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Targeting Borrelia burgdorferi HtpG with a berserker molecule, a strategy for anti-microbial development.
Carlson, Dave L; Kowalewski, Mark; Bodoor, Khaldon; Lietzan, Adam D; Hughes, Philip F; Gooden, David; Loiselle, David R; Alcorta, David; Dingman, Zoey; Mueller, Elizabeth A; Irnov, Irnov; Modla, Shannon; Chaya, Tim; Caplan, Jeffrey; Embers, Monica; Miller, Jennifer C; Jacobs-Wagner, Christine; Redinbo, Matthew R; Spector, Neil; Haystead, Timothy A J.
Affiliation
  • Carlson DL; Department of Pharmacology and Cancer Biology, Duke University, C119 LSRC, Research Drive, Durham NC 27701, USA.
  • Kowalewski M; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, 120 Mason Farm Road, 3(rd) Floor, Genetic Medicine Building, Chapel Hill, NC 27599, USA.
  • Bodoor K; Department of Pharmacology and Cancer Biology, Duke University, C119 LSRC, Research Drive, Durham NC 27701, USA.
  • Lietzan AD; Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, The University of North Carolina at Chapel Hill, 385 South Columbia Street, Chapel Hill, NC 27599, USA.
  • Hughes PF; Department of Pharmacology and Cancer Biology, Duke University, C119 LSRC, Research Drive, Durham NC 27701, USA.
  • Gooden D; Department of Pharmacology and Cancer Biology, Duke University, C119 LSRC, Research Drive, Durham NC 27701, USA.
  • Loiselle DR; Department of Pharmacology and Cancer Biology, Duke University, C119 LSRC, Research Drive, Durham NC 27701, USA.
  • Alcorta D; Department of Pharmacology and Cancer Biology, Duke University, C119 LSRC, Research Drive, Durham NC 27701, USA.
  • Dingman Z; Department of Pharmacology and Cancer Biology, Duke University, C119 LSRC, Research Drive, Durham NC 27701, USA.
  • Mueller EA; Sarafan ChEM-H Institute, Stanford University, 290 Jane Stanford Way, Stanford, CA 94035, USA.
  • Irnov I; Sarafan ChEM-H Institute, Stanford University, 290 Jane Stanford Way, Stanford, CA 94035, USA.
  • Modla S; Delaware Biotechnology Institute, University of Delaware, 590 Avenue 1743, Newark, DE 19713, USA.
  • Chaya T; Delaware Biotechnology Institute, University of Delaware, 590 Avenue 1743, Newark, DE 19713, USA.
  • Caplan J; Delaware Biotechnology Institute, University of Delaware, 590 Avenue 1743, Newark, DE 19713, USA.
  • Embers M; Department of Microbiology and Immunology, 18703 Three Rivers Road, Covington, LA 70433, USA.
  • Miller JC; Galaxy Diagnostics, Inc, P.O. Box 14346 7020 Kit Creek Road, Ste 130, Research Triangle Park, Raliegh, NC 27709, USA.
  • Jacobs-Wagner C; Sarafan ChEM-H Institute, Stanford University, 290 Jane Stanford Way, Stanford, CA 94035, USA; Biology Department, Stanford University, 290 Jane Stanford Way, Stanford, CA 94035, USA; Howard Hughes Medical Institute, Stanford University, 290 Jane Stanford Way, Stanford, CA 94035, USA.
  • Redinbo MR; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, 120 Mason Farm Road, 3(rd) Floor, Genetic Medicine Building, Chapel Hill, NC 27599, USA; Department of Chemistry, University of North Carolina at Chapel Hill, 4350 Genome Sciences Building, 250 Bell Tower Drive,
  • Spector N; Department of Pharmacology and Cancer Biology, Duke University, C119 LSRC, Research Drive, Durham NC 27701, USA.
  • Haystead TAJ; Department of Pharmacology and Cancer Biology, Duke University, C119 LSRC, Research Drive, Durham NC 27701, USA. Electronic address: timothy.haystead@duke.edu.
Cell Chem Biol ; 31(3): 465-476.e12, 2024 Mar 21.
Article in En | MEDLINE | ID: mdl-37918401
Conventional antimicrobial discovery relies on targeting essential enzymes in pathogenic organisms, contributing to a paucity of new antibiotics to address resistant strains. Here, by targeting a non-essential enzyme, Borrelia burgdorferi HtpG, to deliver lethal payloads, we expand what can be considered druggable within any pathogen. We synthesized HS-291, an HtpG inhibitor tethered to the photoactive toxin verteporfin. Reactive oxygen species, generated by light, enables HS-291 to sterilize Borrelia cultures by causing oxidation of HtpG, and a discrete subset of proteins in proximity to the chaperone. This caused irreversible nucleoid collapse and membrane blebbing. Tethering verteporfin to the HtpG inhibitor was essential, since free verteporfin was not retained by Borrelia in contrast to HS-291. For this reason, we liken HS-291 to a berserker, wreaking havoc upon the pathogen's biology once selectively absorbed and activated. This strategy expands the druggable pathogenic genome and offsets antibiotic resistance by targeting non-essential proteins.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Borrelia burgdorferi Language: En Journal: Cell Chem Biol Year: 2024 Document type: Article Affiliation country: Country of publication:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Borrelia burgdorferi Language: En Journal: Cell Chem Biol Year: 2024 Document type: Article Affiliation country: Country of publication: