Na<sup>+</sup>-NQR Confers Aminoglycoside Resistance via the Regulation of <sc>l-</sc>Alanine Metabolism

ABSTRACT Sodium-translocating NADH:quinone oxidoreductase (Na+-NQR) functions as a unique redox-driven sodium pump, generating membrane potential, which is related to aminoglycoside antibiotic resistance. However, whether it modulates other metabolisms to confer antibiotic resistance is unknown. The...

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Autores principales:	Ming Jiang, Su-fang Kuang, Shi-shi Lai, Song Zhang, Jun Yang, Bo Peng, Xuan-xian Peng, Zhuang-gui Chen, Hui Li
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Na+-NQR alanine metabolism aspartate metabolism glutamate metabolism alanine aminoglycoside antibiotics Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bd1c1d10659f459fb696d27541a8291e
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spelling	oai:doaj.org-article:bd1c1d10659f459fb696d27541a8291e2021-11-15T15:55:43ZNa<sup>+</sup>-NQR Confers Aminoglycoside Resistance via the Regulation of <sc>l-</sc>Alanine Metabolism10.1128/mBio.02086-202150-7511https://doaj.org/article/bd1c1d10659f459fb696d27541a8291e2020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02086-20https://doaj.org/toc/2150-7511ABSTRACT Sodium-translocating NADH:quinone oxidoreductase (Na+-NQR) functions as a unique redox-driven sodium pump, generating membrane potential, which is related to aminoglycoside antibiotic resistance. However, whether it modulates other metabolisms to confer antibiotic resistance is unknown. The present study showed that loss of nqrA or nqrF led to differential metabolomes with elevated resistance to aminoglycoside antibiotics. Decreased alanine, aspartate, and glutamate metabolism and depressed abundance of alanine were characterized as the most impacted pathway and crucial biomarker, respectively. Further data showed that higher viability was detected in ΔnqrA and ΔnqrF mutant strains than their parent strain ATCC 33787 in the presence of gentamicin but recovered by exogenous l-alanine. It proceeds by the following events. The loss of nqrA or nqrF led to the decrease of membrane potential, ATPase activity, and then ATP and cyclic AMP (cAMP), which reduced the cAMP/CRP (cAMP receptor protein) complex. The reduced cAMP/CRP complex promoted l-alanine catabolism and inhibited l-alanine anabolism, causing reduced levels of alanine. Reduced alanine affected the expression of antiporter families Atp and Mnh genes. Our results suggest a novel mechanism by which the Na+-NQR system regulates antibiotic resistance via l-alanine metabolism in a cAMP/CRP complex-dependent manner. IMPORTANCE The Na+-NQR complex functions as a unique redox-driven sodium pump, generating membrane potential directly. However, whether it mediates generation of membrane potential indirectly is unknown. The present study shows that the Na+-NQR complex impacts membrane potential through other antiporter families Atp and Mnh. It proceeds by ATP and then cAMP/CRP regulon, which inhibits l-alanine catabolism and promotes l-alanine anabolism. When the Na+-NQR complex is reduced as in antibiotic-resistant bacteria, l-alanine is depressed, which is related to the antibiotic resistance phenotypes. However, exogenous l-alanine reverts the phenotype and promotes antibiotic-mediated killing. These findings suggest a novel mechanism by which the Na+-NQR system regulates antibiotic resistance via l-alanine metabolism in a cAMP/CRP complex-dependent manner.Ming JiangSu-fang KuangShi-shi LaiSong ZhangJun YangBo PengXuan-xian PengZhuang-gui ChenHui LiAmerican Society for MicrobiologyarticleNa+-NQRalanine metabolismaspartate metabolismglutamate metabolismalanineaminoglycoside antibioticsMicrobiologyQR1-502ENmBio, Vol 11, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Na+-NQR alanine metabolism aspartate metabolism glutamate metabolism alanine aminoglycoside antibiotics Microbiology QR1-502
spellingShingle	Na+-NQR alanine metabolism aspartate metabolism glutamate metabolism alanine aminoglycoside antibiotics Microbiology QR1-502 Ming Jiang Su-fang Kuang Shi-shi Lai Song Zhang Jun Yang Bo Peng Xuan-xian Peng Zhuang-gui Chen Hui Li Na<sup>+</sup>-NQR Confers Aminoglycoside Resistance via the Regulation of <sc>l-</sc>Alanine Metabolism
description	ABSTRACT Sodium-translocating NADH:quinone oxidoreductase (Na+-NQR) functions as a unique redox-driven sodium pump, generating membrane potential, which is related to aminoglycoside antibiotic resistance. However, whether it modulates other metabolisms to confer antibiotic resistance is unknown. The present study showed that loss of nqrA or nqrF led to differential metabolomes with elevated resistance to aminoglycoside antibiotics. Decreased alanine, aspartate, and glutamate metabolism and depressed abundance of alanine were characterized as the most impacted pathway and crucial biomarker, respectively. Further data showed that higher viability was detected in ΔnqrA and ΔnqrF mutant strains than their parent strain ATCC 33787 in the presence of gentamicin but recovered by exogenous l-alanine. It proceeds by the following events. The loss of nqrA or nqrF led to the decrease of membrane potential, ATPase activity, and then ATP and cyclic AMP (cAMP), which reduced the cAMP/CRP (cAMP receptor protein) complex. The reduced cAMP/CRP complex promoted l-alanine catabolism and inhibited l-alanine anabolism, causing reduced levels of alanine. Reduced alanine affected the expression of antiporter families Atp and Mnh genes. Our results suggest a novel mechanism by which the Na+-NQR system regulates antibiotic resistance via l-alanine metabolism in a cAMP/CRP complex-dependent manner. IMPORTANCE The Na+-NQR complex functions as a unique redox-driven sodium pump, generating membrane potential directly. However, whether it mediates generation of membrane potential indirectly is unknown. The present study shows that the Na+-NQR complex impacts membrane potential through other antiporter families Atp and Mnh. It proceeds by ATP and then cAMP/CRP regulon, which inhibits l-alanine catabolism and promotes l-alanine anabolism. When the Na+-NQR complex is reduced as in antibiotic-resistant bacteria, l-alanine is depressed, which is related to the antibiotic resistance phenotypes. However, exogenous l-alanine reverts the phenotype and promotes antibiotic-mediated killing. These findings suggest a novel mechanism by which the Na+-NQR system regulates antibiotic resistance via l-alanine metabolism in a cAMP/CRP complex-dependent manner.
format	article
author	Ming Jiang Su-fang Kuang Shi-shi Lai Song Zhang Jun Yang Bo Peng Xuan-xian Peng Zhuang-gui Chen Hui Li
author_facet	Ming Jiang Su-fang Kuang Shi-shi Lai Song Zhang Jun Yang Bo Peng Xuan-xian Peng Zhuang-gui Chen Hui Li
author_sort	Ming Jiang
title	Na<sup>+</sup>-NQR Confers Aminoglycoside Resistance via the Regulation of <sc>l-</sc>Alanine Metabolism
title_short	Na<sup>+</sup>-NQR Confers Aminoglycoside Resistance via the Regulation of <sc>l-</sc>Alanine Metabolism
title_full	Na<sup>+</sup>-NQR Confers Aminoglycoside Resistance via the Regulation of <sc>l-</sc>Alanine Metabolism
title_fullStr	Na<sup>+</sup>-NQR Confers Aminoglycoside Resistance via the Regulation of <sc>l-</sc>Alanine Metabolism
title_full_unstemmed	Na<sup>+</sup>-NQR Confers Aminoglycoside Resistance via the Regulation of <sc>l-</sc>Alanine Metabolism
title_sort	na<sup>+</sup>-nqr confers aminoglycoside resistance via the regulation of <sc>l-</sc>alanine metabolism
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/bd1c1d10659f459fb696d27541a8291e
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Na<sup>+</sup>-NQR Confers Aminoglycoside Resistance via the Regulation of <sc>l-</sc>Alanine Metabolism

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