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Review
. 2017 Jul;15(7):422-434.
doi: 10.1038/nrmicro.2017.28. Epub 2017 Apr 10.

Next-generation Approaches to Understand and Combat the Antibiotic Resistome

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Free PMC article
Review

Next-generation Approaches to Understand and Combat the Antibiotic Resistome

Terence S Crofts et al. Nat Rev Microbiol. .
Free PMC article

Abstract

Antibiotic resistance is a natural feature of diverse microbial ecosystems. Although recent studies of the antibiotic resistome have highlighted barriers to the horizontal transfer of antibiotic resistance genes between habitats, the rapid global spread of genes that confer resistance to carbapenem, colistin and quinolone antibiotics illustrates the dire clinical and societal consequences of such events. Over time, the study of antibiotic resistance has grown from focusing on single pathogenic organisms in axenic culture to studying antibiotic resistance in pathogenic, commensal and environmental bacteria at the level of microbial communities. As the study of antibiotic resistance advances, it is important to incorporate this comprehensive approach to better inform global antibiotic resistance surveillance and antibiotic development. It is increasingly becoming apparent that although not all resistance genes are likely to geographically and phylogenetically disseminate, the threat presented by those that are is serious and warrants an interdisciplinary research focus. In this Review, we highlight seminal work in the resistome field, discuss recent advances in the studies of resistomes, and propose a resistome paradigm that can pave the way for the improved proactive identification and mitigation of emerging antibiotic resistance threats.

Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1. The synteny of antibiotic resistance genes provides historical context and foreshadows future
The genetic context of antibiotic resistance genes can provide important evidence regarding the likelihood of past or future horizontal gene transfer. a | A single β-lactamase (TEM-1) was found in 25 different genetic contexts in a recent cross-habitat resistome study, which provided a historical record of past mobility. Five contexts are shown here. Habitats in which a gene was discovered are indicated on the left (‘human’: human-associated microbial community; ‘animal’: animal-associated microbial community; ‘WWTP’: wastewater treatment plant; ‘latrine’: composting latrine). b | Four resistance determinants that were discovered in functional selections of soil metagenomic libraries (bottom) have high identity with resistance genes from clinical pathogenic isolates. Shading indicates >99% nucleotide identity, which suggests recent horizontal transfer. Resistance genes in pathogens are syntenic with mobility elements and other resistance genes, which suggests that they may be present on a mobile multidrug resistance cassette and are therefore likely to undergo horizontal gene transfer. DDE, Asp-Asp-Glu. Part a is adapted with permission from REF., Macmillan Publishers Limited. Part b is adapted with permission from REF., AAAS.
Figure 2
Figure 2. Next-generation sequencing and functional metagenomic selection accelerate the cataloguing of known and novel resistance genes
a | The catalogue of resistance genes has increased exponentially in the second era of antibiotic resistome studies owing to improvements in next-generation sequencing. This trend is exemplified by the tetracycline efflux pump-encoding gene tetA, by the bla family encoding β-lactamases and by chloramphenicol acetyl transferase (CAT). Data from the UniProt database, which was accessed on 12 October 2016; the database was searched using Enzyme Commission numbers (bla: 3.5.2.6; CAT: 2.3.1.28) or a family name (tetA). Data on sequencing costs are from National Human Genome Research Institute webpage. b | Functional metagenomics is a powerful tool for ascribing antibiotic resistance function to known gene products. Antibiotic resistance proteins identified by functional metagenomic selection of the preterm infant gut microbiome have high amino acid identity to proteins in the National Center for Biotechnology Information (NCBI) database but low amino acid identity to proteins in antibiotic resistance databases. c | In addition, functional metagenomics can reveal entirely sequence-novel resistance determinants. β-Lactamases that were identified by functional metagenomic selection of two human gut resistomes (red squares) encompassed greater phylogenetic diversity than all previously identified classes of β-lactamase (blue squares). Part b is adapted with permission from REF., Macmillan Publishers Limited. Part c is adapted with permission from REF., AAAS.
Figure 3
Figure 3. The integration of next-generation sequencing and screening technologies with drug development and resistance surveillance
The wide application of functional metagenomic selections and next-generation sequencing will steadily increase our knowledge of functionally annotated antibiotic resistance genes and their genetic context. This will enable more intelligent antibiotic resistance surveillance and drug design by accounting for specific mechanisms of resistance and the risk of resistance spread.
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