Collateral sensitivity associated with antibiotic resistance plasmids
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Spain
- Faculty of Veterinary Hygiene and Ecology, University of Veterinary and Pharmaceutical Sciences, Czech Republic
- Centro Nacional de Biotecnología-CSIC, Spain
Abstract
Collateral sensitivity (CS) is a promising alternative approach to counteract the rising problem of antibiotic resistance (ABR). CS occurs when the acquisition of resistance to one antibiotic produces increased susceptibility to a second antibiotic. Recent studies have focused on CS strategies designed against ABR mediated by chromosomal mutations. However, one of the main drivers of ABR in clinically relevant bacteria is the horizontal transfer of ABR genes mediated by plasmids. Here, we report the first analysis of CS associated with the acquisition of complete ABR plasmids, including the clinically important carbapenem-resistance conjugative plasmid pOXA-48. In addition, we describe the conservation of CS in clinical E. coli isolates and its application to selectively kill plasmid-carrying bacteria. Our results provide new insights that establish the basis for developing CS-informed treatment strategies to combat plasmid-mediated ABR.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 3 and S2.Sequencing data have been deposited in the Sequence Read Archive (SRA) repository, BioProject ID: PRJNA644278 (https://www.ncbi.nlm.nih.gov/bioproject/644278).
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DNA Sequence DataSequence Read Archive (SRA) repository, Bioproject PRJNA644278.
Article and author information
Author details
Jerónimo Rodríguez-Beltrán
Ricardo León-Sampedro
Funding
European Research Council (ERC-StG 757440-PLASREVOLUTION)
- Álvaro San Millán
Instituto de Salud Carlos III (PI16-00860)
- Álvaro San Millán
Agencia Estatal de Investigación (IJC2018-035146-I)
- Jerónimo Rodríguez-Beltrán
Instituto de Salud Carlos III (MS15-00012)
- Álvaro San Millán
Comunidad Autonoma de Madrid (PEJD-2018-POST/BMD-8016)
- Cristina Herencias
European Commission (R-GNOSIS-FP7-HEALTH-F3-2011-282512)
- Rafael Cantón
Instituto de Salud Carlos III (REIPIR D16/0016/0011)
- Rafael Cantón
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Herencias et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Collateral sensitivity associated with antibiotic resistance plasmids
eLife 10:e65130.
https://doi.org/10.7554/eLife.65130
Further reading
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- Evolutionary Biology
The majority of highly polymorphic genes are related to immune functions and with over 100 alleles within a population, genes of the major histocompatibility complex (MHC) are the most polymorphic loci in vertebrates. How such extraordinary polymorphism arose and is maintained is controversial. One possibility is heterozygote advantage (HA), which can in principle maintain any number of alleles, but biologically explicit models based on this mechanism have so far failed to reliably predict the coexistence of significantly more than 10 alleles. We here present an eco-evolutionary model showing that evolution can result in the emergence and maintenance of more than 100 alleles under HA if the following two assumptions are fulfilled: first, pathogens are lethal in the absence of an appropriate immune defence; second, the effect of pathogens depends on host condition, with hosts in poorer condition being affected more strongly. Thus, our results show that HA can be a more potent force in explaining the extraordinary polymorphism found at MHC loci than currently recognised.
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- Ecology
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Understanding the origins of novel, complex phenotypes is a major goal in evolutionary biology. Poison frogs of the family Dendrobatidae have evolved the novel ability to acquire alkaloids from their diet for chemical defense at least three times. However, taxon sampling for alkaloids has been biased towards colorful species, without similar attention paid to inconspicuous ones that are often assumed to be undefended. As a result, our understanding of how chemical defense evolved in this group is incomplete. Here, we provide new data showing that, in contrast to previous studies, species from each undefended poison frog clade have measurable yet low amounts of alkaloids. We confirm that undefended dendrobatids regularly consume mites and ants, which are known sources of alkaloids. Thus, our data suggest that diet is insufficient to explain the defended phenotype. Our data support the existence of a phenotypic intermediate between toxin consumption and sequestration — passive accumulation — that differs from sequestration in that it involves no derived forms of transport and storage mechanisms yet results in low levels of toxin accumulation. We discuss the concept of passive accumulation and its potential role in the origin of chemical defenses in poison frogs and other toxin-sequestering organisms. In light of ideas from pharmacokinetics, we incorporate new and old data from poison frogs into an evolutionary model that could help explain the origins of acquired chemical defenses in animals and provide insight into the molecular processes that govern the fate of ingested toxins.
