A 2018–2019 patent review of metallo beta-lactamase inhibitors

ABSTRACT

Introduction

Antibiotic resistance caused by beta-lactamase expressing bacteria poses a concern given its global dissemination and proliferation. The emergence of the metallo beta-lactamases is an indefinite health threat toward which current antibiotics have limited clinical efficacy. One solution is to develop metallo beta-lactamase inhibitors (MBLIs) capable of restoring the activity of beta-lactam drugs.

Areas covered

This review focuses on potential metallo beta-lactamase inhibitors that have been patented during the period of 2018–2019. The aim is to provide insight into the diverse class of compounds which exhibit a synergistic inhibitory effect on carbapenem-resistant bacteria, when co-administered with a beta-lactam antibiotic.

Expert opinion

The treatment strategy, of creating a broad-spectrum beta-lactamase inhibitor, is beneficial to the health sector as well as rural communities. Unfortunately, most of the inhibitors lack published data from both in vitro and in vivo evaluation, thus preventing an expert opinion on the likelihood to progress as candidates for clinical trials. From this report, the bismuth complexes, pyridinyl-nicotinamide derived sugars, boronic acid, and thiazole sulfonamide derivatives, portray promising properties for further advancement. Since there is currently no FDA approved MBLI, there remains an urgent need for the development of these combination treatment strategies.

KEYWORDS:

• Beta-lactamase inhibitors
• carbapenem resistant Enterobacteriaceae
• metallo beta-lactamase inhibitors
• serine beta-lactamase inhibitors

Article highlights

• The rapid and widespread dissemination together with the proliferation of CRE’s presents as an urgent worldwide threat to human health.

• Substantial progress has been made on the development of SBLs with many FDA approved SBLI/antibiotic combinations available for antimicrobial therapy; however, the situation is drastically different for MBLIs, where there is no FDA approved or commercially available inhibitor.

• Chemical entities such as the bismuth complexes, pyridinyl-nicotinamide derived sugars, boronic acid, and thiazole sulphonamide derivatives are promising MBLI candidates that have the potential to be considered for entry into clinical trials.

• The concept of creating a broad-spectrum BLI as well as triple combination therapy has gained a significant amount of attention, as evidenced by the reviewed patents.

• Another key finding is the use of a targeting strategies that function by reducing premature chelation before the target beta-lactamase is encountered.

This box summarizes key points contained in the article.

Author contributions

N Reddy performed the literature searches, wrote, and prepared the manuscript. M Shungube co-wrote the manuscript and drew all chemical compounds. The remaining authors are supervisors that conceptualized the topic, guided the writing and preparation of the manuscript.

Declaration of interest

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.

Additional information

Funding

This paper was funded by the National Research Foundation (105216 and 105303), the Medical Research Council, and the Technology Innovation Agency of South Africa.