Non-antibiotic pharmaceuticals promote the transmission of multidrug resistance plasmids through intra- and intergenera conjugation

Abstract

Antibiotic resistance is a global threat to public health. The use of antibiotics at sub-inhibitory concentrations has been recognized as an important factor in disseminating antibiotic resistance via horizontal gene transfer. Although non-antibiotic, human-targeted pharmaceuticals are widely used by society (95% of the pharmaceuticals market), the potential contribution to the spread of antibiotic resistance is not clear. Here, we report that commonly consumed, non-antibiotic pharmaceuticals, including nonsteroidal anti-inflammatories (ibuprofen, naproxen, diclofenac), a lipid-lowering drug (gemfibrozil), and a β-blocker (propranolol), at clinically and environmentally relevant concentrations, significantly accelerated the dissemination of antibiotic resistance via plasmid-borne bacterial conjugation. Various indicators were used to study the bacterial response to these drugs, including monitoring reactive oxygen species (ROS) and cell membrane permeability by flow cytometry, cell arrangement, and whole-genome RNA and protein sequencing. Enhanced conjugation correlated well with increased production of ROS and cell membrane permeability. Additionally, these non-antibiotic pharmaceuticals induced responses similar to those detected when bacteria are exposed to antibiotics, such as inducing the SOS response and enhancing efflux pumps. The findings advance understanding of the transfer of antibiotic resistance genes, emphasizing the concern that non-antibiotic, human-targeted pharmaceuticals enhance the spread of antibiotic resistance among bacterial populations.

Non-antibiotic pharmaceuticals promote conjugative plasmid transfer at a community-wide level

“…This indicated that nonantibiotic pharmaceuticals could specifically elevate the plasmid uptake ability of such pathogenic microbes. Moreover, in addition to the above-mentioned relative abundance of transconjugant or recipient bacterial community under the exposure of non-antibiotic pharmaceuticals, the absolute number of donor bacteria was not significantly changed when challenged with these nonantibiotic pharmaceuticals [46]. This indicated bacterial community variation was due to the influence of external non-antibiotic pharmaceuticals, rather than bacterial number.…”

“…It should be noted that the absolute number of donor bacteria was not significantly changed when challenged with these non-antibiotic pharmaceuticals [42]. This indicated bacterial community variation was due to the influence of external non-antibiotic pharmaceuticals, rather than bacterial number.…”

A bistable orthogonal prokaryotic differentiation system underlying development of conjugative transfer competence

“…A further central question to solve is the influence of environmental or physiological cues (such as 3CBA metabolism in case of ICEclc) on the proportion of appearing tc cells. Such cues or changes in environmental conditions may unwillingly influence gene transfer rates within microbial communities [49][50][51] , and this may lead to enhanced adaptation of pathogenic isolates to antibiotic resistances carried by the ICE.…”

A bistable prokaryotic differentiation system underlying development of conjugative transfer competence

“…A further central question to solve is the influence of environmental or physiological cues (such as 3CBA metabolism in case of ICEclc) on the proportion of appearing tc cells. Such cues or changes in environmental conditions may unwillingly influence gene transfer rates within microbial communities [53][54][55], and this may lead to enhanced adaptation of pathogenic isolates to antibiotic resistances carried by the ICE.…”