Metallo-beta-lactamases: mechanisms, treatment challenges, and future prospects

ABSTRACT

Introduction

Metallo-beta-lactamases (MBLs) are responsible for resistance to almost all beta-lactam antibiotics. Found predominantly in Gram-negative bacteria, they severely limit treatment options. Understanding the epidemiology, risk factors, treatment, and prevention of infections caused by MBL-producing organisms is essential to reduce their burden.

Areas covered

The origins and structure of MBLs are discussed. We describe the mechanisms of action that differentiate MBLs from other beta-lactamases. We discuss the global epidemiology of MBL-producing organisms and their impact on patients’ outcomes. By exposing the mechanisms of transmission of MBLs among bacterial populations, we emphasize the importance of infection prevention and control.

Expert opinion

MBLs are spreading globally and challenging the majority of available antibacterial agents. Genotypic tests play an important role in the identification of MBL production. Phenotypic tests are less specific but may be used in low-resource settings, where MBLs are more predominant. Infection prevention and control are critical to reduce the spread of organisms producing MBL in healthcare systems. New combinations such as avibactam-aztreonam and new agents such as cefiderocol have shown promising results for the treatment of infections caused by MBL-producing organisms. New antibiotic and non-antibiotic agents are being developed and may improve the management of infections caused by MBL-producing organisms.

KEYWORDS:

• Antimicrobial resistance
• carbapenemase
• carbapenemase-producing organisms
• metallo-beta-lactamase
• imipenemase
• New Delhi metallo-beta-lactamase
• Verona integron-encoded metallo-beta-lactamase

Article highlights

• MBLs’ diverse structural properties and low sequence homology, the presence of a metal ion at their core, and their shallow active site groove allow for these enzymes to hydrolyze most beta-lactams but also to withstand all the available beta-lactamase inhibitors.

• MBLs’ ability to globally disseminate is mainly due to their presence on mobile genetic elements (MGE), allowing them to spread within various bacteria, as well as the ability of MBL-producing organisms to establish an environmental reservoir and be carried asymptomatically by healthy hosts. A One Health approach is crucial to control the emergence and spread of MBL-carrying organisms.

• The development of metallo-beta-lactamase inhibitors (MBLI) is faced with multiple challenges. These include their structural diversity complicating designing a broad-spectrum MBLI for all B1 subclass of MBL, with taniborbactam and its low efficacy against IMP illustrating this. Their ubiquity and diverse functions possibly pose a risk of toxicity to humans.

• The decision to treat a patient with a positive culture for an MBL-producing organism depends on the site of the collected sample, the clinical scenario and the immune status of the host as treating solely based on a positive culture exposes the patient to drug toxicity, adverse events and emerging resistance.

• Ceftazidime avibactam and aztreonam in combination were found to be effective against MBL-producing Enterobacterales. This combination, however, has proved to be much less effective against MBL-producing P. aeruginosa and A. baumannii due to intrinsic resistance mechanisms.

Declaration of interest

S.S. Kanj receives honoraria as a speaker and an advisory board member in activities of Pfizer, Menarini, and MSD.

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

This paper was not funded.