Editors' ChoiceAntibiotic Discovery

Target Practice

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Science Translational Medicine  09 Mar 2011:
Vol. 3, Issue 73, pp. 73ec32
DOI: 10.1126/scitranslmed.3002340

The recent refrain of the Infectious Disease Society of America, “Bad Bugs, No Drugs,” underscores the rise in often-lethal bacterial infections caused by invasive, drug-resistant Staphylococcus aureus. For methicillin-resistant S. aureus (MRSA)—which can be a serious problem in both the community and in hospitals—a relatively short list of antibiotics (including vancomycin) are critically important in the dodging of a dangerous bacterial infection. These grim realities remind researchers that creative efforts are required to address the paucity of diversely functioning, effective antibiotics.

With the ultimate goal of finding previously unknown antibacterial agents that stem S. aureus, Olson et al. defined both a new drug target—a component of the RNA degradation machinery—and an effective inhibitor of this process.

Previous research suggests that bacteria regulate the expression of virulence factors using a molecular switch that functions at the level of mRNA turnover. Olson and colleagues extended this prediction to S. aureus by demonstrating a stark difference between turnover of virulence factor transcripts—and, indeed, global RNA decay processes—during exponential growth of the bacteria versus its stationary phase. The authors then showed that the essential S. aureus protein RnpA, a component of the bacterial RNA degradation machinery, is one of the major workhorses of the transcript turnover process. This finding motivated the researchers to seek small-molecule inhibitors of RnpA in order to assess whether this protein represents a promising antibacterial target. Using a fluorescence-based high-throughput assay to measure bacterial RNA decay, Olson et al. screened 29,066 molecules, 14 of which caused a 50% or greater decrease in the RNA degradation activity.

RNPA1000, the most promising RnpA inhibitor unearthed by the screen, demonstrated antimicrobial activity in vitro against clinically important S. aureus strains [MRSA (including the predominant community-acquired strain) and vancomycin–intermediate susceptible and vancomycin-resistant S. aureus]. Furthermore, treatment of a mouse model of acute lethal S. aureus infection with RNPA1000 lowered mortality relative to that of untreated controls. Lastly, RNPA1000 displayed efficacy in reducing bacterial burden in the context of biofilm-associated S. aureus. RNPA1000 caused mild cytotoxicity in human cells after 48 hours of exposure, which precludes development of the compound as a therapeutic agent in its current form. However, the elucidation of a new antibacterial target and the discovery of an effective cognate inhibitor represent major steps toward more potent, less toxic drugs with which to battle bad bugs.

P. D. Olson et al., Small molecule inhibitors of Staphylococcus aureus RnpA alter cellular mRNA turnover, exhibit antimicrobial activity, and attenuate pathogenesis. PLoS Pathog. 7, e1001287 (2011). [Full Text]

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