2. Academic Validation
  3. Targeting Borrelia burgdorferi HtpG with a berserker molecule, a strategy for anti-microbial development

Targeting Borrelia burgdorferi HtpG with a berserker molecule, a strategy for anti-microbial development

  • Cell Chem Biol. 2023 Nov 1:S2451-9456(23)00340-9. doi: 10.1016/j.chembiol.2023.10.004.
Dave L Carlson 1,  Mark Kowalewski 2,  Khaldon Bodoor 1,  Adam D Lietzan 3,  Philip F Hughes 1,  David Gooden 1,  David R Loiselle 1,  David Alcorta 1,  Zoey Dingman 1,  Elizabeth A Mueller 4,  Irnov Irnov 4,  Shannon Modla 5,  Tim Chaya 5,  Jeffrey Caplan 5,  Monica Embers 6,  Jennifer C Miller 7,  Christine Jacobs-Wagner 8,  Matthew R Redinbo 9,  Neil Spector 1,  Timothy A J Haystead 10
Affiliations

Affiliations

  • 1 Department of Pharmacology and Cancer Biology, Duke University, C119 LSRC, Research Drive, Durham NC 27701, USA.
  • 2 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.
  • 3 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.
  • 4 Sarafan ChEM-H Institute, Stanford University, 290 Jane Stanford Way, Stanford, CA 94035, USA.
  • 5 Delaware Biotechnology Institute, University of Delaware, 590 Avenue 1743, Newark, DE 19713, USA.
  • 6 Department of Microbiology and Immunology, 18703 Three Rivers Road, Covington, LA 70433, USA.
  • 7 Galaxy Diagnostics, Inc, P.O. Box 14346 7020 Kit Creek Road, Ste 130, Research Triangle Park, Raliegh, NC 27709, USA.
  • 8 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.
  • 9 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, Chapel Hill, NC 27599-3290, USA. Electronic address: [email protected].
  • 10 Department of Pharmacology and Cancer Biology, Duke University, C119 LSRC, Research Drive, Durham NC 27701, USA. Electronic address: [email protected].
PMID: 37918401 DOI: 10.1016/j.chembiol.2023.10.004
Abstract

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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