TY - JOUR
T1 - A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus
AU - Kim, Wooseong
AU - Zou, Guijin
AU - Hari, Taylor P.A.
AU - Wilt, Ingrid K.
AU - Zhu, Wenpeng
AU - Galle, Nicolas
AU - Faizi, Hammad A.
AU - Hendricks, Gabriel L.
AU - Tori, Katerina
AU - Pan, Wen
AU - Huang, Xiaowen
AU - Steele, Andrew D.
AU - Csatary, Erika E.
AU - Dekarske, Madeline M.
AU - Rosen, Jake L.
AU - De Queiroz Ribeiro, Noelly
AU - Lee, Kiho
AU - Port, Jenna
AU - Fuchs, Beth Burgwyn
AU - Vlahovska, Petia M.
AU - Wuest, William M.
AU - Gao, Huajian
AU - Ausubel, Frederick M.
AU - Mylonakis, Eleftherios
N1 - Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019
Y1 - 2019
N2 - Treatment of Staphylococcus aureus infections is complicated by the development of antibiotic tolerance, a consequence of the ability of S. aureus to enter into a nongrowing, dormant state in which the organisms are referred to as persisters. We report that the clinically approved anthelmintic agent bithionol kills methicillinresistant S. aureus (MRSA) persister cells, which correlates with its ability to disrupt the integrity of Gram-positive bacterial membranes. Critically, bithionol exhibits significant selectivity for bacterial compared with mammalian cell membranes. All-atom molecular dynamics (MD) simulations demonstrate that the selectivity of bithionol for bacterial membranes correlates with its ability to penetrate and embed in bacterial-mimic lipid bilayers, but not in cholesterol-rich mammalian-mimic lipid bilayers. In addition to causing rapid membrane permeabilization, the insertion of bithionol increases membrane fluidity. By using bithionol and nTZDpa (another membraneactive antimicrobial agent), as well as analogs of these compounds, we show that the activity of membrane-active compounds against MRSA persisters positively correlates with their ability to increase membrane fluidity, thereby establishing an accurate biophysical indicator for estimating antipersister potency. Finally, we demonstrate that, in combination with gentamicin, bithionol effectively reduces bacterial burdens in a mouse model of chronic deep-seated MRSA infection. This work highlights the potential repurposing of bithionol as an antipersister therapeutic agent.
AB - Treatment of Staphylococcus aureus infections is complicated by the development of antibiotic tolerance, a consequence of the ability of S. aureus to enter into a nongrowing, dormant state in which the organisms are referred to as persisters. We report that the clinically approved anthelmintic agent bithionol kills methicillinresistant S. aureus (MRSA) persister cells, which correlates with its ability to disrupt the integrity of Gram-positive bacterial membranes. Critically, bithionol exhibits significant selectivity for bacterial compared with mammalian cell membranes. All-atom molecular dynamics (MD) simulations demonstrate that the selectivity of bithionol for bacterial membranes correlates with its ability to penetrate and embed in bacterial-mimic lipid bilayers, but not in cholesterol-rich mammalian-mimic lipid bilayers. In addition to causing rapid membrane permeabilization, the insertion of bithionol increases membrane fluidity. By using bithionol and nTZDpa (another membraneactive antimicrobial agent), as well as analogs of these compounds, we show that the activity of membrane-active compounds against MRSA persisters positively correlates with their ability to increase membrane fluidity, thereby establishing an accurate biophysical indicator for estimating antipersister potency. Finally, we demonstrate that, in combination with gentamicin, bithionol effectively reduces bacterial burdens in a mouse model of chronic deep-seated MRSA infection. This work highlights the potential repurposing of bithionol as an antipersister therapeutic agent.
KW - Bacterial persister
KW - Drug repurposing
KW - MRSA
KW - Membrane selectivity
KW - Membrane-active antimicrobials
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U2 - 10.1073/pnas.1904700116
DO - 10.1073/pnas.1904700116
M3 - Article
C2 - 31358625
AN - SCOPUS:85070696455
SN - 0027-8424
VL - 116
SP - 16529
EP - 16534
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 33
ER -