Recommendations to Synthetize Old and New β-Lactamases Inhibitors: A Review to Encourage Further Production

Abstract

The increasing emergence of bacteria producing β-lactamases enzymes (BLEs), able to inactivate the available β-lactam antibiotics (BLAs), causing the hydrolytic opening of their β-lactam ring, is one of the global major warnings. According to Ambler classification, BLEs are grouped in serine-BLEs (SBLEs) of class A, C, and D, and metal-BLEs (MBLEs) of class B. A current strategy to restore no longer functioning BLAs consists of associating them to β-lactamase enzymes inhibitors (BLEsIs), which, interacting with BLEs, prevent them hydrolyzing to the associated antibiotic. Worryingly, the inhibitors that are clinically approved are very few and inhibit only most of class A and C SBLEs, leaving several class D and all MBLEs of class B untouched. Numerous non-clinically approved new molecules are in development, which have shown broad and ultra-broad spectrum of action, some of them also being active on the New Delhi metal-β-lactamase-1 (NDM-1), which can hydrolyze all available BLAs except for aztreonam. To not duplicate the existing review concerning this topic, we have herein examined BLEsIs by a chemistry approach. To this end, we have reviewed both the long-established synthesis adopted to prepare the old BLEsIs, those proposed to achieve the BLEsIs that are newly approved, and those recently reported to prepare the most relevant molecules yet in development, which have shown high potency, providing for each synthesis the related reaction scheme.

Antimicrobial Peptides and Cationic Nanoparticles: A Broad-Spectrum Weapon to Fight Multi-Drug Resistance Not Only in Bacteria

“…Antibiotic adjuvants have been developed and used in therapy to restore the activity of existing drugs no longer functioning, such as, for example, the β-lactamase inhibitors, including clavulanic acid, β-lactam-like sulfones (sulbactam and tazobactam), diazabicyclooctanes (avibactam and relebactam) and boronic acids (vaborbactam) [ 19 ]. In fact, unfortunately, the appearance of new variants of β-lactamase enzymes and the emergence and spread of the ultra-broad-spectrum metallo-β-lactamases of class B dramatically reduce the effectiveness of this strategy [ 19 ]. Other approaches to overcome MDR include the use of inhibitors of drug efflux pumps and outer membrane permeabilizers able to promote antibiotic uptake and to improve their concentration at target sites [ 20 , 21 ], as well as the employment of membrane disruptor molecules.…”

Potent and Broad-Spectrum Bactericidal Activity of a Nanotechnologically Manipulated Novel Pyrazole

“…Furthermore, CR232-G5K NPs showed very low MIC values against a MDR strain of P. aeruginosa isolated from a cystic fibrosis patient (MIC = 0.72 µM), against both a MDR strain of P. aeruginosa and a strain of KPCs-producing K. pneumoniae that are also resistant to colistin (MICs = 0.72 µM), and against a strain of MDR P. aeruginosa that is also resistant to the avibactam-ceftazidime combination (MIC = 2.89 µM) clinically used to counteract bacterial resistance to carbapenems [27]. The activity of CR232-G5K NPs against these particularly drug-resistant strains of P. aeruginosa and K. pneumoniae is particularly relevant considering that these pathogens represent frightening superbugs responsible for severe nosocomial infections associated with dramatic outcomes [17].…”

Correction: Alfei, S.; Zuccari, G. Recommendations to Synthetize Old and New β-Lactamases Inhibitors: A Review to Encourage Further Production. Pharmaceuticals 2022, 15, 384

“…In the original publication [ 1 ], there were two mistakes in Table 3 as published. In the chemical structure of ANT-3310 (column 2, row 16) the NO bond was not clearly visible, and in the chemical structure of ANT-2681 (column 2, row 22), an amide functionality, was linked to the thiazole ring in place of an acid one.…”