The influence of the phylum Planctomycetota in the environmental resistome.

Antimicrobial resistance is one of the leading causes of death worldwide and research on this topic has been on the spotlight for a long time. More recently and in agreement with the One Health Approach, the focus has moved towards the environmental resistome. Members of the phylum Planctomycetota are ubiquitously present in the environment including in hotspots for antimicrobial resistance selection and dissemination. Furthermore, phenotypic broad-range resistance has been observed in diverse members of this phylum. Here we review the evidence available on antimicrobial resistance in the underexploited Planctomycetota and highlight key aspects for future studies.

A review on the effects of discharging conventionally treated livestock waste to the environmental resistome.

Globally, animal production has developed rapidly as a consequence of the ongoing population growth, to support food security. This has consequently led to an extensive use of antibiotics to promote growth and prevent diseases in animals. However, most antibiotics are not fully metabolized by these animals, leading to their excretion within urine and faeces, thus making these wastes a major reservoir of antibiotics residues, antibiotic resistance genes (ARGs) and antibiotic resistant bacteria (ARB) in the environment. Farmers normally depend on conventional treatment methods to mitigate the environmental impact of animal waste; however, these methods are not fully efficient to remove the environmental resistome. The present study reviewed the variability of residual antibiotics, ARB, as well as ARGs in the conventionally treated waste and assessed how discharging it could increase resistome in the receiving environments. Wherein, considering the efficiency and environmental safety, an addition of pre-treatments steps with these conventional treatment methods could enhance the removal of antibiotic resistance agents from livestock waste.

Sub-MIC antibiotics influence the microbiome, resistome and structure of riverine biofilm communities.

The effects of sub-minimum inhibitory concentrations (sub-MICs) of antibiotics on aquatic environments is not yet fully understood. Here, we explore these effects by employing a replicated microcosm system fed with river water where biofilm communities were continuously exposed over an eight-week period to sub-MIC exposure (1/10, 1/50, and 1/100 MIC) to a mix of common antibiotics (ciprofloxacin, streptomycin, and oxytetracycline). Biofilms were examined using a structure-function approach entailing microscopy and metagenomic techniques, revealing details on the microbiome, resistome, virulome, and functional prediction. A comparison of three commonly used microbiome and resistome databases was also performed. Differences in biofilm architecture were observed between sub-MIC antibiotic treatments, with an overall reduction of extracellular polymeric substances and autotroph (algal and cyanobacteria) and protozoan biomass, particularly at the 1/10 sub-MIC condition. While metagenomic analyses demonstrated that microbial diversity was lowest at the sub-MIC 1/10 antibiotic treatment, resistome diversity was highest at sub-MIC 1/50. This study also notes the importance of benchmarking analysis tools and careful selection of reference databases, given the disparity in detected antimicrobial resistance genes (ARGs) identity and abundance across methods. Ultimately, the most detected ARGs in sub-MICs exposed biofilms were those that conferred resistance to aminoglycosides, tetracyclines, ß-lactams, sulfonamides, and trimethoprim. Co-occurrence of microbiome and resistome features consistently showed a relationship between Proteobacteria genera and aminoglycoside ARGs. Our results support the hypothesis that constant exposure to sub-MICs antibiotics facilitate the transmission and promote prevalence of antibiotic resistance in riverine biofilms communities, and additionally shift overall microbial community metabolic function.

Tracking Antibiotic Resistance from the Environment to Human Health.

Antimicrobial resistance (AMR) is one of the threats to our world according to the World Health Organization (WHO). Resistance is an evolutionary dynamic process where host-associated microbes have to adapt to their stressful environments. AMR could be classified according to the mechanism of resistance or the biome where resistance takes place. Antibiotics are one of the stresses that lead to resistance through antibiotic resistance genes (ARGs). The resistome could be defined as the collection of all ARGs in an organism's genome or metagenome. Currently, there is a growing body of evidence supporting that the environment is the largest source of ARGs, but to what extent the environment does contribute to the antimicrobial resistance evolution is a matter of investigation. Monitoring the ARGs transfer route from the environment to humans and vice versa is a nature-to-nature feedback loop where you cannot set an accurate starting point of the evolutionary event. Thus, tracking resistome evolution and transfer to and from different biomes is crucial for the surveillance and prediction of the next resistance outbreak.Herein, we review the overlap between clinical and environmental resistomes and the available databases and computational analysis tools for resistome analysis through ARGs detection and characterization in bacterial genomes and metagenomes. Till this moment, there is no tool that can predict the resistance evolution and dynamics in a distinct biome. But, hopefully, by understanding the complicated relationship between the environmental and clinical resistome, we could develop tools that track the feedback loop from nature to nature in terms of evolution, mobilization, and transfer of ARGs.

Environmental Biofilms as Reservoirs for Antimicrobial Resistance.

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.

Antibiotic residues in the aquatic environment - current perspective and risk considerations.

Antimicrobial resistance is a major concern for human and animal health, projected to deteriorate with time and given current trends of antimicrobial usage. Antimicrobial use, particularly in healthcare and agriculture, can result in the release of antimicrobials into surface waters, promoting the development of antibiotic resistance in the environment, and potentially leading to human health risks. This study reviews relevant literature, and investigates current European and Irish antimicrobial usage trends in humans and animals, as well as potential pathways that antibiotics can take into surface waters following use. Reported levels in the aquatic environment are summarized, with particular focus on Ireland. There are relatively few studies examining Irish water bodies or sewage effluent for antibiotic residues, however, five antibiotics, namely azithromycin, ciprofloxacin, clarithromycin, metronidazole, and trimethoprim, have been measured in Irish waters, in concentrations predicted to select for resistance. Numerous isolates of multi-drug resistant bacteria have also been found in water bodies throughout Ireland and Europe. The value of risk assessment methodologies in understanding risks posed by antibiotic residues is reviewed including the advantages and disadvantages of specific approaches. Hazard quotient and bespoke Monte Carlo approaches are predominant risk assessment tools used to examine antimicrobial release and their complex pathways. This study highlights the need for monitoring of antimicrobial releases and the potential for resistance development, persistence and transmission while highlighting the role of risk assessment methodologies in assessing potential human and environmental health impacts.

Twenty-first century molecular methods for analyzing antimicrobial resistance in surface waters to support One Health assessments.

Antimicrobial resistance (AMR) in the environment is a growing global health concern, especially the dissemination of AMR into surface waters due to human and agricultural inputs. Within recent years, research has focused on trying to understand the impact of AMR in surface waters on human, agricultural and ecological health (One Health). While surface water quality assessments and surveillance of AMR have historically utilized culture-based methods, culturing bacteria has limitations due to difficulty in isolating environmental bacteria and the need for a priori information about the bacteria for selective isolation. The use of molecular techniques to analyze AMR at the genetic level has helped to overcome the difficulties with culture-based techniques since they do not require advance knowledge of the bacterial population and can analyze uncultivable environmental bacteria. The aim of this review is to provide an overview of common contemporary molecular methods available for analyzing AMR in surface waters, which include high throughput real-time polymerase chain reaction (HT-qPCR), metagenomics, and whole genome sequencing. This review will also feature how these methods may provide information on human and animal health risks. HT-qPCR works at the nanoliter scale, requires only a small amount of DNA, and can analyze numerous gene targets simultaneously, but may lack in analytical sensitivity and the ability to optimize individual assays compared to conventional qPCR. Metagenomics offers more detailed genomic information and taxonomic resolution than PCR by sequencing all the microbial genomes within a sample. Its open format allows for the discovery of new antibiotic resistance genes; however, the quantity of DNA necessary for this technique can be a limiting factor for surface water samples that typically have low numbers of bacteria per sample volume. Whole genome sequencing provides the complete genomic profile of a single environmental isolate and can identify all genetic elements that may confer AMR. However, a main disadvantage of this technique is that it only provides information about one bacterial isolate and is challenging to utilize for community analysis. While these contemporary techniques can quickly provide a vast array of information about AMR in surface waters, one technique does not fully characterize AMR nor its potential risks to human, animal, or ecological health. Rather, a combination of techniques (including both molecular- and culture-based) are necessary to fully understand AMR in surface waters from a One Health perspective.

Unearthing Antibiotic Resistance Associated with Disturbance-Induced Permafrost Thaw in Interior Alaska.

Monitoring antibiotic resistance genes (ARGs) across ecological niches is critical for assessing the impacts distinct microbial communities have on the global spread of resistance. In permafrost-associated soils, climate and human driven disturbances augment near-surface thaw shifting the predominant bacteria that shape the resistome in overlying active layer soils. This thaw is of concern in Alaska, because 85% of land is underlain by permafrost, making soils especially vulnerable to disturbances. The goal of this study is to assess how soil disturbance, and the subsequent shift in community composition, will affect the types, abundance, and mobility of ARGs that compose the active layer resistome. We address this goal through the following aims: (1) assess resistance phenotypes through antibiotic susceptibility testing, and (2) analyze types, abundance, and mobility of ARGs through whole genome analyses of bacteria isolated from a disturbance-induced thaw gradient in Interior Alaska. We found a high proportion of isolates resistant to at least one of the antibiotics tested with the highest prevalence of resistance to ampicillin. The abundance of ARGs and proportion of resistant isolates increased with disturbance; however, the number of ARGs per isolate was explained more by phylogeny than isolation site. When compared to a global database of soil bacteria, RefSoil+, our isolates from the same genera had distinct ARGs with a higher proportion on plasmids. These results emphasize the hypothesis that both phylogeny and ecology shape the resistome and suggest that a shift in community composition as a result of disturbance-induced thaw will be reflected in the predominant ARGs comprising the active layer resistome.

The dissemination of antibiotic resistance in various environmental objects (Russia).

Environmental objects (surface and groundwater, soil, bottom sediments, wastewater) are reservoirs in which large-scale multidirectional exchange of determinants of antibiotic resistance between clinical strains and natural bacteria takes place. The review discusses the results of studies on antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARG) isolated from environmental objects (water, soil, sewage, permafrost) of the Russian Federation. Despite the relevance of the topic, the number of available publications examining the resistomes of Russian water bodies and soils is small. The most studied environmental objects are surface waters (rivers, lakes), permafrost deposits. Soil resistomes are less studied. Data on ARG and ARB in wastewater are the least covered in publications. In most of the studies, antibiotic resistance of isolated pure bacterial cultures was determined phenotypically. A significant number of publications are devoted to the resistance of natural isolates of Vibrio cholerae, since the lower reaches of the Volga and Don rivers are endemic to cholera. Molecular genetic methods were used in a small number of studies. Geographically, the south of the European part of Russia is the most studied. There are also publications on the distribution of ARG in water bodies of Siberia and the Russian Far East. There are practically no publications on such developed regions of Russia as the center and northwest of the European part of Russia. The territory of the country is very large, anthropogenic and natural factors in its various regions vary significantly; therefore, it seems interesting to combine all available data in one work.

Impacts of multi-year field exposure of agricultural soil to macrolide antibiotics on the abundance of antibiotic resistance genes and selected mobile genetic elements.

Exposure of environmental bacteria to antibiotics may be increasing the global resistome. Antibiotic residues are entrained into agricultural soil through the application of animal and human wastes, and irrigation with reclaimed water. The impact of a mixture of three macrolide antibiotics on the abundance of selected genes associated with antibiotic resistance and genetic mobility were determined in a long-term field experiment undertaken in London, Canada. Replicated plots received annual applications of a mixture of erythromycin, clarithromycin and azithromycin every spring since 2010. Each antibiotic was added directly to the soil at a concentration of either 0.1 or 10 mg kg soil-1 and all plots were cropped to soybeans. By means of qPCR, no gene targets were enriched in soil exposed to the 0.1 mg kg soil-1 dose compared to untreated control. In contrast, the relative abundance of several gene targets including int1, sul2 and mphE increased significantly with the annual exposure to the 10 mg kg soil-1 dose. By means of high-throughput qPCR, numerous gene targets associated with resistance to aminoglycosides, sulfonamides, trimethoprim, streptomycin, quaternary ammonium chemicals as well as mobile genetic elements (tnpA, IS26 and IS6100) were detected in soil exposed to 10 mg kg soil-1, but not the lower dose. Overall, exposure of soil to macrolide antibiotics increased the relative abundance of numerous gene targets associated with resistance to macrolides and other antibiotics, and mobile genetic elements. This occurred at an exposure dose that is unrealistically high, but did not occur at the lower more realistic exposure dose.

Antibiotic resistance patterns of Pseudomonas spp. isolated from faecal wastes in the environment and contaminated surface water.

The Pseudomonas genus, which includes environmental and pathogenic species, is known to present antibiotic resistances, and can receive resistance genes from multi-resistant enteric bacteria released into the environment via faecal rejects. This study was aimed to investigate the resistome of Pseudomonas populations that have been in contact with these faecal bacteria. Thus, faecal discharges originating from human or cattle were sampled (from 12 points and two sampling campaigns) and 41 Pseudomonas species identified (316 isolates studied). The resistance phenotype to 25 antibiotics was determined in all isolates, and we propose a specific antibiotic resistance pattern for 14 species (from 2 to 9 resistances). None showed resistance to aminoglycosides, tetracycline, or polymyxins. Four species carried a very low number of resistances, with none to ß-lactams. Interestingly, we observed the absence of the transcriptional activator soxR gene in these four species. No plasmid transfer was highlighted by conjugation assays, and a few class 1 but no class 2 integrons were detected in strains that may have received resistance genes from Enterobacteria. These results imply that the contribution of the Pseudomonas genus to the resistome of an ecosystem first depends on the structure of the Pseudomonas populations, as they may have very different resistance profiles.

An exploration of the gut and environmental resistome in a community in northern Vietnam in relation to antibiotic use.

Background: Antibiotic resistance is a major global public health threat. Antibiotic use can directly impact the antibiotic resistant genes (ARGs) profile of the human intestinal microbiome and consequently the environment through shedding. Methods: We determined the resistome of human feces, animal stools, human food and environmental (rain, well, and irrigative water) samples (n = 304) in 40 households within a community cohort and related the data to antibiotic consumption. Metagenomic DNA was isolated and qPCR was used to determine presence of mobile colistin resistance (mcr) genes, genes encoding extended-spectrum ß-lactamases (ESBL), carbapenemases and quinolone resistance genes. Results: Nearly 40 % (39.5%, 120/304) of samples contained ESBL genes (most frequent were CTX-M-9 (23.7% [72/304]), CTX-M-1 (18.8% [57/304]). Quinolone resistance genes (qnrS) were detected in all human and 91% (41/45) of animal stool samples. Mcr-1 and mcr-3 were predominantly detected in human feces at 88% (82/93) and 55% (51/93) and animal feces at 93% (42/45) and 51% (23/45), respectively. Mcr-2, mrc-4 and mcr-5 were not detected in human feces, and only sporadically (< 6%) in other samples. Carbapenemase-encoding genes were most common in water (15% [14/91]) and cooked food (13% [10/75]) samples, while their prevalence in human and animal stools was lower at 4% in both human (4/93) and animal (2/45) samples. We did not find an association between recent antibiotic consumption and ARGs in human stools. Principal component analysis showed that the resistome differs between ecosystems with a strong separation of ARGs profiles of human and animal stools on the one hand versus cooked food and water samples on the other. Conclusions: Our study indicated that ARGs were abundant in human and animal stools in a rural Vietnamese community, including ARGs targeting last resort antibiotics. The resistomes of animal and human stools were similar as opposed to the resistomes from water and food sources. No association between antibiotic use and ARG profiles was found in a setting of high background rates of AMR.

Antibiotic Pollution in the Environment: From Microbial Ecology to Public Policy.

The ability to fight bacterial infections with antibiotics has been a longstanding cornerstone of modern medicine. However, wide-spread overuse and misuse of antibiotics has led to unintended consequences, which in turn require large-scale changes of policy for mitigation. In this review, we address two broad classes of corollaries of antibiotics overuse and misuse. Firstly, we discuss the spread of antibiotic resistance from hotspots of resistance evolution to the environment, with special concerns given to potential vectors of resistance transmission. Secondly, we outline the effects of antibiotic pollution independent of resistance evolution on natural microbial populations, as well as invertebrates and vertebrates. We close with an overview of current regional policies tasked with curbing the effects of antibiotics pollution and outline areas in which such policies are still under development.

Microbial diversity and antibiotic resistance in a final effluent-receiving lake.

Wastewater treatment plants have been recognised as hotspots for antibiotic resistance genes and antibiotic-resistant bacteria which enter the environment. However, the persistence of these genes and bacteria in receiving ecosystems remains poorly understood. The aim of the study was to evaluate the effect of final effluent release on microbial diversity and the antibiotic resistance gene pool in a final effluent-receiving lake. The numbers of total culturable heterotrophs and unculturable bacteria (represented as the 16S rRNA gene copy number) were significantly reduced during the treatment process. The number of ampicillin-resistant bacteria was higher in the sediment than in water samples, suggesting accumulation of ampicillin-resistant bacteria in freshwater sediments. Using an exogenous method, we captured 56 resistance plasmids which were further characterised. Next-generation sequencing revealed that the microbial phyla represented in the studied metagenomes were typical of corresponding environments. The highest relative abundance of antibiotic resistance genes was observed in the final effluent, suggesting that a considerable number of genes were released from the wastewater treatment plant. However, the lowest relative abundance and lowest diversity of the genes in the lake water, compared to the other studied metagenomes, suggest a negligible effect of treated sewage release on antibiotic resistance within water microbial communities of the lake. Furthermore, uncontrolled sewage dumping into this reservoir in the past as well as lower quality of the water upstream of the lake indicated that the wastewater treatment plant protected the studied ecosystem.

Rhodobacter sp. Rb3, an aerobic anoxygenic phototroph which thrives in the polyextreme ecosystem of the Salar de Huasco, in the Chilean Altiplano.

The Salar de Huasco is an evaporitic basin located in the Chilean Altiplano, which presents extreme environmental conditions for life, i.e. high altitude (3800 m.a.s.l.), negative water balance, a wide salinity range, high daily temperature changes and the occurrence of the highest registered solar radiation on the planet (> 1200 W m-2). This ecosystem is considered as a natural laboratory to understand different adaptations of microorganisms to extreme conditions. Rhodobacter, an anoxygenic aerobic phototrophic bacterial genus, represents one of the most abundant groups reported based on taxonomic diversity surveys in this ecosystem. The bacterial mat isolate Rhodobacter sp. strain Rb3 was used to study adaptation mechanisms to stress-inducing factors potentially explaining its success in a polyextreme ecosystem. We found that the Rhodobacter sp. Rb3 genome was characterized by a high abundance of genes involved in stress tolerance and adaptation strategies, among which DNA repair and oxidative stress were the most conspicuous. Moreover, many other molecular mechanisms associated with oxidative stress, photooxidation and antioxidants; DNA repair and protection; motility, chemotaxis and biofilm synthesis; osmotic stress, metal, metalloid and toxic anions resistance; antimicrobial resistance and multidrug pumps; sporulation; cold shock and heat shock stress; mobile genetic elements and toxin-antitoxin system were detected and identified as potential survival mechanism features in Rhodobacter sp. Rb3. In total, these results reveal a wide set of strategies used by the isolate to adapt and thrive under environmental stress conditions as a model of polyextreme environmental resistome.

Aquaculture changes the profile of antibiotic resistance and mobile genetic element associated genes in Baltic Sea sediments.

Antibiotics are commonly used in aquaculture and they can change the environmental resistome by increasing antibiotic resistance genes (ARGs). Sediment samples were collected from two fish farms located in the Northern Baltic Sea, Finland, and from a site outside the farms (control). The sediment resistome was assessed by using a highly parallel qPCR array containing 295 primer sets to detect ARGs, mobile genetic elements and the 16S rRNA gene. The fish farm resistomes were enriched in transposon and integron associated genes and in ARGs encoding resistance to antibiotics which had been used to treat fish at the farms. Aminoglycoside resistance genes were also enriched in the farm sediments despite the farms not having used aminoglycosides. In contrast, the total relative abundance values of ARGs were higher in the control sediment resistome and they were mainly genes encoding efflux pumps followed by beta-lactam resistance genes, which are found intrinsically in many bacteria. This suggests that there is a natural Baltic sediment resistome. The resistome associated with fish farms can be from native ARGs enriched by antibiotic use at the farms and/or from ARGs and mobile elements that have been introduced by fish farming.

Antimicrobial resistance dashboard application for mapping environmental occurrence and resistant pathogens.

An antibiotic resistance (AR) Dashboard application is being developed regarding the occurrence of antibiotic resistance genes (ARG) and bacteria (ARB) in environmental and clinical settings. The application gathers and geospatially maps AR studies, reported occurrence and antibiograms, which can be downloaded for offline analysis. With the integration of multiple data sets, the database can be used on a regional or global scale to identify hot spots for ARGs and ARB; track and link spread and transmission, quantify environmental or human factors influencing presence and persistence of ARG harboring organisms; differentiate natural ARGs from those distributed via human or animal activity; cluster and compare ARGs connections in different environments and hosts; and identify genes that can be used as proxies to routinely monitor anthropogenic pollution. To initially populate and develop the AR Dashboard, a qPCR ARG array was tested with 30 surface waters, primary influent from three waste water treatment facilities, ten clinical isolates from a regional hospital and data from previously published studies including river, park soil and swine farm samples. Interested users are invited to download a beta version (available on iOS or Android), submit AR information using the application, and provide feedback on current and prospective functionalities.

The urgent need for risk assessment on the antibiotic resistance spread via sewage sludge land application.

Sewage sludge is an ever-increasing by-product of the wastewater treatment process frequently used as a soil fertiliser. To control its quality and prevent any possible hazardous impact of fertilisation, some mandatory limits of heavy metal content have been established by the European Commission (Sewage Sludge Directive). However, since the implementation of the limits, new emerging contaminants have been reported worldwide. Regardless of the wastewater treatment process, sewage sludge contains antibiotics, antibiotic-resistant bacteria and antibiotic resistance genes, which can be released into the environment through its land application. Such a practice may even boost the dissemination and further development of antibiotic resistance phenomenon - already a global problem challenging modern medicine. Due to the growing pharmaceutical pollution in the environment, the time is ripe to assess the risk for the human and environmental health of sewage sludge land application in the context of antibiotic resistance spread. In this review we present the current knowledge in the field and we emphasise the necessity for more studies.

The antibiotic resistance "mobilome": searching for the link between environment and clinic.

Antibiotic resistance is an ancient problem, owing to the co-evolution of antibiotic-producing and target organisms in the soil and other environments over millennia. The environmental "resistome" is the collection of all genes that directly or indirectly contribute to antibiotic resistance. Many of these resistance determinants originate in antibiotic-producing organisms (where they serve to mediate self-immunity), while others become resistance determinants only when mobilized and over-expressed in non-native hosts (like plasmid-encoded ß-lactamases). The modern environmental resistome is under selective pressure from human activities such as agriculture, which may influence the composition of the local resistome and lead to gene transfer events. Beyond the environment, we are challenged in the clinic by the rise in both frequency and diversity of antibiotic resistant pathogens. We assume that clinical resistance originated in the environment, but few examples of direct gene exchange between the environmental resistome and the clinical resistome have been documented. Strong evidence exists to suggest that clinical aminoglycoside and vancomycin resistance enzymes, the extended-spectrum ß-lactamase CTX-M and the quinolone resistance gene qnr have direct links to the environmental resistome. In this review, we highlight recent advances in our understanding of horizontal gene transfer of antibiotic resistance genes from the environment to the clinic. Improvements in sequencing technologies coupled with functional metagenomic studies have revealed previously underappreciated diversity in the environmental resistome, and also established novel genetic links to the clinic. Understanding mechanisms of gene exchange becomes vital in controlling the future dissemination of antibiotic resistance.

Antibiotics as selectors and accelerators of diversity in the mechanisms of resistance: from the resistome to genetic plasticity in the ß-lactamases world.

Antibiotics and antibiotic resistance determinants, natural molecules closely related to bacterial physiology and consistent with an ancient origin, are not only present in antibiotic-producing bacteria. Throughput sequencing technologies have revealed an unexpected reservoir of antibiotic resistance in the environment. These data suggest that co-evolution between antibiotic and antibiotic resistance genes has occurred since the beginning of time. This evolutionary race has probably been slow because of highly regulated processes and low antibiotic concentrations. Therefore to understand this global problem, a new variable must be introduced, that the antibiotic resistance is a natural event, inherent to life. However, the industrial production of natural and synthetic antibiotics has dramatically accelerated this race, selecting some of the many resistance genes present in nature and contributing to their diversification. One of the best models available to understand the biological impact of selection and diversification are ß-lactamases. They constitute the most widespread mechanism of resistance, at least among pathogenic bacteria, with more than 1000 enzymes identified in the literature. In the last years, there has been growing concern about the description, spread, and diversification of ß-lactamases with carbapenemase activity and AmpC-type in plasmids. Phylogenies of these enzymes help the understanding of the evolutionary forces driving their selection. Moreover, understanding the adaptive potential of ß-lactamases contribute to exploration the evolutionary antagonists trajectories through the design of more efficient synthetic molecules. In this review, we attempt to analyze the antibiotic resistance problem from intrinsic and environmental resistomes to the adaptive potential of resistance genes and the driving forces involved in their diversification, in order to provide a global perspective of the resistance problem.