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

Authors

Yan Wang, Ocean University of ChinaFollow
Tian Tian, Peking University
Jingjing Zhang, Ocean University of China
Xin Jin, Peking University
Huan Yue, University of Nebraska - LincolnFollow
Xiao-Hua Zhang, Ocean University of China
Liangcheng Du, University of Nebraska - LincolnFollow
Fan Bai, Peking UniversityFollow

Document Type

Article

Date of this Version

2019

Citation

mBio 10:e00676-19

Comments

© 2019 Wang et al.

Open access

https://doi.org/10.1128/mBio.00676-19

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.