Alternative enzymatic pathways to penicillin
antibiotics
antibiotics
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
The discovery of penicillin, more than a century ago, has been one of the most significant advances in medicine. Despite the growing threat of antimicrobial resistance, which has rendered many other antibiotics ineffective, penicillin derivatives remain among the most widely prescribed antibiotics. Penicillin is biosynthesised by a large nonribosomal peptide synthetase (NRPS) enzyme, which assembles a tripeptide precursor ACV. This intermediate is subsequently cyclised by isopenicillin N synthase (IPNS) to form penicillin. ACV is similar in structure to glutathione, a ubiquitous, tripeptide antioxidant essential for aerobic life forms. Unlike ACV, glutathione is assembled using simpler ligase enzymes rather than complex NRPS machinery. In this paper, we describe an alternative pathway to penicillins that uses stand-alone ligase and epimerase enzymes to generate peptide precursors, which can be transformed to penicillin derivatives using an engineered IPNS enzyme. Unlike the native NRPS assembly line, the ligase pathway provides direct access to therapeutically relevant penicillin G, penicillin V and ampicillin, which are currently produced by semi-synthesis.
Date Issued
2026-04-30
Date Acceptance
2026-04-15
Citation
Nature Communications, 2026, 17
ISSN
2041-1723
Publisher
Nature Portfolio
Journal / Book Title
Nature Communications
Volume
17
Copyright Statement
©The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
10.1038/s41467-026-72466-w
Subjects
Saha
P.
Xu
G.
Panda
D. et al. Alternative enzymatic pathways to penicillin antibiotics. Nat Commun (2026)
Publication Status
Published
Article Number
5891
Date Publish Online
2026-04-30