Thus, until today, more than 7000 β-lactamases have been identified that are classified based on their amino acid sequence in four major classes, A–D ( Naas et al., 2017). The challenges in the design and development of new inhibitors of β-lactamase enzymes is their enormous diversity and continuous evolution. However, the increasing emergence and spread worldwide of evolved pathogens harboring more challenging and sophisticated new β-lactamases enzymes for which these combinations failed, has triggered an intense search in the last years for alternative inhibitors and combinations, which mainly has been carried out by biotechnology companies ( Wright, 2016 Melander and Melander, 2017 Douafer et al., 2019 Hernando-Amado et al., 2019 González-Bello et al., 2020). Good examples are the widely used combination therapies, amoxycillin/clavulanic acid (approved 1984), ampicillin/sulbactam (approved 1986), and piperacillin/tazobactam (approved 1993). To reduce the impact of β-lactamase producing bacteria and restore β-lactam antibiotics efficacy, the use of a β-lactamase inhibitor in combination with the antibiotic has proven to be very successful strategy ( Tyers and Wright, 2019). These pathogens are resistant to carbapenems, which are often considered as antibiotic of last resort, and are linked with the most dangerous healthcare-associated infections, specially on patients with a compromised immune system. This deactivation mechanism represents the most prevalent cause of bacterial resistance to antibiotics in Gram-negative bacteria, in particular in the antibiotic-resistant “priority pathogens” identified by the World Health Organization (WHO) Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae. These enzymes hydrolyze their β-lactam ring to produce products that are inactive against their therapeutic target ( Baren and Bradford, 2019, 2020). The clinical utility of β-lactam antibiotics (penicillins, cephalosporins, monobactams, and carbapenems), which represent about 70% of all antibacterial drugs, is currently threatened by the worldwide proliferation and dissemination of bacteria producing β-lactamases. 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. 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 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.
Hence, a long-pursued goal has been the development of ultrabroad-spectrum inhibitors able to inhibit both serine- and metallo-β-lactamases. 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. 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. 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.
However, its usefulness has been dramatically reduced with the spread and dissemination worldwide of multi-drug resistant bacteria. They are safe and highly effective drugs that have been used for more than 50 years, and, in general, well tolerated by most patients. Β-Lactam antibiotics represent about 70% of all antibacterial agents in clinical use.
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