Cephalosporins as key lead generation beta-lactam antibiotics

Abstract

Antibiotics are antibacterial compounds that interfere with bacterial growth, without harming the infected eukaryotic host. Among the clinical agents, beta-lactams play a major role in treating infected humans and animals. However, the ever-increasing antibiotic resistance crisis is forcing the pharmaceutical industry to search for new antibacterial drugs to combat a range of current and potential multi-resistant bacterial pathogens. In this review, we provide an overview of the development, innovation, and current status of therapeutic applications for beta-lactams with a focus on semi-synthetic cephalosporins. Cephalosporin C (CPC), which is a natural secondary metabolite from the filamentous fungus Acremonium chrysogenum, plays a major and demanding role in both producing modern antibiotics and developing new ones. CPC serves as a core compound for producing semi-synthetic cephalosporins that can control infections with different resistance mechanisms. We therefore summarize our latest knowledge about the CPC biosynthetic pathway and its regulation in the fungal host. Finally, we describe how CPC serves as a key lead generation source for the in vitro and better, in vivo synthesis of 7-aminocephalosporanic acid (7-ACA), the major core compound for the pharmaceutical synthesis of current and future semi-synthetic cephalosporins. KEY POINTS: • Latest literature on cephalosporin generations • Biotechnical production of cephalosporins • In vivo production of 7-ACA.

Keywords: 7-ACA; Antibiotic resistance; Bacterial acylase; Beta-lactam antibiotics; Cephalosporins; Key lead generation.

Fig. 1

The chemical structure of cefiderocol, a novel class of cephalosporins. 7-ACA, the core moiety to construct semi-synthetic cephalosporin antibiotics, is produced from CPC, followed by a series of chemical modifications to add functional groups on the 3′ and 7′ positions of the cephalosporin nucleus. The distinct and essential functional groups of cefiderocol are marked, and the roles contributing to its superior antibacterial activity are noted. Modified from Terreni et al. (2021)

Fig. 2

Cephalosporin C biosynthetic pathway in A. chrysogenum and the conversion products of each metabolite by cephalosporin C acylase. Biosynthetic enzymes are indicated in green, and their encoding genes are written in blue. The cephalosporin C acylase (CCA) protein structure was obtained from the Protein Data Bank entry: 1FM2 (Kim et al. 2000), modified based on Schmitt et al. (2004b)

Fig. 3

The conversion of cephalosporin C to 7-ACA. On the left the chemical process, and on the right the enzymatic manufacturing processes currently applied in the pharmaceutical industry. Achieving one-step bioconversion using cephalosporin C acylase (CCA) is the subject of this study, as highlighted in the middle. C-3 and C-7 are indicated in 7-ACA, the two carbon sites subjected to different side chain modifications to synthesize various cephalosporin antibiotics. At the top, the magenta arrow indicates the acyclic amide bond, and the orange arrow indicates the amide bond in the beta-lactam ring. Modified from Groeger et al. (2017)