Antimicrobial resistance and multidrug-resistant organisms (MDROs) pose a significant threat to global health. With few new antibiotics in the development pipeline, there is an urgent need for novel strategies to combat MDROs.
The gastrointestinal microbiome plays a crucial role as a chemical and physical barrier against invasion of pathogenetic microorganisms. Disruption to the gut microbiota can lead to increased susceptibility of colonisation and overgrowth of MDROs such as carbapenem-resistant Klebsiella pneumoniae (CRE-Kp).
Modulation of the gut microbiota offers a promising strategy to eliminate MDROs from the gut, but significant knowledge gaps remain. This project addresses these knowledge gaps by i) isolating and identifying human commensal species with inhibitory activity against CRE-Kp, ii) defining the mechanisms of bioactive species using an integrative multi-omics approach and iii) developing defined consortia of bioactive species to understand the potential therapeutic activity to clear CRE-Kp in vivo and in vitro.
We have developed miniaturised high throughput assays (co-culture, spot overlay and supernatant) to screen the activity of 1200 gut commensals strains. From this, 49 commensal strains were identified to inhibit in vitro growth of CRE-Kp. Genomic analysis suggested a diverse range of mechanisms (competitive exclusion, production of antimicrobial peptide/secondary metabolite, nutrient competition) are employed by commensals to inhibit CRE-Kp. A combination of two or more commensal strains also resulted in enhanced anti-CRE-Kp activity as compared to a single commensal strain.
Understanding the mechanistic link between the gut microbiota and CRE-Kp is essential for future development of microbiome-based diagnostic and precision biotherapeutics that will be useful in the reducing the burden and potential susceptibility to infection by multidrug-resistant organisms.