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Multiplex Therapeutic Drug Monitoring by Isotope-dilution HPLC-MS/MS of Antibiotics in Critical Illnesses
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PROTAC antibiotics: the time is now.

Jickky Palmae Sarathy1, Courtney C Aldrich2, Mei-Lin Go3

  • 1Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA.

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|April 7, 2023
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Summary
This summary is machine-generated.

Novel antibiotics are developed using targeted protein degradation (TPD). Researchers created BacPROTACs, a new class of antibacterial agents that degrade bacterial proteins, bypassing the need for a host E3 ligase.

Keywords:
Antibacterial drug discoveryproteolysis targeting chimerastargeted protein degradation

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Area of Science:

  • Microbiology
  • Drug Discovery
  • Molecular Biology

Background:

  • Antibiotic resistance necessitates novel therapeutic strategies.
  • Targeted protein degradation (TPD) is a promising approach for human therapeutics but not yet for antibiotics.
  • Bacteria lack the E3 ligase-proteasome system used by human TPD drugs.

Purpose of the Study:

  • To explore TPD as a novel antibiotic discovery strategy.
  • To develop a generalizable method for antibacterial TPD.
  • To investigate the potential of BacPROTACs in combating bacterial infections.

Main Methods:

  • Discovery of pyrazinamide as a monofunctional target-degrading antibiotic.
  • Rational design and synthesis of bifunctional antibacterial target degraders (BacPROTACs).
  • Evaluation of BacPROTAC mechanism and activity in bacteria.

Main Results:

  • Demonstrated pyrazinamide as the first monofunctional target-degrading antibiotic.
  • Successfully designed and characterized BacPROTACs, the first bifunctional antibacterial target degraders.
  • Showcased that BacPROTACs can directly promote target degradation by linking to bacterial protease complexes.

Conclusions:

  • TPD is a viable and novel approach for antibiotic discovery.
  • BacPROTACs offer a generalizable strategy for TPD in bacteria, bypassing the need for host E3 ligases.
  • Antibacterial PROTACs hold potential for expanding the therapeutic target space and improving treatment outcomes.