meanwhile, the weak selectivity of the importer caused cells to take up excessive doses of antibiotics that resulted in cell death. Consistently, btuD deletion and G48Y/K49D substitution led to marked reductions in the uptake of both antibiotics and vitamin B12. This novel mechanism is common across multiple bacterial species, among which the Q-loop amino acid of BtuD proteins is Glu (E) instead of Gln (Q). Interestingly, the antibiotic resistance of Lysobacter spp. can be restored by another small quorum sensing signaling factor, 13-methyltetradecanoic acid, designated LeDSF, in response to bacterial population density. This work highlights the mechanisms underlying dynamic regulation of bacterial antibiotic resistance by small signaling molecules and suggests that the effectiveness of traditional antibiotics could be increased by coupling them with appropriate signaling molecules. IMPORTANCE Recently, signaling molecules were found to play a role in mediating antibiotic resistance. In this study, we demonstrated that indole reversed the intrinsic antibiotic resistance (IRAR) of multiple bacterial species by promoting the expression of a novel dual-function importer. In addition, population-dependent behavior induced by 13-methyltetradecanoic acid, a quorum sensing signal molecule designated LeDSF, was involved in the IRAR process. This study highlights the dynamic regulation of bacterial antibiotic resistance by small signaling molecules and provides direction for new therapeutic strategies using traditional antibiotics in combination with signaling molecules.Yan WangTian TianJingjing ZhangXin JinHuan YueXiao-Hua ZhangLiangcheng DuFan BaiAmerican Society for MicrobiologyarticleLysobacterantibiotic resistancebtuDindolevitamin B12MicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Lysobacter antibiotic resistance btuD indole vitamin B12 Microbiology QR1-502
spellingShingle	Lysobacter antibiotic resistance btuD indole vitamin B12 Microbiology QR1-502 Yan Wang Tian Tian Jingjing Zhang Xin Jin Huan Yue Xiao-Hua Zhang Liangcheng Du Fan Bai Indole Reverses Intrinsic Antibiotic Resistance by Activating a Novel Dual-Function Importer
description	ABSTRACT Bacterial antibiotic resistance modulation by small signaling molecules is an emerging mechanism that has been increasingly reported in recent years. Several studies indicate that indole, an interkingdom signaling molecule, increases bacterial antibiotic resistance. However, the mechanism through which indole reduces antibiotic resistance is largely unknown. In this study, we demonstrated a novel mechanism for indole-mediated reversal of intrinsic antibiotic resistance in Lysobacter. This reversal was facilitated by a novel BtuD-associated dual-function importer that can transfer both vitamin B12 and antibiotics. Indole stimulated btuD overexpression and promoted efficient absorption of extracellular vitamin B12; meanwhile, the weak selectivity of the importer caused cells to take up excessive doses of antibiotics that resulted in cell death. Consistently, btuD deletion and G48Y/K49D substitution led to marked reductions in the uptake of both antibiotics and vitamin B12. This novel mechanism is common across multiple bacterial species, among which the Q-loop amino acid of BtuD proteins is Glu (E) instead of Gln (Q). Interestingly, the antibiotic resistance of Lysobacter spp. can be restored by another small quorum sensing signaling factor, 13-methyltetradecanoic acid, designated LeDSF, in response to bacterial population density. This work highlights the mechanisms underlying dynamic regulation of bacterial antibiotic resistance by small signaling molecules and suggests that the effectiveness of traditional antibiotics could be increased by coupling them with appropriate signaling molecules. IMPORTANCE Recently, signaling molecules were found to play a role in mediating antibiotic resistance. In this study, we demonstrated that indole reversed the intrinsic antibiotic resistance (IRAR) of multiple bacterial species by promoting the expression of a novel dual-function importer. In addition, population-dependent behavior induced by 13-methyltetradecanoic acid, a quorum sensing signal molecule designated LeDSF, was involved in the IRAR process. This study highlights the dynamic regulation of bacterial antibiotic resistance by small signaling molecules and provides direction for new therapeutic strategies using traditional antibiotics in combination with signaling molecules.
format	article
author	Yan Wang Tian Tian Jingjing Zhang Xin Jin Huan Yue Xiao-Hua Zhang Liangcheng Du Fan Bai
author_facet	Yan Wang Tian Tian Jingjing Zhang Xin Jin Huan Yue Xiao-Hua Zhang Liangcheng Du Fan Bai
author_sort	Yan Wang
title	Indole Reverses Intrinsic Antibiotic Resistance by Activating a Novel Dual-Function Importer
title_short	Indole Reverses Intrinsic Antibiotic Resistance by Activating a Novel Dual-Function Importer
title_full	Indole Reverses Intrinsic Antibiotic Resistance by Activating a Novel Dual-Function Importer
title_fullStr	Indole Reverses Intrinsic Antibiotic Resistance by Activating a Novel Dual-Function Importer
title_full_unstemmed	Indole Reverses Intrinsic Antibiotic Resistance by Activating a Novel Dual-Function Importer
title_sort	indole reverses intrinsic antibiotic resistance by activating a novel dual-function importer
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/a707a8111af24e03ba47f7b7550c2dd9
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Indole Reverses Intrinsic Antibiotic Resistance by Activating a Novel Dual-Function Importer

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