scholarly journals Evolutionary pathways to antibiotic resistance are dependent upon environmental structure and bacterial lifestyle

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Alfonso Santos-Lopez ◽  
Christopher W Marshall ◽  
Michelle R Scribner ◽  
Daniel J Snyder ◽  
Vaughn S Cooper
Keyword(s):  
Antibiotic Resistance ◽  
Experimental Evolution ◽  
Drug Targets ◽  
Evolutionary Dynamics ◽  
Selective Sweeps ◽  
Resistance Level ◽  
Bacterial Populations ◽  
Collateral Sensitivity ◽  
Genetic Mechanisms ◽  
Evolution Of Resistance

Bacterial populations vary in their stress tolerance and population structure depending upon whether growth occurs in well-mixed or structured environments. We hypothesized that evolution in biofilms would generate greater genetic diversity than well-mixed environments and lead to different pathways of antibiotic resistance. We used experimental evolution and whole genome sequencing to test how the biofilm lifestyle influenced the rate, genetic mechanisms, and pleiotropic effects of resistance to ciprofloxacin in Acinetobacter baumannii populations. Both evolutionary dynamics and the identities of mutations differed between lifestyle. Planktonic populations experienced selective sweeps of mutations including the primary topoisomerase drug targets, whereas biofilm-adapted populations acquired mutations in regulators of efflux pumps. An overall trade-off between fitness and resistance level emerged, wherein biofilm-adapted clones were less resistant than planktonic but more fit in the absence of drug. However, biofilm populations developed collateral sensitivity to cephalosporins, demonstrating the clinical relevance of lifestyle on the evolution of resistance.

scholarly journals Evolutionary pathways to antibiotic resistance are dependent upon environmental structure and bacterial lifestyle

2019 ◽  
Author(s):  
Alfonso Santos-Lopez ◽  
Christopher W. Marshall ◽  
Michelle R. Scribner ◽  
Daniel Snyder ◽  
Vaughn S. Cooper
Keyword(s):  
Antibiotic Resistance ◽  
Experimental Evolution ◽  
Drug Targets ◽  
Evolutionary Dynamics ◽  
Selective Sweeps ◽  
Resistance Level ◽  
Bacterial Populations ◽  
Collateral Sensitivity ◽  
Genetic Mechanisms ◽  
Evolution Of Resistance

AbstractBacterial populations vary in their stress tolerance and population structure depending upon whether growth occurs in well-mixed or structured environments. We hypothesized that evolution in biofilms would generate greater genetic diversity than well-mixed environments and lead to different pathways of antibiotic resistance. We used experimental evolution and whole genome sequencing to test how the biofilm lifestyle influenced the rate, genetic mechanisms, and pleiotropic effects of resistance to ciprofloxacin inAcinetobacter baumanniipopulations. Both evolutionary dynamics and the identities of mutations differed between lifestyle. Planktonic populations experienced selective sweeps of mutations including the primary topoisomerase drug targets, whereas biofilm-adapted populations acquired mutations in regulators of efflux pumps. An overall trade-off between fitness and resistance level emerged, wherein biofilm-adapted clones were less resistant than planktonic but more fit in the absence of drug. However, biofilm populations developed collateral sensitivity to cephalosporins, demonstrating the clinical relevance of lifestyle on the evolution of resistance.

Modeling the Emergence of Antibiotic Resistance in Bacterial Populations

2018 ◽  
Vol 80 (3) ◽  
pp. 214-220 ◽  
Author(s):  
Michelle A. Williams ◽  
Patricia J. Friedrichsen ◽  
Troy D. Sadler ◽  
Pamela J. B. Brown
Keyword(s):  
Antibiotic Resistance ◽  
Coli Strain ◽  
Science Standards ◽  
Evolutionary Mechanisms ◽  
Resistance Level ◽  
Random Mutation ◽  
Bacterial Populations ◽  
E Coli ◽  
Disk Diffusion Assay ◽  
High School Classroom

Since antibiotics have become routinely used to treat infections, antibiotic resistance is now an emerging concern for public health. To understand how bacteria become resistant to antibiotics, many students draw from the common misconception that bacteria gain resistance upon antibiotic exposure. We have designed models and a corresponding lab that explores how a population of bacteria can evolve antibiotic resistance, with emphasis on dispelling common misconceptions surrounding the mechanism of antibiotic resistance. Using an antibiotic disk diffusion assay, students compare the antibiotic resistance level of a harmless E. coli strain of bacteria over time. Then, students compare their lab data to the models, which together illustrate the roles that initial genetic variation and random mutation play in the evolution of antibiotic resistance. In this guided investigation, basic microbiology concepts and techniques are made accessible to students in a high school classroom. The models developed here are in line with the practices of the Next Generation Science Standards (NGSS). The models, together with the lab, are used to guide students through the process of argumentation using a claim, evidence, and reasoning (CER) format to explain the evolutionary mechanisms of antibiotic resistance.

scholarly journals Rapid decline of bacterial drug-resistance in an antibiotic-free environment through phenotypic reversion

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Anett Dunai ◽  
Réka Spohn ◽  
Zoltán Farkas ◽  
Viktória Lázár ◽  
Ádám Györkei ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antibiotic Resistance ◽  
Practical Importance ◽  
Rapid Decline ◽  
Resistance Mutations ◽  
Resistance Level ◽  
Bacterial Populations ◽  
Bacterial Drug Resistance ◽  
Free Environment ◽  
Phenotypic Reversion

Antibiotic resistance typically induces a fitness cost that shapes the fate of antibiotic-resistant bacterial populations. However, the cost of resistance can be mitigated by compensatory mutations elsewhere in the genome, and therefore the loss of resistance may proceed too slowly to be of practical importance. We present our study on the efficacy and phenotypic impact of compensatory evolution in Escherichia coli strains carrying multiple resistance mutations. We have demonstrated that drug-resistance frequently declines within 480 generations during exposure to an antibiotic-free environment. The extent of resistance loss was found to be generally antibiotic-specific, driven by mutations that reduce both resistance level and fitness costs of antibiotic-resistance mutations. We conclude that phenotypic reversion to the antibiotic-sensitive state can be mediated by the acquisition of additional mutations, while maintaining the original resistance mutations. Our study indicates that restricting antimicrobial usage could be a useful policy, but for certain antibiotics only.

scholarly journals Evolutionary Pathways and Trajectories in Antibiotic Resistance

2021 ◽  
Author(s):  
Fernando Baquero ◽  
Jose L Martinez ◽  
Jeronimo Rodriguez-Beltrán ◽  
Juan-Carlos Galán ◽  
Alvaro San-Millán ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Degrees Of Freedom ◽  
Evolutionary Dynamics ◽  
Negative Influence ◽  
Complex Environments ◽  
Random Mutation ◽  
Bacterial Populations ◽  
Units Of Selection ◽  
Selection Processes ◽  
Evolutionary Trajectories

Evolution is the hallmark of life. Descriptions of the evolution of microorganisms have provided a wealth of information, but knowledge regarding “what happened” has precluded a deeper understanding of “how” evolution has proceeded, as in the case of antimicrobial resistance. The difficulty in answering the “how” question lies in the multihierarchical dimensions of evolutionary processes, nested in complex networks, encompassing all units of selection, from genes to communities and ecosystems. At the simplest ontological level (as resistance genes), evolution proceeds by random (mutation and drift) and directional (natural selection) processes; however, sequential pathways of adaptive variation can occasionally be observed, and under fixed circumstances (particular fitness landscapes), evolution is predictable. At the highest level (such as that of plasmids, clones, species, microbiotas), the system’s degrees of freedom increase dramatically, related to the variable dispersal, fragmentation, relatedness or coalescence of bacterial populations, depending on heterogeneous and changing niches and selective gradients in complex environments. Evolutionary trajectories of antibiotic resistance find their way in these moving, frequently random landscapes and become highly entropic and therefore unpredictable. However, experimental, phylogenetic and ecogenetic analyses reveal preferential frequented paths (highways) where antibiotic resistance flows and propagates, allowing some understanding of evolutionary dynamics, modelling and designing interventions. Studies on antibiotic resistance have an applied aspect in improving individual health, one health and global health, as well as an academic value for understanding evolution. Most importantly, they have a heuristic significance as a model to reduce the negative influence of anthropogenic effects on the environment.

scholarly journals Evolving Antibiotics against Resistance: a Potential Platform for Natural Product Development?

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Kristofer Wollein Waldetoft ◽  
James Gurney ◽  
Joseph Lachance ◽  
Paul A. Hoskisson ◽  
Sam P. Brown
Keyword(s):  
Antibiotic Resistance ◽  
Experimental Evolution ◽  
Rational Design ◽  
Antibiotic Production ◽  
Molecular Targets ◽  
Resistance Mechanisms ◽  
Mechanisms Of Resistance ◽  
Complex Functions ◽  
Evolution Of Resistance ◽  
Antibiotic Discovery

ABSTRACT To avoid an antibiotic resistance crisis, we need to develop antibiotics at a pace that matches the rate of evolution of resistance. However, the complex functions performed by antibiotics—combining, e.g., penetration of membranes, counteraction of resistance mechanisms, and interaction with molecular targets—have proven hard to achieve with current methods for drug development, including target-based screening and rational design. Here, we argue that we can meet the evolution of resistance in the clinic with evolution of antibiotics in the laboratory. On the basis of the results of experimental evolution studies of microbes in general and antibiotic production in Actinobacteria in particular, we propose methodology for evolving antibiotics to circumvent mechanisms of resistance. This exploits the ability of evolution to find solutions to complex problems without a need for design. We review evolutionary theory critical to this approach and argue that it is feasible and has important advantages over current methods for antibiotic discovery.

scholarly journals A Naturally Occurring Single Nucleotide Polymorphism in a Multicopy Plasmid Produces a Reversible Increase in Antibiotic Resistance

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Alfonso Santos-Lopez ◽  
Cristina Bernabe-Balas ◽  
Manuel Ares-Arroyo ◽  
Rafael Ortega-Huedo ◽  
Andreas Hoefer ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Antibiotic Resistance ◽  
Experimental Evolution ◽  
Pasteurella Multocida ◽  
Single Mutation ◽  
Multicopy Plasmid ◽  
Nucleotide Polymorphism ◽  
Resistance Level ◽  
Single Nucleotide ◽  
Content Type

ABSTRACT ColE1 plasmids are small mobilizable replicons that play an important role in the spread of antibiotic resistance in Pasteurellaceae. In this study, we describe how a natural single nucleotide polymorphism (SNP) near the origin of replication of the ColE1-type plasmid pB1000 found in a Pasteurella multocida clinical isolate generates two independent plasmid variants able to coexist in the same cell simultaneously. Using the Haemophilus influenzae Rd KW20 strain as a model system, we combined antibiotic susceptibility tests, quantitative PCRs, competition assays, and experimental evolution to characterize the consequences of the coexistence of the pB1000 plasmid variants. This coexistence produced an increase of the total plasmid copy number (PCN) in the host bacteria, leading to a rise in both the antibiotic resistance level and the metabolic burden produced by pB1000. Using experimental evolution, we showed that in the presence of ampicillin, the bacteria maintained both plasmid variants for 300 generations. In the absence of antibiotics, on the other hand, the bacteria are capable of reverting to the single-plasmid genotype via the loss of one of the plasmid variants. Our results revealed how a single mutation in plasmid pB1000 provides the bacterial host with a mechanism to increase the PCN and, consequently, the ampicillin resistance level. Crucially, this mechanism can be rapidly reversed to avoid the extra cost entailed by the increased PCN in the absence of antibiotics.

scholarly journals Allele-specific collateral and fitness effects determine the dynamics of fluoroquinolone-resistance evolution

2020 ◽  
Author(s):  
Apostolos Liakopoulos ◽  
Linda B. S. Aulin ◽  
Matteo Buffoni ◽  
J. G. Coen van Hasselt ◽  
Daniel E. Rozen
Keyword(s):  
Antibiotic Resistance ◽  
Combination Treatment ◽  
Evolutionary Dynamics ◽  
Fluoroquinolone Resistance ◽  
Resistant Bacteria ◽  
Resistance Mutations ◽  
Collateral Sensitivity ◽  
Resistance Evolution ◽  
Fitness Effects ◽  
Collateral Effects

AbstractCollateral sensitivity (CS), which arises when resistance to one antibiotic increases sensitivity towards other antibiotics, offers novel treatment opportunities to constrain or reverse the evolution of antibiotic resistance. The applicability of CS-informed treatments remains uncertain, in part because we lack an understanding of the generality of CS effects for different resistance mutations, singly or in combination. Here we address this issue in the Gram-positive pathogen S. pneumoniae by quantifying collateral and fitness effects of a series of clinically relevant first-step (gyrA or parC) mutations, and their combinations, that confer resistance to fluoroquinolones. We integrated these results in a mathematical model which allowed us to evaluate how different in silico combination treatments impact the dynamics of resistance evolution. We identified common and conserved CS effects of different gyrA and parC mutations; however, the spectrum of collateral effects was unique for each mutation or mutation pair. This indicated that mutation identity, even different mutations to the same amino acid, can impact the evolutionary dynamics of resistance evolution during monotreatment and combination treatment. In addition, we observed that epistatic effects between gyrA and parC mutations strongly alter the strength of collateral effects against different antibiotics. Our model simulations, which included the experimentally derived antibiotic susceptibilities and fitness effects, and antibiotic specific pharmacodynamics, revealed that both collateral and fitness effects impact the population dynamics of resistance evolution. Overall, we provide evidence that the gene, mutational identity, and interactions between resistance mutations can have a pronounced impact on collateral effects to different antibiotics and suggest that these need to be considered in models examining CS-based therapies.SignificanceA promising strategy to overcome the evolution of antibiotic resistant bacteria is to use collateral sensitivity-informed antibiotic treatments that rely on cycling or mixing of antibiotics, such that that resistance towards one antibiotic confers increased sensitivity to the other. Here, focusing on multi-step fluoroquinolone resistance in Streptococcus pneumoniae, we show that antibiotic-resistance induces diverse collateral responses, whose magnitude and direction are determined by mutation identity and epistasis between resistance mutations. Using mathematical simulations, we show that these effects can be exploited via combination treatment regimens to suppress the de novo emergence of resistance during treatment.

Surveillance of Antibiotic Resistance Among Enterobacteriaceae Strains Isolated in an Infectious Diseases Hospital from Romania

2018 ◽  
Vol 69 (5) ◽  
pp. 1240-1243
Author(s):  
Manuela Arbune ◽  
Mioara Decusara ◽  
Luana Andreea Macovei ◽  
Aurelia Romila ◽  
Alina Viorica Iancu ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Infectious Diseases ◽  
Salmonella Spp ◽  
Resistance Level ◽  
E Coli ◽  
Bacterial Genus ◽  
Antibiotic Resistance Profile ◽  
Carbapenem Resistant ◽  
Invasive Infections ◽  
Klebsiella Spp

The aim of the present study was to characterize the antibiotic resistance profile of enterobacteriaceae strains isolated in Infectious Diseases Hospital Galati, Romania, during 2016, in order to guide the local antibiotic stewardship strategy. There are 597 biological samples with positive cultures for enterobacteriaceae, related to invasive and non-invasive infections. The main bacterial genus were E. coli 62%, Klebsiella spp 15%, Proteus spp 11% and Salmonella spp 6%. Over a half of isolated strains have one or more antibiotic resistance. The resistance level depends on bacterial genus, with highest level found among the rare isolates: Enterobacter spp, Citrobacter spp, Morganella spp and Serratia spp. The rate of MDR was 17.,6% for E. coli, 40.9% for Klebsiella spp and 50.7% for Proteus spp. while the rate of strains producing Extended Spectrum of Beta Lactamase are 7.2% for E. coli, 28.4% for Klebsiella spp and 12.3% for Proteus spp. The carbapenem resistant strains were found in 1.1% cases.

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