Molecular Basis of Bicyclic Boronate β-Lactamase Inhibitors of Ultrabroad Efficacy – Insights From Molecular Dynamics Simulation Studies

Abstract

β-Lactam antibiotics represent about 70% of all antibacterial agents in clinical use. They are safe and highly effective drugs that have been used for more than 50 years, and, in general, well tolerated by most patients. However, its usefulness has been dramatically reduced with the spread and dissemination worldwide of multi-drug resistant bacteria. These pathogens elude the therapeutic action of these antibiotics by expressing β-lactamase enzymes that catalyze the hydrolysis of their β-lactam ring to give inactive products, which is one of the most relevant resistance mechanisms in deadly pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae. From the drug development point of view, the design of an efficient β-lactamase inhibitor able to block this antibiotic resistance mechanism and restore β-lactam antibiotics efficacy is challenging. This is due to: (1) the huge structural diversity of these enzymes in both the amino acid sequence and architecture of the active site; (2) the distinct hydrolytic capability against different types of substrates; (3) the variety of enzyme mechanisms of action employed, either involving covalent catalyzed processes (serine hydrolases) or non-covalent catalysis (zinc-dependent hydrolases); and (4) the increasing emergence and spread of bacterial pathogens capable of simultaneously producing diverse β-lactamases. Hence, a long-pursued goal has been the development of ultrabroad-spectrum inhibitors able to inhibit both serine- and metallo-β-lactamases. The recent development of taniborbactam (formerly VNRX-5133) and QPX7728, which are bicyclic boronate inhibitors currently under clinical development, represents a huge step forward in this goal. In this article, the molecular basis of the ultrabroad-spectrum of activity of these boron-based inhibitors is analyzed by molecular dynamics simulation studies using the available crystal structures in complex with both inhibitors, or the models constructed from wild-type forms. The efficacy of taniborbactam and QPX7728 is compared with the cyclic boronate inhibitor vaborbactam, which is the first boron-based β-lactamase inhibitor approved by the FDA in combination with meropenem for the treatment of complicated urinary tract infections.

Structure and Mechanism-Guided Design of Dual Serine/Metallo-Carbapenemase Inhibitors

“…β-Lactam antibiotics in combination with β-lactamase inhibitors have been demonstrated as a clinically effective strategy to overcome β-lactamase-mediated resistance. − Three therapeutically important β-lactam β-lactamase inhibitors, namely, clavulanic acid, tazobactam, and sulbactam, effectively inhibit certain class A SβLs but are mostly inactive against KPC- and OXA-type serine carbapenemases and all metallo-carbapenemases (e.g., NDM-, IMP-, and VIM-type). , These first-generation β-lactamase inhibitors are themselves β-lactams and have driven the rapid evolution of resistance to these structurally similar compounds, for example, through the acquisition of mutations rendering β-lactamases insensitive to these inhibitors. , Recently, the clinical introduction of the diazabicyclooctane (DBO), non-β-lactam-based inhibitors avibactam and relebactam was an important step due to their broad-spectrum inhibition of KPC-type and certain class D OXA-type enzymes . Very recently (2017), vaborbactam (VAB), the first boron-based SβL inhibitor, was approved for use with Meropenem for treating complicated urinary tract infections and pyelonephritis .…”

“…42,43 These first-generation β-lactamase inhibitors are themselves β-lactams and have driven the rapid evolution of resistance to these structurally similar compounds, for example, through the acquisition of mutations rendering β-lactamases insensitive to these inhibitors. 44,45 Recently, the clinical introduction of the diazabicyclooctane (DBO), non-β-lactambased inhibitors avibactam and relebactam was an important step due to their broad-spectrum inhibition of KPC-type and certain class D OXA-type enzymes. 46 Very recently (2017), vaborbactam (VAB), the first boron-based SβL inhibitor, was approved for use with Meropenem for treating complicated urinary tract infections and pyelonephritis.…”

“…34,51,52 The continuous emergence and dissemination of MDR Gram-negative pathogens with acquired serine and metallo-carbapenemase genes has led to an urgent need for the development of broad-spectrum, dual-action inhibitors to conquer carbapenem resistance. 44,53,54 Many review articles about β-lactamases, including carbapenemases, as well as about β-lactamase inhibitors have been published previously. 55−57 This Perspective focuses on inhibitors that deactivate the most prevalent mechanism of antibiotic resistance in Gram-negative opportunistic pathogens, for example, carbapenemases, and specifically, both serine and metallo-carbapenemases simultaneously.…”

In Vitro Activity of Two Cefepime-Based Novel Combinations, Cefepime/Taniborbactam and Cefepime/Zidebactam, against Carbapenemase-Expressing Enterobacterales Collected in India

“…Among the licensed novel β-lactamase inhibitors, avibactam and relebactam are based on the diazabicyclooctane (DBO) pharmacophore; avibactam inhibits Ambler class A, C, and some D enzymes and relebactam inhibits class A and C enzymes, while both lack MBL-inhibitory activity ( 11 ). Vaborbactam, a boronate-based inhibitor with an inhibitory spectrum akin to that of relebactam, also lacks MBL inhibition ( 12 ); however, the structural changes in this pharmacophore have led to newer boronates with an extended β-lactamase-inhibitory spectrum ( 13 ). In this series of β-lactamase inhibitors, taniborbactam is shown to inhibit all four Ambler class A, B, C, and D enzymes (except IMP), and its combination with cefepime has recently completed a registrational phase 3 trial for the indication of complicated urinary tract infection (cUTI) or acute pyelonephritis (AP) in adults ( 14 , 15 ).…”