β-Lactam antibiotics and β-lactamases: historical perspectives and a review of β-lactamase inhibitors derived from natural products

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Nat. Prod. Rep., 2026, Advance ArticleDOI: 10.1039/D5NP00081E, Review Article Open Access &nbsp This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.Phanankosi Moyo, Ikhane O. Albert, Neo Hlungwani, Thulani Sibanda,…

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β-Lactam antibiotics and β-lactamases: historical perspectives and a review of β-lactamase inhibitors derived from natural products

* Corresponding authors

a Department of Plant and Soil Sciences, Faculty of Natural and Agricultural Sciences, University of Pretoria, Pretoria, Gauteng, South Africa

b Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Hatfield, South Africa

c Biodiscovery Centre, Department of Chemistry, University of Pretoria, Pretoria 0028, South Africa
E-mail: [email protected]
Tel: +27 824665466

d Department of Biology, National University of Lesotho, Maseru, Lesotho

e Chemistry Research Laboratory, Department of Chemistry, The Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK

f Sir William Dunn School of Pathology, The Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK

g University of North-Texas Health at Fort Worth, USA

h Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, PMB, Kumasi, Ghana

i Phytomedicine Programme, Department of Paraclinical Sciences, Faculty of Veterinary Science, University of Pretoria, Private Bag X04, Onderstepoort, Pretoria 0110, South Africa

Abstract

Covering: up to the end of November 2025

The history of β-lactam antibiotics and, subsequently, β-lactamase inhibitors highlight the indispensable role of natural products in modern medicine. The isolation and testing of β-lactam bearing natural products led to world-changing therapeutic breakthroughs, yielding efficacious, safe, and cost-effective medicines that are still widely used today. The scientific triumph of β-lactams was, however, followed by a period of reduced research into new antibiotics, during which time bacterial pathogens acquired multiple mechanisms of resistance. The available evidence suggests that this situation is not irretrievable – whereas insufficient medicinal chemistry is currently being carried out to enable a renaissance in antibiotic development, our molecular understanding of antimicrobial modes of action and resistance mechanisms has improved dramatically. The history of β-lactams and many other drug classes suggests that natural product-based approaches will be critical in the future. Here, we summarise the history of β-lactams, focusing on natural product science. We then examine historical and recent efforts to identify new types of β-lactamase inhibitors using natural product-based screening approaches. We conclude by providing a perspective on how we can most efficiently discover β-lactamase inhibitors from microbial and plant-derived natural products.