Antibacterial and β‐Lactamase Inhibitory Activity of Monocyclic β‐Lactams

Abstract

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 β-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 β-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 β-lactamase stability. In that respect, our review covers the updates in the field of monocyclic β-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 β-lactams, classified according to their N-substituent, and the associated antibacterial or β-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 β-lactams and concludes by highlighting the recent developments on siderophore-conjugated classes of monocyclic β-lactams.

In Silico Design and Enantioselective Synthesis of Functionalized Monocyclic 3‐Amino‐1‐carboxymethyl‐β‐lactams as Inhibitors of Penicillin‐Binding Proteins of Resistant Bacteria

“…The pharmacophore consisted of i) a 4‐unsubstituted 3‐amino‐1‐carboxymethyl‐β‐lactam nucleus, securing the limited size of the core skeleton and mimicking the natural substrate of the PBPs, d ‐alanyl‐ d ‐alanine; the carboxylic acid moiety enables crucial molecular interactions with the enzyme's active site and the possibility to form a destabilizing and thus activating hydrogen bond with the β‐lactam carbonyl group, which can, in a second stage, stabilize the ring‐opened azetidin‐2‐one after acylation of the active site serine residue, as was postulated by Dobrowolski et al. ; ii) a renowned 2‐(5‐amino‐1,2,4‐thiadiazol‐3‐yl)‐2‐(hydroxyimino)acetamido substituent linked to the β‐lactam C3‐position (this element will eventually be replaced by a similar 2‐(2‐aminothiazol‐4‐yl)‐2‐(methoxyimino)acetamido group for synthetic reasons); and finally, iii) a side chain “R”, a variable item in our combinatorial library which was carefully examined during the subsequent virtual screening process. Following further fine filtering and conformer generation, the resulting dataset was available for ligand‐based drug design.…”

“…Indeed, as we demonstrated recently via a three‐decade literature overview concerning the structure–activity relationships of diverse classes of monocyclic β‐lactams (e.g. monobactams 3 ), β‐lactams do not require a conformationally constrained bicyclic scaffold to exert their antibacterial properties, suggesting that a suitably functionalized azetidin‐2‐one ring constitutes an adequate pharmacophore . A milestone achievement in the quest for monocyclic β‐lactam inhibitors involved the development of aztreonam 4 , the first, and so far only, synthetic monobactam approved by the FDA in 1986 .…”

“…Originally, they possessed only limited antibacterial activity and required chemical modifications to increase their bioactive potential . Still, however, this class of monocyclic β‐lactams did not receive that much attention . In that respect, the promising potential of the nocardicins, combined with the clinical success of aztreonam 4 , prompted us to pursue the development of novel monocyclic 3‐amino‐1‐carboxymethyl‐β‐lactam analogues with possibly enhanced biological activities.…”

α‐Unsaturated 3‐Amino‐1‐carboxymethyl‐β‐lactams as Bacterial PBP Inhibitors: Synthesis and Biochemical Assessment

“…Our recent preliminary work focused on the in silico design of new 3‐amino‐1‐carboxymethyl‐β‐lactams as direct d ‐Ala‐ d ‐Ala mimetics . Taking into account the recently reviewed knowledge on monocyclic β‐lactam antibacterials, and combining the structural properties of aztreonam 3 (the only FDA‐approved monobactam), the nocardicins 4 (natural monocyclic β‐lactams) and late‐generation cephalosporins 2 (e.g., ceftobiprole), a new pharmacophore 5 was designed and studied (Figure ). It consisted of i .…”

“…a. 3‐Amino‐1‐carboxymethyl‐β‐lactam nucleus, mimicking the natural PBP substrate, d ‐alanyl‐ d ‐alanine, and enabling crucial molecular interactions with the enzyme's active site; b. Optimised 2‐(2‐aminothiazol‐4‐yl)‐2‐(methoxyimino)acetamido substituent; c. Variable side chain based on virtual screening, embedding a lipophilic linker and terminal hydrogen bond‐donating or ‐accepting functionalities, enabling additional non‐covalent interactions with the key residues in the enzyme's active site. B.…”