Researchers, clinicians and governments all recognize antimicrobial resistance as a serious and growing threat worldwide. New antimicrobials are urgently needed, especially for infections caused by Gram-negative bacteria, whose cell envelopes are characterized by low permeability and often contain drug efflux systems. Individual bacteria and populations control their internal concentrations of antibiotics by regulating proteins involved in membrane permeability, such as porins or efflux pumps. Robust methods to quantify and visualize intrabacterial antibiotic concentrations have identified clear correlations between efflux activity and drug diffusion and accumulation in both susceptible and resistant strains, and have also clarified how certain chemical structures can affect drug entry and residence time within the cell. In this PERSPECTIVE, we discuss the biological underpinnings of drug permeability and export using several prototypical influx and efflux systems. We also highlight how new methods for the determination of antibacterial activities enable more careful quantitation and may provide us with a way forward for capturing and correlating the modes of action and kinetics of antibiotic uptake inside bacterial cells. Together, these advances will aid efforts to generate structurally improved molecules with better access and retention within bacteria, thereby reducing the emergence and spread of resistant strains and extending the clinical use of current antibiotics.
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Acknowledgements
We thank all the partners of IMI-Translocation consortium, especially R. A. Stavenger, for their fruitful discussions and suggestions. The research leading to the results discussed here was conducted as part of the translocation consortium (www.translocation.eu) and has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115525, resources which are composed of financial contribution from the European Union's seventh framework program (FP/2007-2013) and EFPIA companies in kind contributions.
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All authors, M.M., M.R., K.M.P. and J.-M.P., have contributed to the preparation of the manuscript. M.M. and J.-M.P. have corrected and improved the manuscript with the input from the referees and editor.
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Masi, M., Réfregiers, M., Pos, K. et al. Mechanisms of envelope permeability and antibiotic influx and efflux in Gram-negative bacteria. Nat Microbiol 2, 17001 (2017). https://doi.org/10.1038/nmicrobiol.2017.1
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DOI: https://doi.org/10.1038/nmicrobiol.2017.1