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Antiepileptic drug carbamazepine promotes horizontal transfer of plasmid-borne multi-antibiotic resistance genes within and across bacterial genera.

ABSTRACT: Antibiotic resistance is a severe global threat for public health, causing around 700,000 deaths per year. Horizontal gene transfer (HGT) is one of the most significant pathways to disseminate antibiotic resistance. It is commonly acknowledged that sub-minimum inhibition concentrations of antibiotics are major contributors in promoting antibiotic resistance through HGT. Pharmaceuticals are occurring in our environments at increased levels, yet little is known whether non-antibiotic pharmaceuticals cause or accelerate the dissemination of antibiotic resistance. Here, we report for the first time that the antiepileptic drug, carbamazepine, promotes conjugative transfer of antibiotic resistance genes. It was seen that environmentally relevant concentrations of carbamazepine (e.g., 0.05?mg/L) significantly enhanced the conjugative transfer of multiresistance genes carried by plasmid within and across bacterial genera. The underlying mechanisms of the enhanced HGT were revealed by detecting oxidative stress and cell membrane permeability, in combination with MinION DNA sequencing, genome-wide RNA sequencing, and proteomic analysis. Carbamazepine induced a series of acute responses, including increased levels of reactive oxygen species, the SOS response; increased cell membrane permeability, and pilus generation. Expressional levels of genes related to these processes were significantly upregulated during carbamazepine exposure. Given that HGT occurs widely among different species in various environments, these findings are an early warning for a wide assessment of the roles of non-antibiotic pharmaceuticals in the spread of antibiotic resistance.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6331567 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Antiepileptic drug carbamazepine promotes horizontal transfer of plasmid-borne multi-antibiotic resistance genes within and across bacterial genera.

Wang Yue Y Lu Ji J Mao Likai L Li Jie J Yuan Zhiguo Z Bond Philip L PL Guo Jianhua J

The ISME journal 20181005 2

Antibiotic resistance is a severe global threat for public health, causing around 700,000 deaths per year. Horizontal gene transfer (HGT) is one of the most significant pathways to disseminate antibiotic resistance. It is commonly acknowledged that sub-minimum inhibition concentrations of antibiotics are major contributors in promoting antibiotic resistance through HGT. Pharmaceuticals are occurring in our environments at increased levels, yet little is known whether non-antibiotic pharmaceutica ...[more]

PMID: 30291330

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Project description:UNLABELLED:Bacterial conjugation constitutes a major horizontal gene transfer mechanism for the dissemination of antibiotic resistance genes among human pathogens. Antibiotic resistance spread could be halted or diminished by molecules that interfere with the conjugation process. In this work, synthetic 2-alkynoic fatty acids were identified as a novel class of conjugation inhibitors. Their chemical properties were investigated by using the prototype 2-hexadecynoic acid and its derivatives. Essential features of effective inhibitors were the carboxylic group, an optimal long aliphatic chain of 16 carbon atoms, and one unsaturation. Chemical modification of these groups led to inactive or less-active derivatives. Conjugation inhibitors were found to act on the donor cell, affecting a wide number of pathogenic bacterial hosts, including Escherichia, Salmonella, Pseudomonas, and Acinetobacter spp. Conjugation inhibitors were active in inhibiting transfer of IncF, IncW, and IncH plasmids, moderately active against IncI, IncL/M, and IncX plasmids, and inactive against IncP and IncN plasmids. Importantly, the use of 2-hexadecynoic acid avoided the spread of a derepressed IncF plasmid into a recipient population, demonstrating the feasibility of abolishing the dissemination of antimicrobial resistances by blocking bacterial conjugation. IMPORTANCE:Diseases caused by multidrug-resistant bacteria are taking an important toll with respect to human morbidity and mortality. The most relevant antibiotic resistance genes come to human pathogens carried by plasmids, mainly using conjugation as a transmission mechanism. Here, we identified and characterized a series of compounds that were active against several plasmid groups of clinical relevance, in a wide variety of bacterial hosts. These inhibitors might be used for fighting antibiotic-resistance dissemination by inhibiting conjugation. Potential inhibitors could be used in specific settings (e.g., farm, fish factory, or even clinical settings) to investigate their effect in the eradication of undesired resistances.

Dataset Information

Antiepileptic drug carbamazepine promotes horizontal transfer of plasmid-borne multi-antibiotic resistance genes within and across bacterial genera.

Publications

Antiepileptic drug carbamazepine promotes horizontal transfer of plasmid-borne multi-antibiotic resistance genes within and across bacterial genera.

Similar Datasets

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