PROTAC antibiotics: the time is now

ABSTRACT

Introduction

Novel antibiotics are needed to keep antibiotic resistance at bay and to improve treatment of the many drug-susceptible infections for which current therapies achieve poor cure rates. While revolutionizing human therapeutics, the concept of targeted protein degradation (TPD) by bifunctional proteolysis targeting chimeras (PROTACs) has not yet been applied to the discovery of antibiotics. A major obstacle precluding successful translation of this strategy to antibiotic development is that bacteria lack the E3 ligase-proteasome system exploited by human PROTACs to facilitate target degradation.

Areas covered

The authors describe the serendipitous discovery of the first monofunctional target-degrading antibiotic pyrazinamide, supporting TPD as a viable and novel approach in antibiotic discovery. They then discuss the rational design, mechanism, and activity of the first bifunctional antibacterial target degrader BacPROTAC, enabling a generalizable approach to TPD in bacteria.

Expert opinion

BacPROTACs demonstrate that linking a target directly to a bacterial protease complex can promote target degradation. BacPROTACs successfully bypass the ‘middleman’ E3 ligase, providing an entry strategy for the generation of antibacterial PROTACs. We speculate that antibacterial PROTACs will not only expand the target space but may also improve treatment by allowing dosage reduction, stronger bactericidal activity and activity against drug-tolerant ‘persisters.’

KEYWORDS:

• Antibacterial drug discovery
• proteolysis targeting chimeras
• targeted protein degradation

Article highlights

• The absence of the human E3 ligase-proteasome machinery in bacteria is the major obstacle for implementing PROTAC approaches for the discovery of antibiotics.

• Recent work generated the first bifunctional PROTAC-like molecules (BacPROTACs) active in intact bacteria.

• BacPROTACs engage a bacterial protease directly to achieve targeted protein degradation (TPD), thus circumventing the need for the E3 ligase.

• BacPROTACs provide (i) proof-of-concept that TPD by PROTAC is a feasible approach for antibacterial drug discovery, and (ii) a first ‘degradation by generation of proximity’ strategy to guide the generation of hits.

• Due to their novel on-target mechanism of action and their modular structure, antibacterial PROTACs are expected to expand the target space to whole bacterial proteomes.

• Due to their target depletion mechanism, PROTAC antibiotics may result in improved treatments by (i) reducing minimum efficacious doses, (ii) enhancing bactericidal activity compared to traditional antibiotics and, (iii) achieving activity against drug-tolerant persisters.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are supported by a grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R01AI32374.