Repurposing Screens Identify Rifamycins as Potential Broad-Spectrum Therapy for Multidrug-Resistant Acinetobacter baumannii and Select Agent Microorganisms

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.

Keywords:

• Acinetobacter baumannii
• Bacillus anthracis
• Francisella tularensis
• rifamycins
• select agent pathogens
• Yersinia pestis

Acknowledgements

The authors are grateful to Steve Smiley for technical advice and critical evaluation of the manuscript. The authors would like to acknowledge Britta Babel of the National Naval Medical Center for her assistance with preparation and shipping of the Acinetobacter strains.

Disclaimer

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Navy, Department of Defense, or the US Government.

Financial & competing interests disclosure

This work was performed under the auspices of the US Department of Energy under contract number DE-AC52-07NA27344. K Petersen is an employee of the US Navy; this work was prepared as part of his official duties. This work was supported by Lawrence Livermore National Laboratory, Laboratory Directed Research and Development awards: 08-ERD-020 and 09-ERD-054. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was performed under the auspices of the US Department of Energy under contract number DE-AC52-07NA27344. K Petersen is an employee of the US Navy; this work was prepared as part of his official duties. This work was supported by Lawrence Livermore National Laboratory, Laboratory Directed Research and Development awards: 08-ERD-020 and 09-ERD-054. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.