Co-occurrence analysis relates a macrolide resistome to the pulmonary microbiome in chronic respiratory disease

Abstract

Background: Macrolide antibiotics are increasingly used in frequent exacerbators with chronic respiratory disease (CRD) however the role of the airway resistome and its relationship to the host microbiome remains unknown.

Methods: We derived airway microbiomes and corresponding resistomes using deep sequencing metagenomic approaches from airway specimens of individuals with and without CRD (severe asthma, COPD and bronchiectasis) (n=85). Gene-Microbe association networks were built using compositionality corrected general boosted linear models to determine possible microbial sources of the airway resistome.

Results: Antibiotic resistance profiles exhibit variability across healthy and diseased states with greatest resistance observed in COPD and bronchiectasis. A ‘core’ airway resistome dominated by macrolide resistance but with high prevalence of β-lactam, fluoroquinolone and tetracycline resistance genes exists, and, is independent of disease status or prior antibiotic exposure. Dysbiosis of the respiratory microbiome is evident across CRDs and gene-microbe association networks of the ‘core’ resistome revealed Streptococcus and Actinomyces as potential microbial reservoirs of macrolide resistance including the ermX, ermF and msrD genes.

Conclusion: Functional metagenomics of the airway reveals a core macrolide resistome harboured by the host microbiome with clinical implications for macrolide use across CRD.

Funding: Singapore Ministry of Health’s National Medical Research Council under its Transition Award (NMRC/TA/0048/2016) (S.H.C); Clinician-Scientist Individual Research Grant (MOH-000141) (S.H.C) and the NTU Integrated Medical, Biological and Environmental Life Sciences (NIMBELS) [NIM/03/2018] (S.H.C).