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

ABSTRACTIntroduction 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 Bmetallo-β-lactamasesMblsinhibitorspatentsantibiotic resistancecarbapenemsDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Declaration of interestsThe 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 disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Author contribution statementAll authors participated to the conceptualization of the topic, literature searches, writing and preparation of the manuscript.AcknowledgmentsThe authors express their gratitude to the French Antibiodeal network of the Promise PPR antibioresistance ANR program for fostering valuable scientific exchanges.Article highlightsThe 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, is 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 towards clinical development.MBL-mediated infections in Pseudomonas aeruginosa and Acinetobacter baumannii are generally more difficult to treat compared to those in Enterobacterales.Additional informationFundingThis 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].