New therapeutics are urgently needed to treat infections caused by drug-resistant variants of bacterial pathogens, particularly pathogens likely to be utilized as weapons of terrorism or biological warfare. The objective of the proposed work is to discover and develop new therapeutics for treatment of infections caused by Bacillus anthracis, which remains the most readily weaponized, easily dispersed and among the deadliest of biological materials that might be employed for purposes of terrorism or biological warfare. B. anthracis bacteria are also easy to obtain from natural sources and are easy to manipulate genetically, even with rudimentary facilities and limited microbiological expertise, making this pathogen the agent of choice for terrorist organizations. Under Phase I funding, we demonstrated that an antisense (AS) RNA expression technology developed at Elitra Pharmaceuticals to identify essential genes is readily adapted for use in B. anthracis. This creates the opportunity to exploit Elitra's highly sensitive, AS-based, whole-cell screening assays to discover drug leads for the development of new B. anthracis therapeutics. As projected in the original Phase I application, the Phase II research program will build directly on the success of the Phase I proof-of-concept studies. We propose to implement the AS-based essential gene discovery survey on a large scale in order to identify both narrow-spectrum and broad-spectrum drug targets. More importantly, we will use AS-sensitized B. anthracis strains to conduct whole-cell screens for discovery of drug leads. Elitra will commit matching funds from other sources to pursue lead-optimization chemistry and pre-clinical development of attractive lead series, driving aggressively to the goal of producing new products of high public health value and strategic importance.
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| Kedar, G C; Brown-Driver, Vickie; Reyes, Daniel R et al. (2007) Evaluation of the metS and murB loci for antibiotic discovery using targeted antisense RNA expression analysis in Bacillus anthracis. Antimicrob Agents Chemother 51:1708-18 |
