Expansion and persistence of antibiotic-specific resistance genes following antibiotic treatment
Kang KangLejla ImamovicMaria-Anna MisiakouMaria SørensenYoshitaro HeshikiYueqiong NiTingting ZhengJun LiMostafa M. H. EllabaanMarta Colomer-LluchAnne RodePeter BytzerGianni PanagiotouMorten Otto Alexander Sommer
39
Citation
65
Reference
10
Related Paper
Citation Trend
Abstract:
Oral antibiotics are commonly prescribed to non-hospitalized adults. However, antibiotic-induced changes in the human gut microbiome are often investigated in cohorts with preexisting health conditions and/or concomitant medication, leaving the effects of antibiotics not completely understood. We used a combination of omic approaches to comprehensively assess the effects of antibiotics on the gut microbiota and particularly the gut resistome of a small cohort of healthy adults. We observed that 3 to 19 species per individual proliferated during antibiotic treatment and Gram-negative species expanded significantly in relative abundance. While the overall relative abundance of antibiotic resistance gene homologs did not significantly change, antibiotic-specific gene homologs with presumed resistance toward the administered antibiotics were common in proliferating species and significantly increased in relative abundance. Virome sequencing and plasmid analysis showed an expansion of antibiotic-specific resistance gene homologs even 3 months after antibiotic administration, while paired-end read analysis suggested their dissemination among different species. These results suggest that antibiotic treatment can lead to a persistent expansion of antibiotic resistance genes in the human gut microbiota and provide further data in support of good antibiotic stewardship.Abbreviation: ARG - Antibiotic resistance gene homolog; AsRG - Antibiotic-specific resistance gene homolog; AZY - Azithromycin; CFX - Cefuroxime; CIP - Ciprofloxacin; DOX - Doxycycline; FDR - False discovery rate; GRiD - Growth rate index value; HGT - Horizontal gene transfer; NMDS - Non-metric multidimensional scaling; qPCR - Quantitative polymerase chain reaction; RPM - Reads per million mapped reads; TA - Transcriptional activity; TE - Transposable element; TPM - Transcripts per million mapped reads.Keywords:
Resistome
Resistome
Horizontal Gene Transfer
Cite
Citations (163)
Despite the documented antibiotic-induced disruption of the gut microbiota, the impact of antibiotic intake on strain-level dynamics, evolution of resistance genes, and factors influencing resistance dissemination potential remains poorly understood. To address this gap we analyzed public metagenomic datasets from 24 antibiotic treated subjects and controls, combined with an in-depth prospective functional study with two subjects investigating the bacterial community dynamics based on cultivation-dependent and independent methods. We observed that short-term antibiotic treatment shifted and diversified the resistome composition, increased the average copy number of antibiotic resistance genes, and altered the dominant strain genotypes in an individual-specific manner. More than 30% of the resistance genes underwent strong differentiation at the single nucleotide level during antibiotic treatment. We found that the increased potential for horizontal gene transfer, due to antibiotic administration, was ∼3-fold stronger in the differentiated resistance genes than the non-differentiated ones. This study highlights how antibiotic treatment has individualized impacts on the resistome and strain level composition, and drives the adaptive evolution of the gut microbiota.
Resistome
Horizontal Gene Transfer
Cite
Citations (60)
Antibiotic resistant bacteria and their resistance determinants have been frequently reported in all types of environments especially in water systems. The collection of antibiotic resistant genes and precursors in host bacteria occupying wastewater environment represents wastewater resistome. This resistome is highly potential to resist almost all types of antibiotics exposed to the environment. Since antimicrobial resistance could be transferred from environmental bacteria to clinical or veterinary pathogens and vice versa, wastewaters systems are spawning grounds for global antibiotic resistance, with potentially serious infection consequences for human and animals. Although the sub-lethal dose of antibiotics is key stimulating factor, however, physiological and environmental stress on bacteria due to various factors including non-antibiotic antimicrobials, organic pollutants like PAHs, chlorinated phenols and heavy metals may also drive the enrichment of antibiotic resistance genes in the environment. Although actual key mechanisms for survival of antibiotic resistance bacteria, proliferation and dissemination of such genes in wastewater are still elusive, this mini review briefly describes environmental resistome, possible drivers and dissemination paths of resistance genes in wastewater systems. Considering the hazards, efficient wastewater treatment technologies are needed to be developed for mitigation of antibiotic resistance bacteria and resistance genes.
Resistome
Cite
Citations (3)
Resistome
Cite
Citations (480)
Antibiotic resistance is a global problem which affects human health. The imprudent use of antibiotics (medicine, agriculture, aquaculture, and food industry) has resulted in the broader dissemination of resistance. Urban wastewater & sewage treatment plants act as the hotspot for the widespread of antimicrobial resistance. Natural environment also plays an important role in the dissemination of resistance. Mapping of antibiotic resistance genes (ARGS) in environment is essential for mitigating antimicrobial resistance (AMR) widespread. Therefore, the review article emphasizes on the application of metagenomics for the surveillance of antimicrobial resistance. Metagenomics is the next generation tool which is being used for cataloging the resistome of diverse environments. We summarize the different metagenomic tools that can be used for mining of ARGs and acquired AMR present in the metagenomic data. Also, we recommend application of targeted sequencing/ capture platform for mapping of resistome with higher specificity and selectivity.
Resistome
Cite
Citations (86)
Characterizing the response of microbial communities to a range of antibiotic concentrations is one of the strategies used to understand the impact of antibiotic resistance. Many studies have described the occurrence and prevalence of antibiotic resistance in microbial communities from reservoirs such as hospitals, sewage, and farm feedlots, where bacteria are often exposed to high and/or constant concentrations of antibiotics. Outside of these sources, antibiotics generally occur at lower, sub-minimum inhibitory concentrations (sub-MICs). The constant exposure to low concentrations of antibiotics may serve as a chemical “cue” that drives development of antibiotic resistance. Low concentrations of antibiotics have not yet been broadly described in reservoirs outside of the aforementioned environments, nor is the transfer and dissemination of antibiotic resistant bacteria and genes within natural microbial communities fully understood. This review will thus focus on low antibiotic-concentration environmental reservoirs and mechanisms that are important in the dissemination of antibiotic resistance to help identify key knowledge gaps concerning the environmental resistome.
Resistome
Cite
Citations (48)
Antibiotic resistance is a global public health issue of growing proportions. All antibiotics are susceptible to resistance. The evidence is now clear that the environment is the single largest source and reservoir of resistance. Soil, aquatic, atmospheric, animal-associated, and built ecosystems are home to microbes that harbor antibiotic resistance elements and the means to mobilize them. The diversity and abundance of resistance in the environment is consistent with the ancient origins of antibiotics and a variety of studies support a long natural history of associated resistance. The implications are clear: Understanding the evolution of resistance in the environment, its diversity, and mechanisms is essential to the management of our existing and future antibiotic resources.
Resistome
Cite
Citations (151)
Antibiotic production is a natural phenomenon employed by microorganisms to control their environment in stress situations. Thus, antibiotic resistance has evolved in parallel to counteract naturally produced antibiotics. On the other hand, excessive use of antibiotics by humans, either for protecting human or animal health, may induce unnaturally high antibiotic stresses leading to enhanced antibiotic resistance, the so-called acquired resistance.
This study is the first to report an initial exploration into the distribution and quantification of antibiotic resistance genes, i.e. resistome, in a mixed-use watershed in Western Newfoundland, along the Humber river. The river was sampled along a gradient of increased human impact, mainly associated with the discharge of municipal wastewaters. The goals of my thesis were to (1) understand the relationship between human impact in the Humber river and the occurrence of antibiotic resistance genes in the environment, and (2) understand the role of the river in mitigating the abundance of these resistance genes, if any role is present.
Total DNA was extracted from the river water samples, sequenced by shotgun sequencing on an Illumina Hiseq platform with sequencing data quality controlled and cleaned at the sequencing facility via a QIIME pipeline, followed by identification and quantification of antibiotic resistance markers through a computational pipeline carried out in ShortBRED against a curated Antibiotic Resistance Genes Database (ARDB). About 400 antibiotic resistance genes, of variable abundance, were identified, distributed across the tested systems, an indication of the wide distribution of antibiotic resistance in the environment. This analysis revealed the distribution and abundance of Antibiotic Resistance Genes (ARGs) within the microbial population in the Humber River.
Quantitative real-time PCR (qRT-PCR) was used to quantify absolute (copies L⁻¹) and relative abundances (copies /16S rRNA) for TetO, TetM and AdeC genes. Relative abundance of ARGs (copies / 16S rRNA) was higher in the upstream locations versus downstream locations.
The results showed evidence that anthropogenic impacts, especially associated with the use of antibiotics, led to an increase in the diversity and total abundance of antibiotic resistance markers in the Humber River.
Resistome
Cite
Citations (0)
SUMMARY The spread of antibiotic-resistance genes in bacteria has severely reduced the efficacy of antibiotics, now contributing to 1.3 million deaths annually. Despite the far-reaching epidemiological implications of this trend, the extent to which antimicrobial resistance load varies within human populations and the drivers that contribute most to this variation remain unclear. Here, we demonstrate in a representative cohort of 7,095 Finnish adults 1 that socio-demographic factors, lifestyle, and gut microbial community composition shape resistance selection and transmission processes. Antimicrobial resistance gene load was linked not only to prior use of antibiotics, as anticipated, but also to frequent consumption of fresh vegetables and poultry, two food groups previously reported to contain antibiotic-resistant bacteria. Interestingly, ARG load was not associated with high-fat and -sugar foods. Furthermore, antimicrobial resistance gene load was systematically higher in females and the generally healthier high-income demographics in urban and densely populated areas. Data from this prospective cohort with a 17-year follow-up suggests that the prognostic potential of antimicrobial resistome is comparable to blood pressure for mortality and sepsis. These findings highlight population-level risks and socio-demographic dimensions of antimicrobial resistance that are particularly relevant in the current context of global urbanization and middle-class growth.
Resistome
Cite
Citations (0)
ABSTRACT The standard use of antibiotics in newborns to empirically treat early-onset sepsis can adversely affect the neonatal gut microbiome, with potential long-term health impacts. Research into the escalating issue of antimicrobial resistance in preterm infants and antibiotic practices in neonatal intensive care units is limited. A deeper understanding of the effects of early antibiotic intervention on antibiotic resistance in preterm infants is crucial. This retrospective study employed metagenomic sequencing to evaluate antibiotic resistance genes (ARGs) in the meconium and subsequent stool samples of preterm infants enrolled in the Routine Early Antibiotic Use in Symptomatic Preterm Neonates study. Microbial metagenomics was conducted using a subset of fecal samples from 30 preterm infants for taxonomic profiling and ARG identification. All preterm infants exhibited ARGs, with 175 unique ARGs identified, predominantly associated with beta-lactam, tetracycline, and aminoglycoside resistance. Notably, 23% of ARGs was found in preterm infants without direct or intrapartum antibiotic exposure. Post-natal antibiotic exposure increases beta-lactam/tetracycline resistance while altering mechanisms that aid bacteria in withstanding antibiotic pressure. Microbial profiling revealed 774 bacterial species, with antibiotic-naive infants showing higher alpha diversity ( P = 0.005) in their microbiota and resistome compared with treated infants, suggesting a more complex ecosystem. High ARG prevalence in preterm infants was observed irrespective of direct antibiotic exposure and intensifies with age. Prolonged membrane ruptures and maternal antibiotic use during gestation and delivery are linked to alterations in the preterm infant resistome and microbiome, which are pivotal in shaping the ARG profiles in the neonatal gut. This study is registered with ClinicalTrials.gov as NCT02784821 . IMPORTANCE A high burden of antibiotic resistance in preterm infants poses significant challenges to neonatal health. The presence of antibiotic resistance genes, along with alterations in signaling, energy production, and metabolic mechanisms, complicates treatment strategies for preterm infants, heightening the risk of ineffective therapy and exacerbating outcomes for these vulnerable neonates. Despite not receiving direct antibiotic treatment, preterm infants exhibit a concerning prevalence of antibiotic-resistant bacteria. This underscores the complex interplay of broader influences, including maternal antibiotic exposure during and beyond pregnancy and gestational complications like prolonged membrane ruptures. Urgent action, including cautious antibiotic practices and enhanced antenatal care, is imperative to protect neonatal health and counter the escalating threat of antimicrobial resistance in this vulnerable population.
Resistome
Neonatal Sepsis
Cite
Citations (0)