Format

Send to

Choose Destination
MBio. 2019 May 28;10(3). pii: e00676-19. doi: 10.1128/mBio.00676-19.

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

Wang Y#1,2,3, Tian T#4, Zhang J#5, Jin X#4, Yue H6, Zhang XH5,2,3, Du L6, Bai F7.

Author information

1
College of Marine Life Sciences, MOE Key Laboratory of Marine Genetics and Breeding, Ocean University of China, Qingdao, China wangy12@ouc.edu.cn fbai@pku.edu.cn.
2
Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, China.
3
Laboratory for Marine Ecology and Environmental Science, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
4
Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China.
5
College of Marine Life Sciences, MOE Key Laboratory of Marine Genetics and Breeding, Ocean University of China, Qingdao, China.
6
Department of Chemistry, University of Nebraska-Lincoln, Nebraska, USA.
7
Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China wangy12@ouc.edu.cn fbai@pku.edu.cn.
#
Contributed equally

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.

KEYWORDS:

Lysobacter; antibiotic resistance; btuD; indole; vitamin B12

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center