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

Abstract

β-lactam antibiotics (BLAs) are crucial molecules among antibacterial drugs, but the increasing emergence of resistance to them, developed by bacteria producing β-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 β-lactam antibiotics (BLAs) and β-lactamase inhibitors (BLEsIs). Unfortunately, while few clinically approved BLEsIs are capable of inhibiting most class-A and -C serine β-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-β-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-β-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.

Enhanced Antibacterial Activity of a Cationic Macromolecule by Its Complexation with a Weakly Active Pyrazole Derivative

“…Concerning clinically approved molecules, bactericidal activity is possessed by ceftolozane, which is a pyrazole-containing recently synthesized broad spectrum fifth-generation semisynthetic cephalosporin. Being quite often inactivated by β-lactamase enzymes produced by several MDR bacteria, ceftolozane is administered in combination with tazobactam, a first generation β-lactamases inhibitor [ 18 ]. Unfortunately, while tazobactam is capable of preventing ceftolozane inactivation by serine-β-lactamases, it is not active against NDM-producing bacteria [ 18 ].…”

“…Unfortunately, while tazobactam is capable of preventing ceftolozane inactivation by serine-β-lactamases, it is not active against NDM-producing bacteria [18]. In this regard, this study describes instead the very powerful and very rapid bactericidal effects of a pyrazole-containing macromolecule, obtained from a pyrazole derivative with weak intrinsic antibacterial effects, on clinically relevant Gram-positive and Gram-negative MDR strains, also includ-ing an isolated producer of beta NDM, against which currently no antibiotic/inhibitor combination is clinically approved [18]. To date, as far as we know, except for CR232-G5K NPs that we have recently developed [22], no other pyrazole-containing macromolecule has been reported for its bactericidal effects.…”

“…Additionally, ceftolozane, which is a pyrazole-containing semi-synthetic, broad-spectrum, fifth-generation cephalosporin antibiotic is well known to possess bactericidal activity against certain Gram-negative and Gram-positive bacteria. Unfortunately, being inactivated by β-lactamase enzymes produced by several MDR bacteria, it is administered in combination with tazobactam, a β-lactamases inhibitor [ 17 , 18 ]. Regrettably, while tazobactam is capable to prevent ceftolozane inactivation by serine-type β-lactamases, it is unable to protect it from metallo-β-lactamases, thus establishing the inactivity of the ceftolozane/tazobactam combination against bacteria producing, for example, highly effective carbapenemases such as the New Delhi metallo-beta-lactamase (NDM) [ 17 ].…”

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

“…As far as DBOs are concerned, after the successful clinical introduction of avibactam and relebactam, several other derivatives of avibactam and relebactam are under clinical investigations in efforts to increase the spectrum of inhibition of this class of compounds [151,152]. In addition to DBOs, boronates are important motifs for the β-lactamase inhibition program which has furnished vaborbactam as second-generation non-β-lactambased BLI, and more cyclic boronates such as taniborbactam and QPX7728 are now in phase III and phase I clinical trials, respectively, against B1 MBLs [151][152][153]. The recently approved BLIs are effective against a large array of SBLs; however, they are not effective against MBLs.…”

“…In this regard, besides DBOs and cyclic boronates, several other motifs have been identified, and have been targeted towards the binding efficiency of those motifs with zinc ions of MBLs. These efforts have led to the introduction of ANT-2681, a thiazole carboxylate derivative, into the clinical trials in combination with diverse number of antibiotics [151]. In addition, a few classes of compounds have demonstrated cross-class inhibition ability against selected SBLs and MBLs.…”