Indole reverses intrinsic antibiotic resistance by activating a novel dual-function importer

Yan Wang, Tian Tian, Jingjing Zhang, Xin Jin, Huan Yue, Xiao Hua Zhang, Liangcheng Du, Fan Bai

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Article numbere00676-19
JournalmBio
Volume10
Issue number3
DOIs
StatePublished - May 1 2019

Fingerprint

Bacterial Drug Resistance
Microbial Drug Resistance
Lysobacter
Anti-Bacterial Agents
Vitamin B 12
Quorum Sensing
Population Density
Cell Death
indole
Amino Acids
Population
Proteins

Keywords

  • Antibiotic resistance
  • BtuD
  • Indole
  • Lysobacter
  • Vitamin B

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Wang, Y., Tian, T., Zhang, J., Jin, X., Yue, H., Zhang, X. H., ... Bai, F. (2019). Indole reverses intrinsic antibiotic resistance by activating a novel dual-function importer. mBio, 10(3), [e00676-19]. https://doi.org/10.1128/mBio.00676-19

Indole reverses intrinsic antibiotic resistance by activating a novel dual-function importer. / Wang, Yan; Tian, Tian; Zhang, Jingjing; Jin, Xin; Yue, Huan; Zhang, Xiao Hua; Du, Liangcheng; Bai, Fan.

In: mBio, Vol. 10, No. 3, e00676-19, 01.05.2019.

Research output: Contribution to journalArticle

Wang, Y, Tian, T, Zhang, J, Jin, X, Yue, H, Zhang, XH, Du, L & Bai, F 2019, 'Indole reverses intrinsic antibiotic resistance by activating a novel dual-function importer', mBio, vol. 10, no. 3, e00676-19. https://doi.org/10.1128/mBio.00676-19
Wang, Yan ; Tian, Tian ; Zhang, Jingjing ; Jin, Xin ; Yue, Huan ; Zhang, Xiao Hua ; Du, Liangcheng ; Bai, Fan. / Indole reverses intrinsic antibiotic resistance by activating a novel dual-function importer. In: mBio. 2019 ; Vol. 10, No. 3.
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