Antibacterial and ß-Lactamase Inhibitory Activity of Monocyclic ß-Lactams.

Due to the widespread emergence of resistant bacterial strains, an urgent need for the development of new antibacterial agents with novel modes of action has emerged. The discovery of naturally occurring monocyclic ß-lactams in the late 1970s, mainly active against aerobic Gram-negative bacteria, has introduced a new approach in the design and development of novel antibacterial ß-lactam agents. The main goal was the derivatization of the azetidin-2-one core in order to improve their antibacterial potency, broaden their spectrum of activity, and enhance their ß-lactamase stability. In that respect, our review covers the updates in the field of monocyclic ß-lactam antibiotics during the last three decades, taking into account an extensive collection of references. An overview of the relationships between the structural features of these monocyclic ß-lactams, classified according to their N-substituent, and the associated antibacterial or ß-lactamase inhibitory activities is provided. The different paragraphs disclose a number of well-established classes of compounds, such as monobactams, monosulfactams, monocarbams, monophosphams, nocardicins, as well as other known representative classes. Moreover, this review draws attention to some less common but, nevertheless, possibly important types of monocyclic ß-lactams and concludes by highlighting the recent developments on siderophore-conjugated classes of monocyclic ß-lactams.

Mechanisms of hepatotoxicity associated with the monocyclic ß-lactam antibiotic BAL30072.

BAL30072 is a new monocyclic ß-lactam antibiotic under development which provides a therapeutic option for the treatment of severe infections caused by multi-drug-resistant Gram-negative bacteria. Despite the absence of liver toxicity in preclinical studies in rats and marmosets and in single dose clinical studies in humans, increased transaminase activities were observed in healthy subjects in multiple-dose clinical studies. We, therefore, initiated a comprehensive program to find out the mechanisms leading to hepatocellular injury using HepG2 cells (human hepatocellular carcinoma cell line), HepaRG cells (inducible hepatocytes derived from a human hepatic progenitor cell line), and human liver microtissue preparations. Our investigations demonstrated a concentration- and time-dependent reduction of the ATP content of BAL30072-treated HepG2 cells and liver microtissues. BAL30072 impaired oxygen consumption by HepG2 cells at clinically relevant concentrations, inhibited complexes II and III of the mitochondrial electron transport chain, increased the production of reactive oxygen species (ROS), and reduced the mitochondrial membrane potential. Furthermore, BAL 30072 impaired mitochondrial fatty acid metabolism, inhibited glycolysis, and was associated with hepatocyte apoptosis. Co-administration of N-acetyl-L-cysteine partially protected hepatocytes from BAL30072-mediated toxicity, underscoring the role of oxidative damage in the observed hepatocellular toxicity. In conclusion, BAL30072 is toxic for liver mitochondria and inhibits glycolysis at clinically relevant concentrations. Impaired hepatic mitochondrial function and inhibition of glycolysis can explain liver injury observed in human subjects receiving long-term treatment with this compound.

Conjugates of monocyclic ß-lactams and siderophore mimetics: a patent evaluation (WO2023023393).

INTRODUCTION: ß-Lactams, which include monobactams, remain the most important class of antibiotics worldwide. Aztreonam, the only monobactam in clinical use, has remarkable activity against many Gram-negative bacteria, but limited activity against some of the most problematic multidrug-resistant (MDR) pathogens, such as MDR Pseudomonas aeruginosa and Acinetobacter baumannii co-expressing extended-spectrum- and metallo-ß-lactamases, which can inactivate aztreonam by hydrolysis. AREAS COVERED: Structurally novel siderophore-conjugated aztreonam derivatives with improved antibacterial properties against several high-priority pathogens are claimed. This invention reports that sidechain extension of aztreonam is tolerated; the coupling of its aminothiazoloxime carboxylic acid part with a siderophore mimetic significantly improved the antibacterial activity against several problematic strains, including MDR A. baumannii isolates with carbapenemase/cephalosporinase activity. EXPERT OPINION: Finding new strategies to tackle bacterial resistance to ß-lactam antibiotics is critical. Considering that ß lactams are validated and safe drugs, this research may stimulate the field to develop new ideas in the arena of antimicrobial drug discovery, particularly with respect to siderophore mimetics.