Novel β-lactamase inhibitors: a therapeutic hope against the scourge of multidrug resistance

Richard R Watkins,Robert A Bonomo,Krisztina M Papp-Wallace,Sarah M Drawz

doi:10.3389/fmicb.2013.00392

Abstract

The increasing incidence and prevalence of multi-drug resistance (MDR) among contemporary Gram-negative bacteria represents a significant threat to human health. Since their discovery, β-lactam antibiotics have been a major component of the armamentarium against these serious pathogens. Unfortunately, a wide range of β-lactamase enzymes have emerged that are capable of inactivating these powerful drugs. In the past 30 years, a major advancement in the battle against microbes has been the development of β-lactamase inhibitors, which restore the efficacy of β-lactam antibiotics (e.g., ampicillin/sulbactam, amoxicillin/clavulanate, ticarcillin/clavulanate, and piperacillin/tazobactam). Unfortunately, many newly discovered β-lactamases are not inactivated by currently available inhibitors. Is there hope? For the first time in many years, we can anticipate the development and introduction into clinical practice of novel inhibitors. Although these inhibitors may still not be effective for all β-lactamases, their introduction is still welcome. This review focuses on the novel β-lactamase inhibitors that are closest to being introduced in the clinic.

Highlights

The ongoing dissemination of multi-drug resistant (MDR) bacteria is a serious threat to global health
A major mechanism for antibiotic resistance among Gram-negative bacteria is the production of β-lactamases. β-lactamases are enzymes that inactivate β-lactam antibiotics by hydrolyzing the amide bond of the β-lactam ring. β-lactamases are bacterial resistance determinants that have been known for more than seventy years, yet the details of their evolution, dissemination and hydrolytic capacity still remains a great scientific challenge
Introduced more than thirty years ago, the Ambler classification system divides β-lactamases into four classes (A, B, C, and D) based on their amino acid sequences (Ambler, 1980)

Summary

Introduction

The ongoing dissemination of multi-drug resistant (MDR) bacteria is a serious threat to global health. Class A enzymes include both plasmid-mediated and chromosomally-encoded β-lactamases that demonstrate broadspectra (e.g., TEM-1 and SHV-1), extended-spectra (e.g., CTX-M15), and carbapenemase activity (e.g., KPC-2). This review will focus on recent data regarding the mechanisms of inhibition of these novel agents, their antimicrobial activity, and the progress in their clinical trials.

Results

Conclusion