Research Summary

Hospital-associated ESKAPE pathogens: Unraveling novel regulatory layers controlling virulence and persistence

The success of Klebsiella pneumoniae (KPN) as a nosocomial pathogen depends on a host of virulence factors that render it resistant to environmental and host-imposed stresses. Adding to its high virulence and persistence, KPN is gaining resistance to last-resort antibiotics. So, it is becoming difficult to treat antibiotic resistant KPN infections using current antibiotics. Therefore, there is a pressing need to identify new drug targets in KPN. The regulatory networks that control the expression of stress responsive genes and virulence factors in KPN are attractive targets for antimicrobial drug design. Consequently, transcriptional control of virulence gene expression by two-component systems and transcriptional regulators in KPN has been investigated before. On the contrary, post-transcriptional control of gene expression in KPN is not well understood. This research intends to elucidate the regulatory mechanisms by which the small-RNAs post-transcriptionally control the virulence, stress tolerance ability and fitness in KPN. The knowledge generated from this project, in the long term will provide insights into previously unknown regulatory mechanisms operational in KPN, which in turn will allow development of novel and reliable therapeutics.

Figure 1. Factors contributing to the success of KPN as a hospital-associated pathogen. Hospital-associated KPN can cause infections of the respiratory tract, urinary tract, blood stream and wounds. This ability of KPN to cause infections at such diverse sites of the human body is mostly due to the array of virulence factors that it encodes along with the machinery required for antibiotic resistance and the means to exchange DNA with other bacteria via horizontal gene transfer. All these key processes, which are critical for successful establishment of disease, are controlled through regulatory networks at multiple levels. Though transcriptional regulation of virulence factor synthesis and antibiotic resistance has been studied in KPN, very little information is available with respect to the post-transcriptional and post-translational modes of regulation.

Figure 2. small-RNA (sRNA) mediated regulation of gene expression. Bacterial sRNAs may act in coordination with RNA chaperons like Hfq or may act independently. On interaction with the target, sRNAs may stabilize mRNA by preventing degradation by RNases (A), promote translation by altering mRNA secondary structure so as to expose the RBS and allow ribosome binding (B), inhibit translation of the target mRNA by sequestering the RBS of the mRNA (C), tag mRNA for degradation by RNases thereby preventing translation (D).