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Amotosalen is a bacterial multidrug efflux pump substrate potentially affecting its pathogen inactivation activity

Alex B. Green, Katelyn E. Zulauf, Katherine A. Truelson, Lucius Chiaraviglio, Meng Cui, Zhemin Zhang, Matthew P. Ware, Willy A. Flegel, Richard L. Haspel, View ORCID ProfileEd Yu, View ORCID ProfileJames E Kirby
doi: https://doi.org/10.1101/2021.03.15.435562
Alex B. Green
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
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Katelyn E. Zulauf
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
bHarvard Medical School, Boston, MA, USA
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Katherine A. Truelson
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
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Lucius Chiaraviglio
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
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Meng Cui
dDepartment of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, 02115, USA
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Zhemin Zhang
eDepartment of Pharmacology, Case Western Reserve University Medical Center, Cleveland, OH, USA
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Matthew P. Ware
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
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Willy A. Flegel
cDepartment of Transfusion Medicine, NIH Clinical Center, National Institutes of Health Bethesda, MD, USA
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Richard L. Haspel
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
bHarvard Medical School, Boston, MA, USA
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Ed Yu
eDepartment of Pharmacology, Case Western Reserve University Medical Center, Cleveland, OH, USA
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  • ORCID record for Ed Yu
James E Kirby
aDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
bHarvard Medical School, Boston, MA, USA
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  • ORCID record for James E Kirby
  • For correspondence: jekirby@bidmc.harvard.edu
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Abstract

Pathogen inactivation is a strategy to improve the safety of transfusion products. The Cerus Intercept technology makes use of a psoralen compound called amotosalen in combination with UVA light to inactivate bacteria, viruses and protozoa. Psoralens have structural similarity to bacterial multidrug-efflux pump substrates. As these efflux pumps are often overexpressed in multidrug-resistant pathogens and with recent reported outbreaks of transfusion-associated sepsis with Acinetobacter, we tested whether contemporary drug-resistant pathogens might show resistance to amotosalen and other psoralens based on multidrug efflux mechanisms through microbiological, biophysical and molecular modeling analysis. The main efflux systems in Enterobacterales and Acinetobacter baumannii, tripartite RND (resistance-nodulation-cell division) systems which span the inner and outer membranes of Gram-negative pathogens and expel antibiotics from the bacterial cytoplasm into the extracellular space, were specifically examined. We found that amotosalen was an efflux substrate for the TolC-dependent RND efflux pumps in E. coli and the AdeABC efflux pump from Acinetobacter baumannii, and that minimal inhibitory concentrations for contemporary bacterial isolates in vitro approached and exceeded the concentration of amotosalen used in the approved platelet and plasma inactivation procedures. These findings suggest that otherwise safe and effective inactivation methods should be further studied to exclude possible gaps in their ability to inactivate contemporary, multidrug-resistant bacterial pathogens.

Importance Pathogen inactivation is a strategy to enhance the safety of transfused blood products. We identify the compound, amotosalen, widely used for pathogen inactivation, as a bacterial multidrug efflux substrate. Specifically, experiments suggest that amotosalen is pumped out of bacteria by the major TolC-dependent RND efflux pumps in E. coli and the AdeABC efflux pump in Acinetobacter baumannii. Such efflux pumps are often overexpressed in multidrug-resistant pathogens. Importantly, the minimal inhibitory concentrations for contemporary multidrug-resistant Enterobacterales, Acinetobacter baumannii, Pseudomonas aeruginosa, Burkholderia spp., and Stenotrophomonas maltophilia isolates approached or exceeded the amotosalen concentration used in approved platelet and plasma inactivation procedures, potentially as a result of efflux pump activity. Although there are important differences in methodology between our experiments and blood product pathogen inactivation, these findings suggest that otherwise safe and effective inactivation methods should be further studied to exclude possible gaps in their ability to inactivate contemporary, multidrug-resistant bacterial pathogens.

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Posted March 16, 2021.
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Amotosalen is a bacterial multidrug efflux pump substrate potentially affecting its pathogen inactivation activity
Alex B. Green, Katelyn E. Zulauf, Katherine A. Truelson, Lucius Chiaraviglio, Meng Cui, Zhemin Zhang, Matthew P. Ware, Willy A. Flegel, Richard L. Haspel, Ed Yu, James E Kirby
bioRxiv 2021.03.15.435562; doi: https://doi.org/10.1101/2021.03.15.435562
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Amotosalen is a bacterial multidrug efflux pump substrate potentially affecting its pathogen inactivation activity
Alex B. Green, Katelyn E. Zulauf, Katherine A. Truelson, Lucius Chiaraviglio, Meng Cui, Zhemin Zhang, Matthew P. Ware, Willy A. Flegel, Richard L. Haspel, Ed Yu, James E Kirby
bioRxiv 2021.03.15.435562; doi: https://doi.org/10.1101/2021.03.15.435562

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