An updated patent review of metallo-β-lactamase inhibitors (2020–2023)

ABSTRACT

Introduction

Metallo-β-lactamases (MBLs) are enzymes produced by bacteria that confer resistance to most β-lactam antibiotics, including carbapenems, which have the broadest spectrum of activity. This resistance mechanism poses a significant threat to public health as it drastically reduces treatment options for severe bacterial infections. Developing effective inhibitors against MBLs is crucial to restore susceptibility to β-lactam antibiotics.

Areas covered

This review aims to provide an updated analysis of patents describing novel MBL inhibitors and their potential therapeutic applications that were filed between January 2020 and May 2023.

Expert opinion

Significant advancements were made in the development of selective MBL inhibitors with zinc-binding and zinc-chelating mechanisms of action. Dual inhibitors, targeting simultaneously both serine-β-lactamases (SBLs) and MBLs, represent an interesting alternative approach that is increasingly pertinent for the treatment of infections involving multiple β-lactamases from different Ambler classes. Most examples of MBL-specific inhibitors were focused on the treatment of MBL-mediated infections in Enterobacterales, where IMP-1 was a more difficult target compared with VIM-1 or NDM-1, and much less on Pseudomonas aeruginosa or Acinetobacter baumannii, which are more challenging to address.

KEYWORDS:

• Class B
• metallo-β-lactamases
• MBLs
• inhibitors
• patents
• antibiotic resistance
• carbapenems

Article highlights

• The treatment of infections involving metallo-β-lactamases (MBLs) is currently a critical healthcare problem in the absence of any MBL inhibitor approved for clinical use.

• Important progress was made in the development of narrow-spectrum inhibitors targeting MBLs, with either zinc-binding or zinc-chelating mechanisms.

• Large-spectrum dual inhibitors, targeting simultaneously both serine-β-lactamases (SBLs) and MBLs, are an interesting approach for the treatment of infections involving multiple β-lactamases.

• Two dual SBL/MBL inhibitors (taniborbactam and xeruborbactam) are currently in clinical trials, and several narrow-spectrum MBL inhibitors are progressing toward clinical development.

• MBL-mediated infections in Pseudomonas aeruginosa and Acinetobacter baumannii are generally more difficult to treat compared to those in Enterobacterales.

Acknowledgments

The authors express their gratitude to the French Antibiodeal network of the Promise PPR antibioresistance ANR program for fostering valuable scientific exchanges.

Declaration of interests

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Author contribution statement

All authors participated in the conceptualization of the topic, literature searches, writing, and preparation of the manuscript.

Additional information

Funding

This paper was funded in part by the Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LERMIT) [Grant No. ANR-10-LABX-33], by the JPIAMR transnational project DesInMBL [Grant No. ANR-14-JAMR-0002], by the Région Ile-de-France (DIM Malinf) and by the French Priority Research Program (PPR) on antibiotic resistance [Grant No. ANR-20-PAMR-0010].