From gut microbiome to pathogen genomics: Understanding antimicrobial resistance in Southeast Asia and Salmonella Paratyphi A

The human gut microbiome is crucial for maintaining health and influencing disease, particularly as a reservoir for antimicrobial resistance (AMR) genes. This thesis firstly investigated the gut microbiome of a healthy Southeast Asian population, focusing on AMR gene circulation and the public health risks it poses. Additionally, the genomics and AMR mechanisms of Salmonella Paratyphi A, a major cause of enteric fever in Asia were explored. The distribution and ecology of S. Paratyphi A are closely linked to the gut microbiome potentially contributing to resistance gene landscape. In comparison to Salmonella Typhi, S. Paratyphi A is less well studied. Therefore, the epidemiology and genomic characteristics of circulating S. Paratyphi A in South Asia were analysed, with particular focus on isolates from a 2019 outbreak in India. This genomic analysis provided key insights into the epidemiology, AMR profiles, and virulence factors of S. Paratyphi A in an endemic setting. Identifying common genotypes and tracking AMR genes enhances our understanding of the molecular mechanisms underlying bacterial resistance and pathogenicity. Additionally, this research addresses emerging resistance to azithromycin, a key treatment for enteric fever, linked to mutations in the acrB gene of the AcrAB-TolC efflux system. The impact of these mutations on resistance mechanisms was explored, highlighting their contribution to the growing threat of resistance in typhoidal Salmonella. Among the 132 AMR genes identified in the human gut of a Southeast Asian population, macrolide and tetracycline resistance genes (e.g., ermB and tetA) were the most prevalent. Notably, children were identified as a significant reservoir of AMR genes. In India, the only AMR marker detected in S. Paratyphi A isolates were mutations in gyrA, which is associated with reduced susceptibility to fluoroquinolones, and was found in 100% of the isolates. Furthermore, acrB mutations lead to reduced susceptibility to azithromycin without imposing a fitness cost on S. Paratyphi A. This data suggested that S. Paratyphi A can adapt and thrive in an environment with antimicrobial pressures without compromising the bacteria viability. The findings from this work can have implications for both regional and global public health. By shedding light on microbial composition and AMR gene circulation in healthy Southeast Asian populations, alongside genomic drivers of resistance in S. Paratyphi A, this research informs strategies for AMR surveillance, treatment, and outbreak control. Addressing these challenges is essential to mitigate the spread of resistance and maintain the efficacy of antimicrobial therapies, particularly in endemic regions for enteric fever.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Pereira-Dias, Joana

Advisor dc:contributor.advisor

• Baker, Stephen

• Enteric fever
• AMR
• Azithromycin
• Genomics
• Salmonella Paratyphi A

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/1879ef1c-58dc-43ae-b0de-7444c82c0fd0/download
• http://purl.org/NET/rdflicense/allrightsreserved

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.118494

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/384530