Biswas Pilot Project Summary
Acinetobacter baumannii, a gram-negative opportunistic pathogen, is becoming an important nosocomial causing a wide range of diseases and infections including ventilator-associated pneumonia and septicemia as well as urinary tract infections. The pathogen has emerged as one of the most highly antibiotic resistant in the US and elsewhere. Nearly, 70% of A. baumannii clinical isolates are now resistant to all drugs except collistin or tigecycline (known as extremely drug resistant or XDR). Furthermore, infections caused by A. baumannii that are resistant to all available antibiotics (known as pan-drug resistant or PDR) have already emerged and continue to increase since no new drug is in the pipeline that targets A. baumannii. The traditional antibiotics that target cell viability and growth perhaps are not the answer since they will drive the appearance of XDR or PDR further. The innovative approach would be the development of drugs that target the bacterial pathogenesis by inhibiting or controlling expressing of virulence factors. Hfq is a pleiotropic virulence regulator found in many pathogenic bacteria. It is a conserved protein that functions as a post-transcriptional regulator and displays RNA chaperone activity. Inactivation of hfq makes the cells sensitive to various environmental stresses, such as oxidative stress, displaying enhanced susceptibility to various antibiotics, and alteration of the synthesis of several proteins. Furthermore, pathogens lacking a functional Hfq protein are all attenuated for virulence. Therefore, Hfq is an ideal target for drug development to control a wide range of pathogens including A. baumannii.
The major goal of this study is to develop assays for a high-throughput screen (HTS) of small molecule inhibitors of Hfq using a heterologous reporter system and a native expression system. We expect that successful completion of this limited term study will establish an assay system than can be explored further for potential small molecule inhibitors of Hfq. Our long term goal is to stimulate new therapeutic strategies for A. baumannii infections by targeting Hfq and its regulatory mechanisms.