Plasmid copy number control in bacterial pathogenesis and antibiotic resistance

Plasmids in Enterobacteriaceae often encode virulence determinants and multi-antibiotic resistance that contribute to the fitness of bacteria during infection.

We previously demonstrated Yersinia up-regulates its plasmid as an essential virulent mechanism, and this tactic is most likely widespread amongst plasmid-carrying bacteria, enabling rapid adjustments of plasmid-encoded functions in response to environmental cues.

Recently, we identified several antibiotic-resistant Klebsiella pneumoniae mutants carrying plasmids with significantly increased copy numbers upon antibiotic exposure.

This type of transient gene dosage-dependent resistance is unstable and largely overlooked in clinical settings, and likely to be one of the causes for antibiotic treatment failure.

In this project, we will investigate the prevalence and impact of antibiotic-regulated plasmid copy number (PCN) on resistance development and horizontal transmission using several clinically important bacterial species.

We will also further dissect plasmid replication control in Yersinia and investigate mechanisms of antibiotic-regulated PCN control.

Our approaches include a dedicated array of previously established molecular biological, genetic and biochemical assays in combination with NGS techniques.

By integrating both in vitro and in vivo omics data, our proposed research will provide us with a comprehensive picture of the genotype and phenotype correlations on plasmid-encoded resistance.