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

Abstract

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.