Convergent biosynthetic pathways to β-lactam antibiotics

Abstract

Five naturally-occurring β-lactams have inspired a class of drugs that constitute >60% of the antimicrobials used in human medicine. Their biosynthetic pathways reveal highly individualized synthetic strategies that yet converge on a common azetidinone ring assembled in structural contexts that confer selective binding and inhibition of D,D-transpeptidases that play essential roles in bacterial cell wall (peptidoglycan) biosynthesis. These enzymes belong to a single “clan” of evolutionarily distinct serine hydrolases whose active site geometry and mechanism of action is specifically matched by these antibiotics for inactivation that is kinetically competitive with their native function. Unusual enzyme-mediated reactions and catalytic multitasking in these pathways are discussed with particular attention to the diverse ways the β-lactam itself is generated, and more broadly how the intrinsic reactivity of this core structural element is modulated in natural systems through the introduction of ring strain and electronic effects.

Roles of 2-oxoglutarate oxygenases and isopenicillin N synthase in β-lactam biosynthesis

“…Biosynthetic studies of the carbapenems have primarily focused on the simplest carbapenem, (5 R )-carbapen-2-em-3-carboxylic acid, and the more structurally complex and potent antibiotic thienamycin. 4 , 11 , 13 The biosynthetic pathways to these two carbapenems may initially follow a common pathway, but diverge in later steps involving the desaturation and epimerisation of the five-membered ring, as well as the functionalisation at C-2 and C-6 as present in thienamycin. 4 , 11 , 13 , 156 , 157 …”

“…3 ). 4 , 8 , 13 , 16 , 22 These β-lactam synthetases catalyse formation of the β-lactam ring from appropriate β-amino acid precursors, i.e. in effect they catalyse the reverse of β-lactamase catalysis ( Fig.…”

“…Thus, in these pathways, 2OG oxygenases play roles both in forming a bicyclic β-lactam ring system (clavams) and in modifying a bicyclic β-lactam ring system (carbapenems) to create antibacterials. 4 , 8 , 13 , 16 , 18 – 22 …”

Promiscuous Enzyme Activity as a Driver of Allo and Iso Convergent Evolution, Lessons from the β-Lactamases

“…Four of them block the DD-peptidase: carbapenems, penicillin/cephalosporin, monocyclic β-lactams, and sulfazecin/monobactam. These families are synthesized by different biosynthetic pathways [ 31 ] and therefore evolved via allo-convergent evolution. It is possible that the β-lactamase activity evolved many times (from promiscuous activity) in response to one of these β-lactams synthesis pathways.…”

Monobactam formation in sulfazecin by a nonribosomal peptide synthetase thioesterase

“…The monobactams, however, having structurally distinct N -sulfonated β-lactam rings, are poor substrates for these metalloproteins, yet remain active against bacterial cell wall biosynthesis. We describe here the biosynthetic route to the monobactam sulfazecin, which is distinct from the three other known tactics in nature to generate β-lactam rings 4 .…”