Indole enhanced the bactericidal efficacy of tetracycline against pathogen <italic style="font-style: italic">Vibrio splendidus</italic>

Jinxia ZHANG; Zhixin MU; Qiling ZHOU; Weiwei ZHANG

doi:10.1007/s00343-025-4202-5

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Indole enhanced the bactericidal efficacy of tetracycline against pathogen Vibrio splendidus

Biology | Updated：2025-10-16

- Indole enhanced the bactericidal efficacy of tetracycline against pathogen Vibrio splendidus
- Indole enhanced the bactericidal efficacy of tetracycline against pathogen Vibrio splendidus
- 海洋湖沼学报(英文) 2025年43卷第5期页码：1623-1635
- Affiliations：
  
  School of Marine Sciences, Ningbo University, Ningbo 315832, China
- Author bio：
  
  zhangweiwei1@nbu.edu.cn
- Funds：
  
  the Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholar(LR20C190001);the National Natural Science Foundation of China(42376103);the Natural Science Foundation of Ningbo City(2021J062);the K. C. Wong Magna Fund in Ningbo University
- DOI：10.1007/s00343-025-4202-5
  中图分类号：
- 收稿：2024-07-24，
  
  录用：2024-10-16，
  
  纸质出版：2025-09-01
- Accepted：
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Indole enhanced the bactericidal efficacy of tetracycline against pathogen Vibrio splendidus[J]. 海洋湖沼学报(英文), 2025,43(5):1623-1635.

ZHANG Jinxia,MU Zhixin,ZHOU Qiling,et al.Indole enhanced the bactericidal efficacy of tetracycline against pathogen Vibrio splendidus[J].Journal of Oceanology and Limnology,2025,43(05):1623-1635.
Indole enhanced the bactericidal efficacy of tetracycline against pathogen Vibrio splendidus[J]. 海洋湖沼学报(英文), 2025,43(5):1623-1635. DOI： 10.1007/s00343-025-4202-5.

ZHANG Jinxia,MU Zhixin,ZHOU Qiling,et al.Indole enhanced the bactericidal efficacy of tetracycline against pathogen Vibrio splendidus[J].Journal of Oceanology and Limnology,2025,43(05):1623-1635. DOI： 10.1007/s00343-025-4202-5.

摘要

Abstract

Recently

more and more bacteria have been reported to become tolerant to antibiotics. In this study

one

tnaA

gene involved in indole production

and the effect of exogenous indole on the formation of persister cells specific to tetracycline in

Vibrio

splendidus

were characterized. The

tnaA

gene was first cloned and conditionally expressed in

Escherichia

coli

Rosetta (DE3). To investigate the regulatory effect of TnaA

the

tnaA

deletion strain AJ01/∆

tnaA

was constructed by in-frame deletion. The undetected extracellular indole in the AJ01/∆

tnaA

indicated that TnaA was the solo enzyme to produce indole in

splendidus

. The drop plate method showed that AJ01/∆

tnaA

was more tolerant to the higher concentration of tetracycline than that of AJ01

being 340-fold higher in the proportion of survived cells when cell density OD

600

≈0.65. Moreover

the synergistic effects of indole and tetracycline on killing of

splendidus

were determined. Results show that addition of 2-mmol/L indole increased the susceptibility of both AJ01 and AJ01/∆

tnaA

to 10×minimum inhibitory concentration tetracycline. To explore the genes and pathways regulated by TnaA

the transcriptomic analysis between AJ01 and AJ01/∆

tnaA

was performed. Result shows that TCA cycle

arginine biosynthesis

quorum sensing and microbial metabolism in diverse environments were downregulated

while the ribosome pathways

the protein metabolic process

peptide biosynthetic and metabolic process were upregulated in the AJ01/∆

tnaA

. This study shows that indole could enhance the bactericidal effect of tetracycline on

splendidus

by decreased ribosome level probably but increased ATP level.

关键词

Keywords

references

Andersson D I , Balaban N Q , Baquero F et al . 2020 . Antibiotic resistance: turning evolutionary principles into clinical reality . FEMS Microbiology Reviews , 44 ( 2 ): 171 - 188 , https://doi.org/10.1093/femsre/fuaa001 https://doi.org/10.1093/femsre/fuaa001 .

Brauner A , Fridman O , Gefen O et al . 2016 . Distinguishing between resistance, tolerance and persistence to antibiotic treatment . Nature Reviews Microbiology , 14 ( 5 ): 320 - 330 , https://doi.org/10.1038/nrmicro.2016.34 https://doi.org/10.1038/nrmicro.2016.34 .

Bryksin A V , Matsumura I . 2010 . Overlap extension PCR cloning: a simple and reliable way to create recombinant plasmids . BioTechniques , 48 ( 6 ): 463 - 465 , https://doi.org/10.2144/000113418 https://doi.org/10.2144/000113418 .

Chant E L , Summers D K . 2007 . Indole signaling contributes to the stable maintenance of Escherichia coli multicopy plasmids . Molecular Microbiology , 63 ( 1 ): 35 - 43 , https://doi.org/10.1111/j.1365-2958.2006.05481.x https://doi.org/10.1111/j.1365-2958.2006.05481.x .

Cui P , Niu H X , Shi W L et al . 2018 . Identification of genes involved in bacteriostatic antibiotic-induced persister formation. Frontiers in Microbiology , 9 : 413 , https://doi.org/10.3389/fmicb.2018.00413 https://doi.org/10.3389/fmicb.2018.00413 .

Gao L , Yuan Z H , Li Y F et al . 2022 . Genome-wide comparative analysis of DNAJ genes and their co-expression patterns with HSP70s in aestivation of the sea cucumber Apostichopus japonicus . Functional Integrative Genomics , 22 ( 3 ): 317 - 330 , https://doi.org/10.1007/s10142-022-00830-2 https://doi.org/10.1007/s10142-022-00830-2 .

Goode O , Smith A , Zarkan A et al . 2021 . Persister Escherichia coli cells have a lower intracellular pH than susceptible cells but maintain their pH in response to antibiotic treatment . mBio , 12 ( 4 ): e00909 - 21 , https://doi.org/10.1128/mBio.00909-21 https://doi.org/10.1128/mBio.00909-21 .

Grossman T H . 2016 . Tetracycline antibiotics and resistance . Cold Spring Harbor Perspectives in Medicine , 6 ( 4 ): a 025387 , https://doi.org/10.1101/cshperspect.a025387 https://doi.org/10.1101/cshperspect.a025387 .

Han J T , Li D Y , Zhang M Y et al . 2021 . EmhR is an indole-sensing transcriptional regulator responsible for the indole-induced antibiotic tolerance in Pseudomonas fluorescens . Environmental Microbiology , 23 ( 4 ): 2054 - 2069 , https://doi.org/10.1111/1462-2920.15354 https://doi.org/10.1111/1462-2920.15354 .

Han T H , Lee J H , Cho M H et al . 2011 . Environmental factors affecting indole production in Escherichia coli . Research in Microbiology , 162 ( 2 ): 108 - 116 , https://doi.org/10.1016/j.resmic.2010.11.005 https://doi.org/10.1016/j.resmic.2010.11.005 .

Han Y , Wang Y , Yu Y M et al . 2017 . Indole-induced reversion of intrinsic multiantibiotic resistance in Lysobacter enzymogenes . Applied and Environmental Microbiology , 83 ( 17 ): e00995 - 17 , https://doi.org/10.1128/AEM.00995-17 https://doi.org/10.1128/AEM.00995-17 .

Hirakawa H , Kodama T , Takumi-Kobayashi A et al . 2009 . Secreted indole serves as a signal for expression of type III secretion system translocators in enterohaemorrhagic Escherichia coli O 157 :H 7 . Microbiology , 155 ( 2 ): 541 - 550 , https://doi.org/10.1099/mic.0.020420-0 https://doi.org/10.1099/mic.0.020420-0 .

Hobbs A M , Kluthe K E , Carlson K A et al . 2021 . Interruption of the tricarboxylic acid cycle in Staphylococcus aureus leads to increased tolerance to innate immunity . AIMS Microbiology , 7 ( 4 ): 513 - 527 , https://doi.org/10.3934/microbiol.2021031 https://doi.org/10.3934/microbiol.2021031 .

Hossain A , Habibullah-Al-Mamun M , Nagano I et al . 2022 . Antibiotics, antibiotic-resistant bacteria, and resistance genes in aquaculture: risks, current concern, and future thinking . Environmental Science and Pollution Research , 29 ( 8 ): 11054 - 11075 , https://doi.org/10.1007/s11356-021-17825-4 https://doi.org/10.1007/s11356-021-17825-4 .

Hu Y , Kwan B W , Osbourne D O et al . 2015 . Toxin YafQ increases persister cell formation by reducing indole signalling . Environmental Microbiology , 17 ( 4 ): 1275 - 1285 . https://doi.org/10.1111/1462-2920.12567 https://doi.org/10.1111/1462-2920.12567 .

Jiang G H , Li Y N , Li Y et al . 2022a . Selection of the amino acid and saccharide that increase the tetracycline susceptibility of Vibrio splendidus . Frontiers in Veterinary Science , 8 : 823332 , https://doi.org/10.3389/fvets.2021.823332 https://doi.org/10.3389/fvets.2021.823332 .

Kaldalu N , Hauryliuk V , Tenson T . 2016 . Persisters—as elusive as ever . Applied Microbiology and Biotechnology , 100 ( 15 ): 6545 - 6553 , https://doi.org/10.1007/s00253-016-7648-8 https://doi.org/10.1007/s00253-016-7648-8 .

Kim J S , Wood T K . 2017 . Tolerant, growing cells from nutrient shifts are not persister cells . mBio , 8 ( 2 ): e00354 - 17 , https://doi.org/10.1128/mBio.00354-17 https://doi.org/10.1128/mBio.00354-17 .

Kim J W , Kim H K , Kang G S et al . 2016 . The SAV1322 gene from Staphylococcus aureus : genomic and proteomic approaches to identification and characterization of gene function . BMC Microbiology , 16 ( 1 ): 206 , https://doi.org/10.1186/s12866-016-0824-2 https://doi.org/10.1186/s12866-016-0824-2 .

Kim J , Shin B , Park C et al . 2017 . Indole-induced activities of β-lactamase and efflux pump confer ampicillin resistance in Pseudomonas putida KT2440. Frontiers in Microbiology , 8 : 433 , https://doi.org/10.3389/fmicb.2017.00433 https://doi.org/10.3389/fmicb.2017.00433 .

Lang M , Krin E , Korlowski C et al . 2021 . Sleeping ribosomes: bacterial signaling triggers RaiA mediated persistence to aminoglycosides . iScience , 24 ( 10 ): 103128 , https://doi.org/10.1016/j.isci.2021.103128 https://doi.org/10.1016/j.isci.2021.103128 .

Lee J H , Kim Y G , Baek K H et al . 2015 . The multifaceted roles of the interspecies signalling molecule indole in Agrobacterium tumefaciens . Environmental Microbiology , 17 ( 4 ): 1234 - 1244 , https://doi.org/10.1111/1462-2920.12560 https://doi.org/10.1111/1462-2920.12560 .

Lee J H , Kim Y G , Gwon G et al . 2016 . Halogenated indoles eradicate bacterial persister cells and biofilms . AMB Express , 6 ( 1 ): 123 , https://doi.org/10.1186/s13568-016-0297-6 https://doi.org/10.1186/s13568-016-0297-6 .

Lee J , Jayaraman A , Wood T K . 2007 . Indole is an inter-species biofilm signal mediated by SdiA . BMC Microbiology , 7 ( 1 ): 42 , https://doi.org/10.1186/1471-2180-7-42 https://doi.org/10.1186/1471-2180-7-42 .

Li G , Young K D . 2013 . Indole production by the tryptophanase TnaA in Escherichia coli is determined by the amount of exogenous tryptophan . Microbiology , 159 ( 2 ): 402 - 410 , https://doi.org/10.1099/mic.0.064139-0 https://doi.org/10.1099/mic.0.064139-0 .

Li X , Yang Q , Dierckens K et al . 2014 . RpoS and indole signaling control the virulence of Vibrio anguillarum towards Gnotobiotic Sea Bass ( Dicentrarchus labrax ) Larvae . PLoS One , 9 ( 10 ): e 111801 , https://doi.org/10.1371/journal.pone.0111801 https://doi.org/10.1371/journal.pone.0111801 .

Li Y N , Wood T K , Zhang W W et al . 2021 . Vibrio splendidus persister cells induced by host coelomic fluids show a similar phenotype to antibiotic-induced counterparts . Environmental Microbiology , 23 ( 9 ): 5605 - 5620 , https://doi.org/10.1111/1462-2920.15717 https://doi.org/10.1111/1462-2920.15717 .

Li Z Y , Sun F Q , Fu X M et al . 2022 . 5-Methylindole kills various bacterial pathogens and potentiates aminoglycoside against methicillin-resistant Staphylococcus aureus . PeerJ , 10 : e 14010 , https://doi.org/10.7717/peerj.14010 https://doi.org/10.7717/peerj.14010 .

Liu H Z , Wang Y S , Zhang Z Q et al . 2023 . Nutrient condition modulates the antibiotic tolerance of Pseudomonas aeruginosa . Science of the Total Environment , 904 : 166749 , https://doi.org/10.1016/j.scitotenv.2023.166749 https://doi.org/10.1016/j.scitotenv.2023.166749 .

Liu J F , Gefen O , Ronin I et al . 2020 . Effect of tolerance on the evolution of antibiotic resistance under drug combinations . Science , 367 ( 6474 ): 200 - 204 , https://doi.org/10.1126/science.aay3041 https://doi.org/10.1126/science.aay3041 .

Molina-Santiago C , Daddaoua A , Fillet S et al . 2014 . Interspecies signalling: Pseudomonas putida efflux pump TtgGHI is activated by indole to increase antibiotic resistance . Environmental Microbiology , 16 ( 5 ): 1267 - 1281 , https://doi.org/10.1111/1462-2920.12368 https://doi.org/10.1111/1462-2920.12368 .

Morino Y , Snell E E . 1970 . [54 ] Tryptophanase ( Escherichia coli B) . Methods in Enzymology , 17 : 439 - 446 , https://doi.org/10.1016/0076-6879(71)17224-2 https://doi.org/10.1016/0076-6879(71)17224-2 .

Munita J M , Arias C A . 2016 . Mechanisms of antibiotic resistance . Microbiology Spectrum , 4 ( 2 ), http s://doi.org/10.1128/microbiolspec.VMBF-0016- 2015.

Sun F Q , Bian M M , Li Z Y et al . 2020 . 5-Methylindole potentiates aminoglycoside against gram-positive bacteria including Staphylococcus aureus persisters under hypoionic conditions. Frontiers in Cellular and Infection Microbiology , 10 : 84 , https://doi.org/10.3389/fcimb.2020.00084 https://doi.org/10.3389/fcimb.2020.00084 .

Tacconelli E , Carrara E , Savoldi A et al . 2018 . Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis . The Lancet Infectious Diseases , 18 ( 3 ): 318 - 327 , https://doi.org/10.1016/S1473-3099(17)30753-3 https://doi.org/10.1016/S1473-3099(17)30753-3 .

Tamura K , Stecher G , Kumar S . 2021 . MEGA11: molecular evolutionary genetics analysis version 11 . Molecular Biology and Evolution , 38 ( 7 ): 3022 - 3027 , https://doi.org/10.1093/molbev/msab120 https://doi.org/10.1093/molbev/msab120 .

Vega N M , Allison K R , Khalil A S et al . 2012 . Signaling-mediated bacterial persister formation . Nature Chemical Biology , 8 ( 5 ): 431 - 433 , https://doi.org/10.1038/nchembio.915 https://doi.org/10.1038/nchembio.915 .

Williamson K S , Richards L A , Perez-Osorio A C et al . 2012 . Heterogeneity in Pseudomonas aeruginosa biofilms includes expression of ribosome hibernation factors in the antibiotic-tolerant subpopulation and hypoxia-induced stress response in the metabolically active population . Journal of Bacteriology , 194 ( 8 ): 2062 - 2073 , https://doi.org/10.1128/JB.00022-12 https://doi.org/10.1128/JB.00022-12 .

Wu X Q , Zhang S S , Xu X X et al . 2019 . RAFT-derived polymethacrylates as a superior treatment for recurrent vulvovaginal candidiasis by targeting biotic biofilms and persister cells. Frontiers in Microbiology , 10 : 2592 , https://doi.org/10.3389/fmicb.2019.02592 https://doi.org/10.3389/fmicb.2019.02592 .

Yang H R , Song H M , Zhang J X et al . 2023 . Proteomic analysis reveals the adaptation of Vibrio splendidus to an iron deprivation condition . Applied Microbiology and Biotechnology , 107 ( 7-8 ): 2533 - 2546 , https://doi.org/10.1007/s00253-023-12460-0 https://doi.org/10.1007/s00253-023-12460-0 .

Zhang Q , Ma H M , Mai K S et al . 2010 . Interaction of dietary Bacillus subtilis and fructooligosaccharide on the growth performance, non-specific immunity of sea cucumber, Apostichopus japonicus . Fish Shellfish Immunology , 29 ( 2 ): 204 - 211 , https://doi.org/10.1016/j.fsi.2010.03.009 https://doi.org/10.1016/j.fsi.2010.03.009 .

Zhang S S , Liu N N , Liang W K et al . 2017a . Quorum sensing-disrupting coumarin suppressing virulence phenotypes in Vibrio splendidus . Applied Microbiology and Biotechnology , 101 ( 8 ): 3371 - 3378 , https://doi.org/10.1007/s00253-016-8009-3 https://doi.org/10.1007/s00253-016-8009-3 .

Zhang S S , Shao Y N , Zhao X L et al . 2020 . Indole contributes to tetracycline resistance via the outer membrane protein OmpN in Vibrio splendidus . World Journal of Microbiology and Biotechnology , 36 ( 3 ): 36 , https://doi.org/10.1007/s11274-020-02813-6 https://doi.org/10.1007/s11274-020-02813-6 .

Zhang S S , Zhang W W , Liu N N et al . 2017b . Indole reduces the expression of virulence related genes in Vibrio splendidus pathogenic to sea cucumber Apostichopus japonicus . Microbial Pathogenesis , 111 : 168 - 173 , https://doi.org/10.1016/j.micpath.2017.08.032 https://doi.org/10.1016/j.micpath.2017.08.032 .

Zhang T , Qiu L M , Sun Z B et al . 2014 . The specifically enhanced cellular immune responses in Pacific oyster ( Crassostrea gigas ) against secondary challenge with Vibrio splendidus . Developmental Comparative Immunology , 45 ( 1 ): 141 - 150 , https://doi.org/10.1016/j.dci.2014.02.015 https://doi.org/10.1016/j.dci.2014.02.015 .

Zhang W W , Sun L . 2007 . Cloning, characterization, and molecular application of a beta-agarase gene from Vibrio sp. Strain V134 . Applied and Environmental Microbiology , 73 ( 9 ): 2825 - 2831 , https://doi.org/10.1128/AEM.02872-06 https://doi.org/10.1128/AEM.02872-06 .

Zhang W , Yamasaki R , Song S et al . 2019 . Interkingdom signal indole inhibits Pseudomonas aeruginosa persister cell waking . Journal of Applied Microbiology , 127 ( 6 ): 1768 - 1775 , https://doi.org/10.1111/jam.14434 https://doi.org/10.1111/jam.14434 .

Zhen J F , Yan S Q , Li Y Z et al . 2020 . L-Alanine specifically potentiates fluoroquinolone efficacy against Mycobacterium persisters via increased intracellular reactive oxygen species . Applied Microbiology and Biotechnology , 104 ( 5 ): 2137 - 2147 , https://doi.org/10.1007/s00253-020-10358-9 https://doi.org/10.1007/s00253-020-10358-9 .

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Indole enhanced the bactericidal efficacy of tetracycline against pathogen Vibrio splendidus

Indole enhanced the bactericidal efficacy of tetracycline against pathogen Vibrio splendidus

DOI：10.1007/s00343-025-4202-5

摘要

Abstract

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Keywords

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