β-Lactam Antibiotics and β-Lactamase Enzymes Inhibitors, Part 2: Our Limited Resources

beta-lactam antibiotics (BLAs) are crucial molecules among antibacterial drugs, but the increasing emergence of resistance to them, developed by bacteria producing beta-lactamase enzymes (BLEs), is becoming one of the major warnings to the global public health. Since only a small number of novel antibiotics are in development, a current clinical approach to limit this phenomenon consists of administering proper combinations of beta-lactam antibiotics (BLAs) and beta-lactamase inhibitors (BLEsIs). Unfortunately, while few clinically approved BLEsIs are capable of inhibiting most class-A and -C serine beta-lactamases (SBLEs) and some carbapenemases of class D, they are unable to inhibit most part of the carbapenem hydrolyzing enzymes of class D and the worrying metallo-beta-lactamases (MBLEs) of class B. Particularly, MBLEs are a set of enzymes that catalyzes the hydrolysis of a broad range of BLAs by a zinc-mediated mechanism, and currently no clinically available molecule capable of inhibiting MBLEs exists. Additionally, new types of alarming "superbugs", were found to produce the New Delhi metallo-beta-lactamases (NDMs) encoded by increasing variants of a plasmid-mediated gene capable of rapidly spreading among bacteria of the same species and even among different species. Particularly, NDM-1 possesses a flexible hydrolysis mechanism that inactivates all BLAs, except for aztreonam. The present review provides first an overview of existing BLAs and the most clinically relevant BLEs detected so far. Then, the BLEsIs and their most common associations with BLAs already clinically applied and those still in development are reviewed.