Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void?

  • An Erratum to this article was published on 29 January 2016

Key Points

  • Concern over antibiotic resistance is growing. Resistance of up to 50% has been reported in some regions, including resistance to carbapenems, our current last line of defence.

  • New classes of antibiotics are needed, particularly against Gram-negative bacteria. However, even if the scientific hurdles can be overcome, it could take decades before sufficient numbers of such antibiotics become available.

  • As an interim solution, antibiotic resistance could be 'broken' by co-administering appropriate non-antibiotic drugs with failing antibiotics.

  • Several marketed drugs that do not currently have antibacterial indications can directly kill bacteria, reduce the antibiotic minimum inhibitory concentration when used in combination with existing antibiotics, modulate host defence through effects on host innate immunity, particularly inflammation and autophagy, or a combination of these three.

  • This article discusses how such 'antibiotic resistance breakers' (ARBs) could contribute to reducing the antibiotic resistance problem, and analyses a priority list of candidates for further investigation.

Abstract

Concern over antibiotic resistance is growing, and new classes of antibiotics, particularly against Gram-negative bacteria, are needed. However, even if the scientific hurdles can be overcome, it could take decades for sufficient numbers of such antibiotics to become available. As an interim solution, antibiotic resistance could be 'broken' by co-administering appropriate non-antibiotic drugs with failing antibiotics. Several marketed drugs that do not currently have antibacterial indications can either directly kill bacteria, reduce the antibiotic minimum inhibitory concentration when used in combination with existing antibiotics and/or modulate host defence through effects on host innate immunity, in particular by altering inflammation and autophagy. This article discusses how such 'antibiotic resistance breakers' could contribute to reducing the antibiotic resistance problem, and analyses a priority list of candidates for further investigation.

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Figure 1: Sites of antibacterial action and mechanisms of resistance.

Change history

  • 29 January 2016

    The article contained incorrect information regarding the susceptible bacteria and clinical trial phase of the aztreonam–avibactam combination, and incorrect nomenclature for Salmonella enterica subsp. enterica serovar Typhimurium. These errors have been corrected in the online version of the article.

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Acknowledgements

The author thanks the following for expert discussions on the drugs reviewed: A. Coates (clinical antibiotic resistance and ARB concept); S. Shaunak (clinical antibiotic resistance, TLRs and innate immune system); N. Ktistakis (autophagy); D. Cavalla (drug repurposing); and members of the Science and Technology Advisory Committee of Antibiotics Research UK.

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Correspondence to David Brown.

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Brown, D. Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void?. Nat Rev Drug Discov 14, 821–832 (2015). https://doi.org/10.1038/nrd4675

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