A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus
- 주제(키워드) MRSA , bacterial persister , drug repurposing , membrane-active antimicrobials , membrane selectivity
- 주제(기타) Multidisciplinary Sciences
- 설명문(일반) [Kim, Wooseong; Hendricks, Gabriel L.; Tori, Katerina; Pan, Wen; Huang, Xiaowen; Lee, Kiho; Port, Jenna; Fuchs, Beth Burgwyn; Mylonakis, Eleftherios] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Infect Dis, Providence, RI 02903 USA; [Zou, Guijin; Zhu, Wenpeng; Galle, Nicolas; Gao, Huajian] Brown Univ, Sch Engn, Providence, RI 02903 USA; [Hari, Taylor P. A.; Wilt, Ingrid K.; Steele, Andrew D.; Csatary, Erika E.; Dekarske, Madeline M.; Rosen, Jake L.; Wuest, William M.] Emory Univ, Dept Chem, 1515 Pierce Dr, Atlanta, GA 30322 USA; [Hari, Taylor P. A.; Wilt, Ingrid K.; Steele, Andrew D.; Csatary, Erika E.; Dekarske, Madeline M.; Rosen, Jake L.; Wuest, William M.] Emory Univ, Emory Antibiot Resistance Ctr, Atlanta, GA 30322 USA; [Faizi, Hammad A.] Northwestern Univ, Dept Mech Engn, Evanston, IL 60208 USA; [Huang, Xiaowen] Southern Med Univ, Nanfang Hosp, Dept Dermatol, Guangzhou 510515, Guangdong, Peoples R China; [Ribeiro, Noelly de Queiroz] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Microbiol, BR-31270901 Belo Horizonte, MG, Brazil; [Vlahovska, Petia M.] Northwestern Univ, Dept Engn Sci & Appl Math, Evanston, IL 60208 USA; [Ausubel, Frederick M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA; [Ausubel, Frederick M.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA
- 등재 SCIE, SCOPUS
- 발행기관 NATL ACAD SCIENCES
- 발행년도 2019
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000172025
- 본문언어 영어
- Published As https://dx.doi.org/10.1073/pnas.1904700116
초록/요약
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 methicillin-resistant 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 membrane-active 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.
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