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.
Highlights
Antimicrobial resistance (AMR), the ability of bacteria to resist the effects of antimicrobial agents, is the single most important infectious disease threat to human beings
We investigated whether carbamazepine is able to promote the conjugative transfer of antibiotic multiresistance genes carried by a plasmid within and across bacterial genera
Spontaneous transfer resulted in about 6.85 × 10−5 transconjugants per recipient, and the frequency increased with the dosage of carbamazepine (Fig. S1)
Summary
Antimicrobial resistance (AMR), the ability of bacteria to resist the effects of antimicrobial agents, is the single most important infectious disease threat to human beings. There are concerns that non-antibiotic environmental contaminants present in wastewater are playing roles in the dissemination of ARGs. Recently, a few studies report that environmental contaminants, such as nanomaterials [11], disinfectants [12], disinfection by-products [13], and ionic liquids [14] have the potential to disseminate ARGs by promoting HGT. A few studies report that environmental contaminants, such as nanomaterials [11], disinfectants [12], disinfection by-products [13], and ionic liquids [14] have the potential to disseminate ARGs by promoting HGT While these discoveries are disturbing, the underlying mechanisms of how these contaminants promote HGT has not been determined. As one of the most commonly detected environmental contaminants, the potential roles of non-antibiotic pharmaceuticals in the dissemination of antibiotic resistance are largely neglected
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