Antidepressants promote the spread of antibiotic resistance via horizontally conjugative gene transfer. - Related Documents




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862301.0000Antidepressants promote the spread of antibiotic resistance via horizontally conjugative gene transfer. Antibiotic resistance is a global concern threatening public health. Horizontal gene transfer (HGT) between bacterial species contributes greatly to the dissemination of antibiotic resistance. Conjugation is one of the major HGT pathways responsible for the spread of antibiotic resistance genes (ARGs). Antidepressant drugs are commonly prescribed antipsychotics for major depressive disorders and are frequently detected in aquatic environments. However, little is known about how antidepressants stress bacteria and whether such effect can promote conjugation. Here, we report that commonly prescribed antidepressants, sertraline, duloxetine, fluoxetine, and bupropion, can promote the conjugative transfer of plasmid-borne multidrug resistance genes carried by environmentally and clinically relevant plasmids. Noteworthy, the transfer of plasmids across bacterial genera is significantly enhanced by antidepressants at clinically relevant concentrations. We also reveal the underlying mechanisms of enhanced conjugative transfer by employing flow cytometric analysis, genome-wide RNA sequencing and proteomic analysis. Antidepressants induce the production of reactive oxygen species and the SOS response, increase cell membrane permeability, and upregulate the expression of conjugation relevant genes. Given the contribution of HGT in the dissemination of ARGs, our findings highlight the importance of prudent prescription of antidepressants and to the potential connection between antidepressants and increasing antibiotic resistance.202236054646
862410.9997Antidepressant drugs promote the spread of broad-host-range plasmid in mouse and human gut microbiota. Antibiotic resistance is a global public health challenge. The gut microbiota serves as a reservoir for antibiotic resistance genes (ARGs), facilitating their transfer between bacteria. With the rising incidence of major depressive disorders (MDD), antidepressant prescriptions have surged. Previous pure-culture studies suggest that antidepressants exhibit antibiotic-like side effects, but their impact on gene transfer in microbial communities remains unclear. Here, we report that clinically relevant doses of antidepressants duloxetine and sertraline enhance the transfer of a broad-host range conjugative plasmid across bacterial phyla from mice gut microbiota. Tests in human gut simulators confirmed that duloxetine facilitates plasmid transfer in human gut microbiota. Mechanistic analyses revealed that antidepressants increase reactive oxygen species levels and alter bacterial cell membrane permeability. Using fluorescence-activated cell sorting and 16S rRNA gene sequencing, we discovered that antidepressants alter plasmid transfer patterns at both phylum and genus levels, driving ARG exchange among opportunistic pathogens. Our findings suggest that antidepressant use may promote the spread of antibiotic resistance between commensal and pathogenic bacteria, raising important public health concerns.202540462285
860520.9997Exposure to bisphenol compounds accelerates the conjugative transfer of antibiotic resistance plasmid. Antimicrobial resistance poses the most formidable challenge to public health, with plasmid-mediated horizontal gene transfer playing a pivotal role in its global spread. Bisphenol compounds (BPs), a group of environmental contaminants with endocrine-disrupting properties, are extensively used in various plastic products and can be transmitted to food. However, the impact of BPs on the plasmid-mediated horizontal transfer of antibiotic resistance genes (ARGs) has not yet been elucidated. Herein, we demonstrate that BPs could promote the conjugative transfer frequency of RP4-7 and clinically multidrug-resistant plasmids. Furthermore, the promoting effect of BPs on the plasmid transfer was also confirmed in a murine model. Microbial diversity analysis of transconjugants indicated an increase in α diversity in the BPAF-treated group, along with the declined richness of some beneficial bacteria and elevated richness of Faecalibaculum rodentium, which might serve as an intermediate repository for resistance plasmids. The underlying mechanisms driving the enhanced conjugative transfer upon BPAF treatment include exacerbated oxidative stress, disrupted membrane homeostasis, augmented energy metabolism, and the increased expression of conjugation-related genes. Collectively, our findings highlight the potential risk associated with the exacerbated dissemination of AMR both in vitro and in vivo caused by BPs exposure.202439278585
926430.9996Nanoalumina promotes the horizontal transfer of multiresistance genes mediated by plasmids across genera. Antibiotic resistance is a worldwide public health concern. Conjugative transfer between closely related strains or species of bacteria is an important method for the horizontal transfer of multidrug-resistance genes. The extent to which nanomaterials are able to cause an increase in antibiotic resistance by the regulation of the conjugative transfer of antibiotic-resistance genes in bacteria, especially across genera, is still unknown. Here we show that nanomaterials in water can significantly promote the horizontal conjugative transfer of multidrug-resistance genes mediated by the RP4, RK2, and pCF10 plasmids. Nanoalumina can promote the conjugative transfer of the RP4 plasmid from Escherichia coli to Salmonella spp. by up to 200-fold compared with untreated cells. We also explored the mechanisms behind this phenomenon and demonstrate that nanoalumina is able to induce oxidative stress, damage bacterial cell membranes, enhance the expression of mating pair formation genes and DNA transfer and replication genes, and depress the expression of global regulatory genes that regulate the conjugative transfer of RP4. These findings are important in assessing the risk of nanomaterials to the environment, particularly from water and wastewater treatment systems, and in the estimation of the effect of manufacture and use of nanomaterials on the environment.201222411796
926240.9996Effect of chemotherapeutic agents on natural transformation frequency in Acinetobacter baylyi. Natural transformation is the ability of a bacterial cell to take up extracellular DNA which is subsequently available for recombination into the chromosome (or maintenance as an extrachromosomal element). Like other mechanisms of horizontal gene transfer, natural transformation is a significant driver for the dissemination of antimicrobial resistance. Recent studies have shown that many pharmaceutical compounds such as antidepressants and anti-inflammatory drugs can upregulate transformation frequency in the model species Acinetobacter baylyi. Chemotherapeutic compounds have been shown to increase the abundance of antimicrobial resistance genes and increase colonization rates of potentially pathogenic bacteria in patient gastrointestinal tracts, indicating an increased risk of infection and providing a pool of pathogenicity or resistance genes for transformable commensal bacteria. We here test for the effect of six cancer chemotherapeutic compounds on A. baylyi natural transformation frequency, finding two compounds, docetaxel and daunorubicin, to significantly decrease transformation frequency, and daunorubicin to also decrease growth rate significantly. Enhancing our understanding of the effect of chemotherapeutic compounds on the frequency of natural transformation could aid in preventing the horizontal spread of antimicrobial resistance genes.202439135654
677850.9996Bisphenol S Promotes the Transfer of Antibiotic Resistance Genes via Transformation. The antibiotic resistance crisis has seriously jeopardized public health and human safety. As one of the ways of horizontal transfer, transformation enables bacteria to acquire exogenous genes naturally. Bisphenol compounds are now widely used in plastics, food, and beverage packaging, and have become a new environmental pollutant. However, their potential relationship with the spread of antibiotic resistance genes (ARGs) in the environment remains largely unexplored. In this study, we aimed to assess whether the ubiquitous bisphenol S (BPS) could promote the transformation of plasmid-borne ARGs. Using plasmid pUC19 carrying the ampicillin resistance gene as an extracellular ARG and model microorganism E. coli DH5α as the recipient, we established a transformation system. Transformation assays revealed that environmentally relevant concentrations of BPS (0.1-10 μg/mL) markedly enhanced the transformation frequency of plasmid-borne ARGs into E. coli DH5α up to 2.02-fold. Fluorescent probes and transcript-level analyses suggest that BPS stimulated increased reactive oxygen species (ROS) production, activated the SOS response, induced membrane damage, and increased membrane fluidity, which weakened the barrier for plasmid transfer, allowing foreign DNA to be more easily absorbed. Moreover, BPS stimulates ATP supply by activating the tricarboxylic acid (TCA) cycle, which promotes flagellar motility and expands the search for foreign DNA. Overall, these findings provide important insight into the role of bisphenol compounds in facilitating the horizontal spread of ARGs and emphasize the need to monitor the residues of these environmental contaminants.202439337307
963860.9996Response of microbial antibiotic resistance to pesticides: An emerging health threat. The spread of microbial antibiotic resistance has seriously threatened public health globally. Non-antibiotic stressors have significantly contributed to the evolution of bacterial antibiotic resistance. Although numerous studies have been conducted on the potential risk of pesticide pollution for bacterial antibiotic resistance, a systematic review of these concerns is still lacking. In the present study, we elaborate the mechanism underlying the effects of pesticides on bacterial antibiotic resistance acquisition as well as the propagation of antimicrobial resistance. Pesticide stress enhanced the acquisition of antibiotic resistance in bacteria via various mechanisms, including the activation of efflux pumps, inhibition of outer membrane pores for resistance to antibiotics, and gene mutation induction. Horizontal gene transfer is a major mechanism whereby pesticides influence the transmission of antibiotic resistance genes (ARGs) in bacteria. Pesticides promoted the conjugation transfer of ARGs by increasing cell membrane permeability and increased the proportion of bacterial mobile gene elements, which facilitate the spread of ARGs. This review can improve our understanding regarding the pesticide-induced generation and spread of ARGs and antibiotic resistant bacteria. Moreover, it can be applied to reduce the ecological risks of ARGs in the future.202235977623
677470.9996Both silver ions and silver nanoparticles facilitate the horizontal transfer of plasmid-mediated antibiotic resistance genes. Antibiotic resistance in bacteria is a growing threat to global human health. Horizontal gene transfer (HGT) of antibiotic resistance genes (ARGs) is recognized as the primary contributor to antibiotic resistance dissemination. Silver nanoparticles (AgNPs) are widely used in personal care products as antimicrobial agents. While heavy metals are known to induce antibiotic resistance in bacteria, it is not known whether AgNPs in the environment can stimulate the HGT of ARGs. Here, we report that both AgNPs and ionic silver Ag(+), at environmentally relevant and sub-lethal concentrations, facilitate the conjugative transfer of plasmid-borne ARGs across bacterial genera (from the donor Escherichia coli K-12 LE392 to the recipient Pseudomonas putida KT2440). The underlying mechanisms of the Ag(+)- or AgNPs-promoted HGT were unveiled by detecting oxidative stress and cell membrane permeability, combined with genome-wide RNA sequencing and proteomic analyses. It was found that both Ag(+) and AgNPs exposure induced various bacterial responses that included reactive oxygen species (ROS) generation, membrane damage and the SOS response. This study exposes the potential ecological risks of environmental levels of AgNPs and Ag(+) for promoting the spread of ARGs and highlights concerns regarding the management of nanoparticles and heavy metals.202031783256
401780.9996Non-antibiotic compounds associated with humans and the environment can promote horizontal transfer of antimicrobial resistance genes. Horizontal gene transfer plays a key role in the global dissemination of antimicrobial resistance (AMR). AMR genes are often carried on self-transmissible plasmids, which are shared amongst bacteria primarily by conjugation. Antibiotic use has been a well-established driver of the emergence and spread of AMR. However, the impact of commonly used non-antibiotic compounds and environmental pollutants on AMR spread has been largely overlooked. Recent studies found common prescription and over-the-counter drugs, artificial sweeteners, food preservatives, and environmental pollutants, can increase the conjugative transfer of AMR plasmids. The potential mechanisms by which these compounds promote plasmid transmission include increased membrane permeability, upregulation of plasmid transfer genes, formation of reactive oxygen species, and SOS response gene induction. Many questions remain around the impact of most non-antibiotic compounds on AMR plasmid conjugation in clinical isolates and the long-term impact on AMR dissemination. By elucidating the role of routinely used pharmaceuticals, food additives, and pollutants in the dissemination of AMR, action can be taken to mitigate their impact by closely monitoring use and disposal. This review will discuss recent progress on understanding the influence of non-antibiotic compounds on plasmid transmission, the mechanisms by which they promote transfer, and the level of risk they pose.202437462915
859990.9995Artificial sweeteners stimulate horizontal transfer of extracellular antibiotic resistance genes through natural transformation. Antimicrobial resistance has emerged as a global threat to human health. Natural transformation is an important pathway for horizontal gene transfer, which facilitates the dissemination of antibiotic resistance genes (ARGs) among bacteria. Although it is suspected that artificial sweeteners could exert antimicrobial effects, little is known whether artificial sweeteners would also affect horizontal transfer of ARGs via transformation. Here we demonstrate that four commonly used artificial sweeteners (saccharin, sucralose, aspartame, and acesulfame potassium) promote transfer of ARGs via natural transformation in Acinetobacter baylyi ADP1, a model organism for studying competence and transformation. Such phenomenon was also found in a Gram-positive human pathogen Bacillus subtilis and mice faecal microbiome. We reveal that exposure to these sweeteners increases cell envelope permeability and results in an upregulation of genes encoding DNA uptake and translocation (Com) machinery. In addition, we find that artificial sweeteners induce an increase in plasmid persistence in transformants. We propose a mathematical model established to predict the long-term effects on transformation dynamics under exposure to these sweeteners. Collectively, our findings offer insights into natural transformation promoted by artificial sweeteners and highlight the need to evaluate these environmental contaminants for their antibiotic-like side effects.202234465899
8601100.9995Herbicide promotes the conjugative transfer of multi-resistance genes by facilitating cellular contact and plasmid transfer. The global dissemination of antibiotic resistance genes (ARGs), especially via plasmid-mediated horizontal transfer, is becoming a pervasive health threat. While our previous study found that herbicides can accelerate the horizontal gene transfer (HGT) of ARGs in soil bacteria, the underlying mechanisms by which herbicides promote the HGT of ARGs across and within bacterial genera are still unclear. Here, the underlying mechanism associated with herbicide-promoted HGT was analyzed by detecting intracellular reactive oxygen species (ROS) production, extracellular polymeric substance composition, cell membrane integrity and proton motive force combined with genome-wide RNA sequencing. Exposure to herbicides induced a series of the above bacterial responses to promote HGT except for the ROS response, including compact cell-to-cell contact by enhancing pilus-encoded gene expression and decreasing cell surface charge, increasing cell membrane permeability, and enhancing the proton motive force, providing additional power for DNA uptake. This study provides a mechanistic understanding of the risk of bacterial resistance spread promoted by herbicides, which elucidates a new perspective on nonantibiotic agrochemical acceleration of the HGT of ARGs.202234969463
4012110.9995Augmented dissemination of antibiotic resistance elicited by non-antibiotic factors. The emergence and rapid spread of antibiotic resistance seriously compromise the clinical efficacy of current antibiotic therapies, representing a serious public health threat worldwide. Generally, drug-susceptible bacteria can acquire antibiotic resistance through genetic mutation or gene transfer, among which horizontal gene transfer (HGT) plays a dominant role. It is widely acknowledged that the sub-inhibitory concentrations of antibiotics are the key drivers in promoting the transmission of antibiotic resistance. However, accumulating evidence in recent years has shown that in addition to antibiotics, non-antibiotics can also accelerate the horizontal transfer of antibiotic resistance genes (ARGs). Nevertheless, the roles and potential mechanisms of non-antibiotic factors in the transmission of ARGs remain largely underestimated. In this review, we depict the four pathways of HGT and their differences, including conjugation, transformation, transduction and vesiduction. We summarize non-antibiotic factors accounting for the enhanced horizontal transfer of ARGs and their underlying molecular mechanisms. Finally, we discuss the limitations and implications of current studies.202337327521
8344120.9995Role of environmental stresses in elevating resistance mutations in bacteria: Phenomena and mechanisms. Mutations are an important origin of antibiotic resistance in bacteria. While there is increasing evidence showing promoted resistance mutations by environmental stresses, no retrospective research has yet been conducted on this phenomenon and its mechanisms. Herein, we summarized the phenomena of stress-elevated resistance mutations in bacteria, generalized the regulatory mechanisms and discussed the environmental and human health implications. It is shown that both chemical pollutants, such as antibiotics and other pharmaceuticals, biocides, metals, nanoparticles and disinfection byproducts, and non-chemical stressors, such as ultraviolet radiation, electrical stimulation and starvation, are capable of elevating resistance mutations in bacteria. Notably, resistance mutations are more likely to occur under sublethal or subinhibitory levels of these stresses, suggesting a considerable environmental concern. Further, mechanisms for stress-induced mutations are summarized in several points, namely oxidative stress, SOS response, DNA replication and repair systems, RpoS regulon and biofilm formation, all of which are readily provoked by common environmental stresses. Given bacteria in the environment are confronted with a variety of unfavorable conditions, we propose that the stress-elevated resistance mutations are a universal phenomenon in the environment and represent a nonnegligible risk factor for ecosystems and human health. The present review identifies a need for taking into account the pollutants' ability to elevate resistance mutations when assessing their environmental and human health risks and highlights the necessity of including resistance mutations as a target to prevent antibiotic resistance evolution.202235691443
6772130.9995Disinfectants facilitate the transformation of exogenous antibiotic resistance genes via multiple pathways. The prevalence and spread of multidrug-resistant (MDR) bacteria pose a global challenge to public health. Natural transformation is one of the essential ways for horizontal transfer of antibiotic resistance genes (ARGs). Although disinfectants are frequently used during COVID-19, little is known about whether these disinfectants are associated with the transformation of plasmid-borne ARGs. In our study, we assessed the effect of some disinfectants on bacterial transformation using resistance plasmids as extracellular DNA and E. coli DH5α as the recipient bacteria. The results showed that these disinfectants at environmentally relevant concentrations, including benzalkonium bromide (BB), benzalkonium chloride (BC) and polyhexamethylene guanidine hydrochloride (PHMG), significantly enhanced the transformation of plasmid-encoded ARGs. Furthermore, we investigated the mechanisms underlying the promotive effect of disinfectants on transformation. We revealed that the addition of disinfectants significantly increased the membrane permeability and promoted membrane-related genes expression. Moreover, disinfectants led to the boosted bacterial respiration, ATP production and flagellum motility, as well as increased expression of bacterial secretion system-related genes. Together, our findings shed insights into the spread of ARGs through bacterial transformation and indicate potential risks associated with the widespread use of disinfectants.202336857920
8982140.9995Ampicillin Exposure and Glutathione Deficiency Synergistically Promote Conjugative Transfer of Plasmid-Borne Antibiotic Resistance Genes. Plasmid-mediated conjugation is an important pathway for the spread of antibiotic resistance genes (ARGs), posing a significant risk to global public health. It has been reported that the conjugative transfer of ARGs could be enhanced by oxidative stress. Whether endogenous glutathione (GSH), a major non-protein thiol compound involved in cellular redox homeostasis, influences conjugative transfer is unknown. In this study, we show that the deletion of the GSH biosynthesis gene gshA and ampicillin exposure synergistically promoted the conjugative transfer of plasmid RP4 bearing multiple ARGs from the soil bacterium Enterobacter sp. CZ-1 to Escherichia coli S17-1λπ in co-culture experiments and to diverse soil bacteria belonging to eight phyla, including some potential human pathogens, in a soil incubation experiment. The deletion of gshA increased ROS generation and cell membrane permeability, and upregulated the expression of the genes involved in intracellular oxidative stress regulation, membrane permeability, plasmid replication, and the SOS response process, especially under ampicillin exposure. These results suggest that endogenous GSH is an important factor affecting the spread of plasmid-borne ARGs. Exposure to antibiotics and environmental stresses that cause a depletion of endogenous GSH in vivo are likely to increase the risk of ARG dissemination in the environment.202540346915
9263150.9995The F-pilus biomechanical adaptability accelerates conjugative dissemination of antimicrobial resistance and biofilm formation. Conjugation is used by bacteria to propagate antimicrobial resistance (AMR) in the environment. Central to this process are widespread conjugative F-pili that establish the connection between donor and recipient cells, thereby facilitating the spread of IncF plasmids among enteropathogenic bacteria. Here, we show that the F-pilus is highly flexible but robust at the same time, properties that increase its resistance to thermochemical and mechanical stresses. By a combination of biophysical and molecular dynamics methods, we establish that the presence of phosphatidylglycerol molecules in the F-pilus contributes to the structural stability of the polymer. Moreover, this structural stability is important for successful delivery of DNA during conjugation and facilitates rapid formation of biofilms in harsh environmental conditions. Thus, our work highlights the importance of F-pilus structural adaptations for the efficient spread of AMR genes in a bacterial population and for the formation of biofilms that protect against the action of antibiotics.202337019921
8961160.9995Effect and mechanism of quorum sensing on horizontal transfer of multidrug plasmid RP4 in BAC biofilm. The widespread emergence of antibiotic resistance genes (ARGs) in drinking water systems endangers human health, and may be exacerbated by their horizontal gene transfer (HGT) among microbiota. In our previous study, Quorum sensing (QS) molecules produced by bacteria from biological activated carbon (BAC) biofilms were demonstrated to influence the transfer efficiency of a model conjugative plasmid, here RP4. In this study, we further explored the effect and mechanism of QS on conjugation transfer. The results revealed that Acyl-homoserine lactones producing (AHL-producing) bacteria isolated from BAC biofilm play a role in the propagation of ARGs. We selected several quorum sensing inhibitors (QSIs) to study their effects on AHL-producing bacteria, including the formation of biofilm and the regulating effect on conjugation transfer. In addition, the possible molecular mechanisms for AHLs that promote conjugative transfer were attributable to enhancing the mRNA expression, which involved altered expressions of conjugation-related genes. We also found that QSIs could inhibit conjugative transfer by downregulating the conjugation-relevant genes. We believe that this is the first insightful exploration of the mechanism by which AHLs will facilitate and QSIs will inhibit the conjugative transfer of ARGs. These results provide creative insight into ARG pollution control that involves blocking QS during BAC treatment in drinking water systems.202031493577
4286170.9995Disinfectant resistance in bacteria: Mechanisms, spread, and resolution strategies. Disinfectants are widely acknowledged for removing microorganisms from the surface of the objects and transmission media. However, the emergence of disinfectant resistance has become a severe threat to the safety of life and health and the rational allocation of resources due to the reduced disinfectant effectiveness. The horizontal gene transfer (HGT) of disinfectant resistance genes has also expanded the resistant flora, making the situation worse. This review focused on the resistance mechanisms of disinfectant resistant bacteria on biofilms, cell membrane permeability, efflux pumps, degradable enzymes, and disinfectant targets. Efflux can be the fastest and most effective resistance mechanism for bacteria to respond to stress. The qac genes, located on some plasmids which can transmit resistance through conjugative transfer, are the most commonly reported in the study of disinfectant resistance genes. Whether the qac genes can be transferred through transformation or transduction is still unclear. Studying the factors affecting the resistance of bacteria to disinfectants can find breakthrough methods to more adequately deal with the problem of reduced disinfectant effectiveness. It has been confirmed that the interaction of probiotics and bacteria or the addition of 4-oxazolidinone can inhibit the formation of biofilms. Chemicals such as eugenol and indole derivatives can increase bacterial sensitivity by reducing the expression of efflux pumps. The role of these findings in anti-disinfectant resistance has proved invaluable.202133617866
8602180.9995Beta-blocker drives the conjugative transfer of multidrug resistance genes in pure and complex biological systems. Drug resistance poses a high risk to human health. Extensive use of non-antibiotic drugs contributes to antibiotic resistance genes (ARGs) transfer. However, how they affect the spread of broad-host plasmids in complex biological systems remains unknown. This study investigated the effect of metoprolol on the transfer frequency and host range of ARGs in both intrageneric and intergeneric pure culture systems, as well as in anammox microbiome. The results showed that environmental concentrations of metoprolol significantly promoted the intrageneric and intergeneric conjugative transfer. Initially, metoprolol induced excessive oxidative stress, resulting in high cell membrane permeability and bacterial SOS response. Meanwhile, more pili formation increased the adhesion and contact between bacteria, and the abundance of conjugation-related genes also increased significantly. Activation of the electron transport chain provided more ATP for this energy-consuming process. The underlying mechanism was further verified in the complex anammox conjugative system. Metoprolol induced the enrichment of ARGs and mobile genetic elements. The enhanced bacterial interaction and energy generation facilitated the high conjugative transfer frequency of ARGs. In addition, plasmid-borne ARGs tended to transfer to opportunistic pathogens. This work raises public concerns about the health and ecological risks of non-antibiotic drugs.202439096644
9265190.9995Conjugation is necessary for a bacterial plasmid to survive under protozoan predation. Horizontal gene transfer by conjugative plasmids plays a critical role in the evolution of antibiotic resistance. Interactions between bacteria and other organisms can affect the persistence and spread of conjugative plasmids. Here we show that protozoan predation increased the persistence and spread of the antibiotic resistance plasmid RP4 in populations of the opportunist bacterial pathogen Serratia marcescens. A conjugation-defective mutant plasmid was unable to survive under predation, suggesting that conjugative transfer is required for plasmid persistence under the realistic condition of predation. These results indicate that multi-trophic interactions can affect the maintenance of conjugative plasmids with implications for bacterial evolution and the spread of antibiotic resistance genes.201626843557