Multi-Omic Analyses Provide Links between Low-Dose Antibiotic Treatment and Induction of Secondary Metabolism in <named-content content-type="genus-species">Burkholderia thailandensis</named-content>

ABSTRACT Low doses of antibiotics can trigger secondary metabolite biosynthesis in bacteria, but the underlying mechanisms are generally unknown. We sought to better understand this phenomenon by studying how the antibiotic trimethoprim activates the synthesis of the virulence factor malleilactone i...

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Autores principales: Anran Li, Dainan Mao, Aya Yoshimura, Paul C. Rosen, W. Lance Martin, Étienne Gallant, Martin Wühr, Mohammad R. Seyedsayamdost
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Publicado: American Society for Microbiology 2020
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spelling oai:doaj.org-article:ccfb72223b13473a8b3d92fb7f6da58d2021-11-15T15:56:57ZMulti-Omic Analyses Provide Links between Low-Dose Antibiotic Treatment and Induction of Secondary Metabolism in <named-content content-type="genus-species">Burkholderia thailandensis</named-content>10.1128/mBio.03210-192150-7511https://doaj.org/article/ccfb72223b13473a8b3d92fb7f6da58d2020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03210-19https://doaj.org/toc/2150-7511ABSTRACT Low doses of antibiotics can trigger secondary metabolite biosynthesis in bacteria, but the underlying mechanisms are generally unknown. We sought to better understand this phenomenon by studying how the antibiotic trimethoprim activates the synthesis of the virulence factor malleilactone in Burkholderia thailandensis. Using transcriptomics, quantitative multiplexed proteomics, and primary metabolomics, we systematically mapped the changes induced by trimethoprim. Surprisingly, even subinhibitory doses of the antibiotic resulted in broad transcriptional and translational alterations, with ∼8.5% of the transcriptome and ∼5% of the proteome up- or downregulated >4-fold. Follow-up studies with genetic-biochemical experiments showed that the induction of malleilactone synthesis can be sufficiently explained by the accumulation of methionine biosynthetic precursors, notably homoserine, as a result of inhibition of the folate pathway. Homoserine activated the malleilactone gene cluster via the transcriptional regulator MalR and gave rise to a secondary metabolome which was very similar to that generated by trimethoprim. Our work highlights the expansive changes that low-dose trimethoprim induces on bacterial physiology and provides insights into its stimulatory effect on secondary metabolism. IMPORTANCE The discovery of antibiotics ranks among the most significant accomplishments of the last century. Although the targets of nearly all clinical antibiotics are known, our understanding regarding their natural functions and the effects of subinhibitory concentrations is in its infancy. Stimulatory rather than inhibitory functions have been attributed to low-dose antibiotics. Among these, we previously found that antibiotics activate silent biosynthetic genes and thereby enhance the metabolic output of bacteria. The regulatory circuits underlying this phenomenon are unknown. We take a first step toward elucidating these circuits and show that low doses of trimethoprim (Tmp) have cell-wide effects on the saprophyte Burkholderia thailandensis. Most importantly, inhibition of one-carbon metabolic processes by Tmp leads to an accumulation of homoserine, which induces the production of an otherwise silent cytotoxin via a LuxR-type transcriptional regulator. These results provide a starting point for uncovering the molecular basis of the hormetic effects of antibiotics.Anran LiDainan MaoAya YoshimuraPaul C. RosenW. Lance MartinÉtienne GallantMartin WührMohammad R. SeyedsayamdostAmerican Society for Microbiologyarticleantibioticsbiosynthesisnatural productssecondary metabolismMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution DOAJ
collection DOAJ
language EN
topic antibiotics
biosynthesis
natural products
secondary metabolism
Microbiology
QR1-502
spellingShingle antibiotics
biosynthesis
natural products
secondary metabolism
Microbiology
QR1-502
Anran Li
Dainan Mao
Aya Yoshimura
Paul C. Rosen
W. Lance Martin
Étienne Gallant
Martin Wühr
Mohammad R. Seyedsayamdost
Multi-Omic Analyses Provide Links between Low-Dose Antibiotic Treatment and Induction of Secondary Metabolism in <named-content content-type="genus-species">Burkholderia thailandensis</named-content>
description ABSTRACT Low doses of antibiotics can trigger secondary metabolite biosynthesis in bacteria, but the underlying mechanisms are generally unknown. We sought to better understand this phenomenon by studying how the antibiotic trimethoprim activates the synthesis of the virulence factor malleilactone in Burkholderia thailandensis. Using transcriptomics, quantitative multiplexed proteomics, and primary metabolomics, we systematically mapped the changes induced by trimethoprim. Surprisingly, even subinhibitory doses of the antibiotic resulted in broad transcriptional and translational alterations, with ∼8.5% of the transcriptome and ∼5% of the proteome up- or downregulated >4-fold. Follow-up studies with genetic-biochemical experiments showed that the induction of malleilactone synthesis can be sufficiently explained by the accumulation of methionine biosynthetic precursors, notably homoserine, as a result of inhibition of the folate pathway. Homoserine activated the malleilactone gene cluster via the transcriptional regulator MalR and gave rise to a secondary metabolome which was very similar to that generated by trimethoprim. Our work highlights the expansive changes that low-dose trimethoprim induces on bacterial physiology and provides insights into its stimulatory effect on secondary metabolism. IMPORTANCE The discovery of antibiotics ranks among the most significant accomplishments of the last century. Although the targets of nearly all clinical antibiotics are known, our understanding regarding their natural functions and the effects of subinhibitory concentrations is in its infancy. Stimulatory rather than inhibitory functions have been attributed to low-dose antibiotics. Among these, we previously found that antibiotics activate silent biosynthetic genes and thereby enhance the metabolic output of bacteria. The regulatory circuits underlying this phenomenon are unknown. We take a first step toward elucidating these circuits and show that low doses of trimethoprim (Tmp) have cell-wide effects on the saprophyte Burkholderia thailandensis. Most importantly, inhibition of one-carbon metabolic processes by Tmp leads to an accumulation of homoserine, which induces the production of an otherwise silent cytotoxin via a LuxR-type transcriptional regulator. These results provide a starting point for uncovering the molecular basis of the hormetic effects of antibiotics.
format article
author Anran Li
Dainan Mao
Aya Yoshimura
Paul C. Rosen
W. Lance Martin
Étienne Gallant
Martin Wühr
Mohammad R. Seyedsayamdost
author_facet Anran Li
Dainan Mao
Aya Yoshimura
Paul C. Rosen
W. Lance Martin
Étienne Gallant
Martin Wühr
Mohammad R. Seyedsayamdost
author_sort Anran Li
title Multi-Omic Analyses Provide Links between Low-Dose Antibiotic Treatment and Induction of Secondary Metabolism in <named-content content-type="genus-species">Burkholderia thailandensis</named-content>
title_short Multi-Omic Analyses Provide Links between Low-Dose Antibiotic Treatment and Induction of Secondary Metabolism in <named-content content-type="genus-species">Burkholderia thailandensis</named-content>
title_full Multi-Omic Analyses Provide Links between Low-Dose Antibiotic Treatment and Induction of Secondary Metabolism in <named-content content-type="genus-species">Burkholderia thailandensis</named-content>
title_fullStr Multi-Omic Analyses Provide Links between Low-Dose Antibiotic Treatment and Induction of Secondary Metabolism in <named-content content-type="genus-species">Burkholderia thailandensis</named-content>
title_full_unstemmed Multi-Omic Analyses Provide Links between Low-Dose Antibiotic Treatment and Induction of Secondary Metabolism in <named-content content-type="genus-species">Burkholderia thailandensis</named-content>
title_sort multi-omic analyses provide links between low-dose antibiotic treatment and induction of secondary metabolism in <named-content content-type="genus-species">burkholderia thailandensis</named-content>
publisher American Society for Microbiology
publishDate 2020
url https://doaj.org/article/ccfb72223b13473a8b3d92fb7f6da58d
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