Non-antibiotic pharmaceuticals enhance the transmission of exogenous antibiotic resistance genes through bacterial transformation

Abstract

Antibiotic resistance is a serious global threat for public health. Considering the high abundance of cell-free DNA encoding antibiotic resistance genes (ARGs) in both clinical and environmental settings, natural transformation is an important horizontal gene transfer pathway to transmit antibiotic resistance. It is acknowledged that antibiotics are key drivers for disseminating antibiotic resistance, yet the contributions of non-antibiotic pharmaceuticals on transformation of ARGs are overlooked. In this study, we report that some commonly consumed non-antibiotic pharmaceuticals, at clinically and environmentally relevant concentrations, significantly facilitated the spread of antibiotic resistance through the uptake of exogenous ARGs. This included nonsteroidal anti-inflammatories, ibuprofen, naproxen, diclofenac, the lipid-lowering drug, gemfibrozil, and the β-blocker propranolol. Based on the results of flow cytometry, whole-genome RNA sequencing and proteomic analysis, the enhanced transformation of ARGs was affiliated with promoted bacterial competence, enhanced stress levels, over-produced reactive oxygen species and increased cell membrane permeability. In addition, a mathematical model was proposed and calibrated to predict the dynamics of transformation during exposure to non-antibiotic pharmaceuticals. Given the high consumption of non-antibiotic pharmaceuticals, these findings reveal new concerns regarding antibiotic resistance dissemination exacerbated by non-antibiotic pharmaceuticals.

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Fig. 1: Transformation of free plasmid harbouring ARGs induced by non-antibiotic pharmaceuticals.
Fig. 2: The effect of non-antibiotic pharmaceuticals causing increased ROS generation and altering the cell membrane integrity in A. baylyi.
Fig. 3: Genotypic RNA and protein analyses for A. baylyi under the exposure of non-antibiotic pharmaceuticals.
Fig. 4: The simulated changes in the number of bacteria with the increase of transformation time.
Fig. 5: The overall mechanisms explaining the roles of non-antibiotic pharmaceuticals causing enhanced transformation of exogenous ARGs.

Data availability

All data were deposited in publicly accessible databases. RNA sequence data are accessible through the Gene Expression Omnibus of NCBI (GSE142061). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [44] partner repository with the dataset identifier of PXD016798.

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Acknowledgements

We acknowledge the Australian Research Council for funding support through Future Fellowship (FT170100196). JG would like to thank the support by UQ Foundation Research Excellence Awards. YW would like to thank the support from China Scholarship Council. We would like to thank Prof. Pål Jarle Johnsen (The Arctic University of Norway) for providing the Acinetobacter baylyi ADP1 strain. We would like to thank Dr Michael Nefedov (The University of Queensland) for providing technical support on flow cytometry. We would also like to thank Dr Amanda Nouwens (The University of Queensland) for conducting SWATH-MS tests. The MIC measurement in this work was performed at the Queensland node of the Australian National Fabrication Facility.

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JG and YW conceived and designed this study. YW performed the transformation experiment, flow cytometry, DNA, RNA and protein extractions and model simulation. JE helped to construct the mathematical model of natural transformation. JL, SZ and PD performed RNA and protein extraction. LM and YW analysed the transcriptomic data. JG, YW, PLB and JE provided critical biological interpretations of the data. YW wrote the paper. JG, ZY, PLB and JE edited the paper.

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Correspondence to Jianhua Guo.

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Wang, Y., Lu, J., Engelstädter, J. et al. Non-antibiotic pharmaceuticals enhance the transmission of exogenous antibiotic resistance genes through bacterial transformation. ISME J 14, 2179–2196 (2020). https://doi.org/10.1038/s41396-020-0679-2

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