Repurposing screens identify rifamycins as potential broad-spectrum therapy for multidrug-resistant Acinetobacter baumannii and select agent microorganisms. (August 2012)

• Record Type: Journal Article
• Authors: Chromy, Brett A; Elsheikh, Maher; Christensen, Tova L; Livingston, Doug; Petersen, Kyle; Bearinger, Jane P; Hoeprich, Paul D
• Is Part Of: Future microbiology. Volume 7:Number 8(2012)
• Page Start: 1011
• Page End: 1020
• Publication Date: 2012-08
• Subjects: Acinetobacter baumannii -- Bacillus anthracis -- Francisella tularensis -- rifamycins -- select agent pathogens -- Yersinia pestis; Microbiology -- Research -- Periodicals; 616.9041
• DOI: 10.2217/fmb.12.75
• Languages: English
• ISSNs: 1746-0913

Abstract

Aims: Estimates suggest that the drug discovery and development processes take between 10 and 15 years, with costs ranging between US$500 million and $2 billion. A growing number of bacteria have become resistant to approved antimicrobials. For example, the Gram-negative bacterium Acinetobacter baumannii has become multidrug resistant (MDR) and is now an important pathogen to the US military in terms of wound infections. Industry experts have called for a 'disruptive' transformation of the drug discovery process to find new chemical entities for treating drug-resistant infections. One such attempt is drug 'repurposing' or 'repositioning' – that is, identification and development of new uses for existing or abandoned pharmacotherapies.Materials & methods: Using a novel combination of screening technologies based on cell growth and cellular respiration, we screened 450 US FDA-approved drugs from the NIH National Clinical Collection against a dozen clinical MDR A. baumannii (MDRAb) isolates from US soldiers and Marines. We also screened the collection against a diverse set of select agent surrogate pathogens.Results: Seventeen drugs showed promising antimicrobial activity against all MDRAb isolates and select agent surrogates; three of these compounds – all rifamycins – were found to be effective at preventing growth and preventing cellular respiration of MDRAb and select agent surrogate bacteria when evaluated in growth prevention assays, highlighting the potential for repurposing.Conclusion: We report the discovery of a class of known compounds whose repurposing may be useful in solving the current problem with MDRAb and may lead to the discovery of broad-spectrum antimicrobials.