An omics-based framework for assessing the health risk of antimicrobial resistance genes

An-Ni Zhang,Shijie Zhao,Chengzhen L Dai,Edward Topp,Jeffry M Gaston,Mathilde Poyet,James M Tiedje,Tong Zhang,Eric J Alm,Mark C M Van Loosdrecht,Xiaole Yin,William P Hanage,Michael R Gillings,Li-Guan Li,Katya Moniz,Mathieu Groussin

doi:10.1038/s41467-021-25096-3

Abstract

Antibiotic resistance genes (ARGs) are widespread among bacteria. However, not all ARGs pose serious threats to public health, highlighting the importance of identifying those that are high-risk. Here, we developed an ‘omics-based’ framework to evaluate ARG risk considering human-associated-enrichment, gene mobility, and host pathogenicity. Our framework classifies human-associated, mobile ARGs (3.6% of all ARGs) as the highest risk, which we further differentiate as ‘current threats’ (Rank I; 3%) - already present among pathogens - and ‘future threats’ (Rank II; 0.6%) - novel resistance emerging from non-pathogens. Our framework identified 73 ‘current threat’ ARG families. Of these, 35 were among the 37 high-risk ARGs proposed by the World Health Organization and other literature; the remaining 38 were significantly enriched in hospital plasmids. By evaluating all pathogen genomes released since framework construction, we confirmed that ARGs that recently transferred into pathogens were significantly enriched in Rank II (‘future threats’). Lastly, we applied the framework to gut microbiome genomes from fecal microbiota transplantation donors. We found that although ARGs were widespread (73% of genomes), only 8.9% of genomes contained high-risk ARGs. Our framework provides an easy-to-implement approach to identify current and future antimicrobial resistance threats, with potential clinical applications including reducing risk of microbiome-based interventions.

Highlights

IntroductionNot all Antibiotic resistance genes (ARGs) pose serious threats to public health, highlighting the importance of identifying those that are high-risk
Antibiotic resistance genes (ARGs) are widespread among bacteria
Total environmental concentration of antibiotics varied by two orders of magnitude, with the lowest concentrations in pristine natural environments such as permafrost and marine sediment, and the highest concentrations being in strongly human-associated environments such as wastewater treatment plants (WWTPs) and industrial livestock waste streams (Fig. 1a, references in Supplementary Data 1, methods in Supplementary Methods)

Summary

Introduction

Not all ARGs pose serious threats to public health, highlighting the importance of identifying those that are high-risk. We developed an ‘omics-based’ framework to evaluate ARG risk considering human-associated-enrichment, gene mobility, and host pathogenicity. We found that ARGs were widespread (73% of genomes), only 8.9% of genomes contained high-risk ARGs. Our framework provides an easy-to-implement approach to identify current and future antimicrobial resistance threats, with potential clinical applications including reducing risk of microbiome-based interventions. Antimicrobial resistance (AMR) has been declared a global public health threat by the U.S Center for Disease Control (CDC) and World Health Organization (WHO)2 Mitigating this threat requires a multipronged approach that considers the risks of novel AMR emergence and transfer to pathogens, transmission of resistant pathogens, and targeted, evidence-based strategies for reducing the factors that contribute to each of those steps. Gene mobility and host pathogenicity have been proposed as evaluative factors for ARG risk by previous studies, and were included in this study

Methods

Results

Conclusion