Integron activity accelerates the evolution of antibiotic resistance

AbstractMobile integrons are widespread genetic platforms that allow bacteria to modulate the expression of antibiotic resistance cassettes by shuffling their position from a common promoter. Antibiotic stress induces the expression of an integrase that excises and integrates cassettes, and this unique recombination and expression system is thought to allow bacteria to ‘evolve on demand’ in response to antibiotic pressure. To test this hypothesis, we inserted a custom three cassette integron into P. aeruginosa, and used experimental evolution to measure the impact of integrase activity on adaptation to gentamicin. Crucially, integrase activity accelerated evolution by increasing the expression of a gentamicin resistance cassette through duplications and by eliminating redundant cassettes. Importantly, we found no evidence of deleterious off-target effects of integrase activity. In summary, integrons accelerate resistance evolution by rapidly generating combinatorial variation in cassette composition while maintaining genomic integrity.

Download Full-text

Integron activity accelerates the evolution of antibiotic resistance

eLife ◽

10.7554/elife.62474 ◽

2021 ◽

Vol 10 ◽

Cited By ~ 1

Author(s):

Célia Souque ◽

José Antonio Escudero ◽

R Craig MacLean

Keyword(s):

Antibiotic Resistance ◽

Experimental Evolution ◽

Expression System ◽

Genomic Integrity ◽

Resistance Evolution ◽

On Demand ◽

Accelerated Evolution ◽

Gentamicin Resistance ◽

The Impact ◽

Target Effects

Mobile integrons are widespread genetic platforms that allow bacteria to modulate the expression of antibiotic resistance cassettes by shuffling their position from a common promoter. Antibiotic stress induces the expression of an integrase that excises and integrates cassettes, and this unique recombination and expression system is thought to allow bacteria to ‘evolve on demand’ in response to antibiotic pressure. To test this hypothesis, we inserted a custom three-cassette integron into Pseudomonas aeruginosa and used experimental evolution to measure the impact of integrase activity on adaptation to gentamicin. Crucially, integrase activity accelerated evolution by increasing the expression of a gentamicin resistance cassette through duplications and by eliminating redundant cassettes. Importantly, we found no evidence of deleterious off-target effects of integrase activity. In summary, integrons accelerate resistance evolution by rapidly generating combinatorial variation in cassette composition while maintaining genomic integrity.

Download Full-text

Within-host dynamics explain patterns of antibiotic resistance in commensal bacteria

10.1101/217232 ◽

2017 ◽

Cited By ~ 5

Author(s):

Nicholas G. Davies ◽

Stefan Flasche ◽

Mark Jit ◽

Katherine E. Atkins

Keyword(s):

Antibiotic Resistance ◽

Management Strategies ◽

Resistance Management ◽

Population Level ◽

Antibiotic Consumption ◽

Mathematical Framework ◽

Host Immune Responses ◽

Resistance Evolution ◽

Resistant Strains ◽

The Impact

The spread of antibiotic resistance, a major threat to human health, is poorly understood. Empirically, resistant strains gradually increase in prevalence as antibiotic consumption increases, but current mathematical models predict a sharp transition between full sensitivity and full resistance. In other words, we do not understand what drives persistent coexistence between resistant and sensitive strains of disease-causing bacteria in host populations. Without knowing what drives patterns of resistance, we cannot accurately predict the impact of potential strategies for managing resistance. Here, we show that within-host dynamics—bacterial growth, strain competition, and host immune responses—promote frequency-dependent selection for resistant strains, explaining patterns of resistance at the population level. By capturing these processes in a parsimonious mathematical framework, we resolve a long-standing conflict between theory and observation. Our models capture widespread coexistence for multiple bacteria-drug combinations across 30 European countries and explain associations between carriage prevalence and resistance prevalence among bacterial subtypes. A mechanistic understanding of resistance evolution is needed to accurately forecast the impact and effectiveness of resistance-management strategies.

Download Full-text

GENERAL PRINCIPLES OF ANTIBIOTIC RESISTANCE EVOLUTION IN BACTERIA (REVIEW OF LITERATURE)

Russian Clinical Laboratory Diagnostics ◽

10.18821/0869-2084-2020-65-6-387-393 ◽

2020 ◽

Vol 65 (6) ◽

pp. 387-393

Author(s):

N. V. Davidovich ◽

Natalya Nilolaevna Kukalevskaya ◽

E. N. Bashilova ◽

T. A. Bazhukova

Keyword(s):

Antibiotic Resistance ◽

Resistance Genes ◽

Molecular Genetic ◽

Antibiotic Resistance Genes ◽

Human Pathogens ◽

Intrinsic Resistance ◽

Resistance Evolution ◽

Genes Encoding ◽

The Impact

Currently, the impact of antibiotic resistance on human health is a worldwide problem and its study is of great interest from a molecular genetic, environmental and clinical view-point. This review summarizes the latest data about antibiotic resistance, the classification of microorganisms as sensitive and resistant to the action of antibiotics, reveals the concept of minimum inhibitory concentration from modern positions. The resistance of microorganisms to antibacterial agents can be intrinsic and acquired, as well as being one of the examples of evolution that are currently available for study. Modern methods of whole-genome sequencing and complex databases of nucleotide-tagged libraries give an idea of the multifaceted nature of the mechanisms of intrinsic resistance to antibiotics and are able to provide information on genes encoding metabolic enzymes and proteins that regulate the basic processes of the physiology of bacteria. The article describes the main ways of spreading the resistance of microorganisms, reflects the concepts of “founder effect” and the fitness cost of bacteria, which underlie the emergence and evolution of antibiotic resistance. It is shown that the origin of antibiotic resistance genes that human pathogens currently possess can be traced by studying the surrounding not only clinical, but also non-clinical (ecological) habitats. As well as microorganisms of the surrounding ecosystems are the donors of resistance genes in horizontal gene transfer.

Download Full-text

Quantifying the impact of treatment history on plasmid-mediated resistance evolution in human gut microbiota

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1912188116 ◽

2019 ◽

Vol 116 (46) ◽

pp. 23106-23116 ◽

Cited By ~ 2

Author(s):

Burcu Tepekule ◽

Pia Abel zur Wiesch ◽

Roger D. Kouyos ◽

Sebastian Bonhoeffer

Keyword(s):

Antibiotic Resistance ◽

Gut Microbiota ◽

Drug Exposure ◽

Center Of Mass ◽

Antibiotic Use ◽

Resistance Evolution ◽

Treatment History ◽

Resistant Infection ◽

The Impact

To understand how antibiotic use affects the risk of a resistant infection, we present a computational model of the population dynamics of gut microbiota including antibiotic resistance-conferring plasmids. We then describe how this model is parameterized based on published microbiota data. Finally, we investigate how treatment history affects the prevalence of resistance among opportunistic enterobacterial pathogens. We simulate treatment histories and identify which properties of prior antibiotic exposure are most influential in determining the prevalence of resistance. We find that resistance prevalence can be predicted by 3 properties, namely the total days of drug exposure, the duration of the drug-free period after last treatment, and the center of mass of the treatment pattern. Overall this work provides a framework for capturing the role of the microbiome in the selection of antibiotic resistance and highlights the role of treatment history for the prevalence of resistance.

Download Full-text

Competition and diversity determine vaccine impact on antibiotic resistance evolution

10.1101/610188 ◽

2019 ◽

Cited By ~ 1

Author(s):

Nicholas G. Davies ◽

Stefan Flasche ◽

Mark Jit ◽

Katherine E. Atkins

Keyword(s):

Antibiotic Resistance ◽

Pneumococcal Vaccination ◽

Antibiotic Use ◽

Relative Strength ◽

Antibiotic Resistant ◽

Resistance Evolution ◽

Pneumococcal Carriage ◽

Bacterial Transmission ◽

Vaccine Impact ◽

The Impact

Bacterial vaccines can protect recipients from contracting potentially antibiotic-resistant infections. But by altering the selective balance between sensitive and resistant strains, vaccines may also help suppress—or spread—antibiotic resistance among unvaccinated individuals. Predicting the outcome requires knowing the drivers of resistance evolution. Using mathematical modelling, we identify competition and diversity as key mediators of resistance evolution. Specifically, we show that the frequency of penicillin resistance in Streptococcus pneumoniae (pneumococcus) across 27 European countries can be explained by between-host diversity in antibiotic use, heritable diversity in pneumococcal carriage duration, or within-host competition. We use our calibrated model to predict the impact of universal pneumococcal vaccination upon the prevalence of carriage, incidence of disease, and frequency of resistance for S. pneumoniae. The relative strength and directionality of competition between resistant and sensitive pneumococcal strains determines whether vaccination promotes, inhibits, or has little effect on the evolution of antibiotic resistance. Finally, we find that differences in overall bacterial transmission and carriage alter predictions, suggesting that evidence-based policies for managing resistance with vaccines must be tailored to both pathogen and setting.One sentence summaryCompetition and diversity are key to antibiotic resistance evolution and determine whether vaccines will prevent or increase resistant infections.

Download Full-text

Cross-feeding modulates the rate and mechanism of antibiotic resistance evolution in a model microbial community of Escherichia coli and Salmonella enterica

10.1101/722561 ◽

2019 ◽

Author(s):

Elizabeth M. Adamowicz ◽

Michaela A. Muza ◽

Jeremey M. Chacón ◽

William R. Harcombe

Keyword(s):

Antibiotic Resistance ◽

Species Interactions ◽

Resistance Mechanisms ◽

Community Context ◽

Resistance Mutations ◽

Intrinsic Resistance ◽

Adaptive Mutations ◽

Resistance Evolution ◽

Metabolic Interactions ◽

The Impact

AbstractWith antibiotic resistance rates on the rise, it is critical to understand how microbial species interactions influence the evolution of resistance. We have previously shown that in obligate mutualisms the survival of any one species (regardless of its intrinsic resistance) is contingent on the resistance of its cross-feeding partners, setting the community antibiotic tolerance at that of the ‘weakest link’ species. In this study, we extended that hypothesis to test whether obligate cross-feeding would limit the extent and mechanisms of antibiotic resistance evolution. In both rifampicin and ampicillin treatments, we observed that resistance evolved more slowly in obligate co-cultures of E. coli and S. enterica than in monocultures. While we observed similar mechanisms of resistance arising under rifampicin selection, under ampicillin selection different resistance mechanisms arose in co-cultures and monocultures. In particular, mutations in an essential cell division protein, ftsI, arose in S. enterica only in co-culture. A simple mathematical model demonstrated that reliance on a partner is sufficient to slow the rate of adaptation, and can change the distribution of adaptive mutations that are acquired. Our results demonstrate that cooperative metabolic interactions can be an important modulator of resistance evolution in microbial communities.Significance statementLittle is known about how ecological interactions between bacteria influence the evolution of antibiotic resistance. We tested the impact of metabolic interactions on resistance evolution in an engineered two-species bacterial community. Through experimental and modeling work, we found that obligate metabolic interdependency slows the rate of resistance acquisition, and can change the type and magnitude of resistance mutations that evolve. This work suggests that resistance evolution may be slowed by targeting both a pathogen and its metabolic partners with antibiotics. Additionally, we showed that community context can generate novel trajectories through which antibiotic resistance evolves.

Download Full-text

Comparing treatment strategies to reduce antibiotic resistance in an in vitro epidemiological setting

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2023467118 ◽

2021 ◽

Vol 118 (13) ◽

pp. e2023467118

Author(s):

Daniel C. Angst ◽

Burcu Tepekule ◽

Lei Sun ◽

Balázs Bogos ◽

Sebastian Bonhoeffer

Keyword(s):

Antibiotic Resistance ◽

Experimental Evolution ◽

Treatment Strategies ◽

Antibiotic Use ◽

Resistance Evolution ◽

Liquid Handling ◽

New Antibiotics ◽

Dynamical Parameters ◽

Experimental Approaches

The rapid rise of antibiotic resistance, combined with the increasing cost and difficulties to develop new antibiotics, calls for treatment strategies that enable more sustainable antibiotic use. The development of such strategies, however, is impeded by the lack of suitable experimental approaches that allow testing their effects under realistic epidemiological conditions. Here, we present an approach to compare the effect of alternative multidrug treatment strategies in vitro using a robotic liquid-handling platform. We use this framework to study resistance evolution and spread implementing epidemiological population dynamics for treatment, transmission, and patient admission and discharge, as may be observed in hospitals. We perform massively parallel experimental evolution over up to 40 d and complement this with a computational model to infer the underlying population-dynamical parameters. We find that in our study, combination therapy outperforms monotherapies, as well as cycling and mixing, in minimizing resistance evolution and maximizing uninfecteds, as long as there is no influx of double resistance into the focal treated community.

Download Full-text