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

The contribution of fungi to the global economy

“…Since then, in total five generations of cephalosporin-derived antibiotics were developed, further improving upon its selectivity against drug resistant bacteria (Lin and Kück 2022). Among the indications are skin infections, with and without multi drug resistant bacteria and meningitis, to name a few (Lin and Kück 2022). The global cephalosporin market size First generation cephalosporins are commonly used to manage skin and soft tissue infections caused by susceptible strains of Staphylococcus aureus and group A Streptococcus.…”

“…The global cephalosporin market size First generation cephalosporins are commonly used to manage skin and soft tissue infections caused by susceptible strains of Staphylococcus aureus and group A Streptococcus. Those include cefazolin, a parenteral formulation, and cephalexin, an oral equivalent, among others (Lin and Kück 2022).…”

“…Second generation cephalosporins have a better performance against Gram-negative bacterial infections than the first-generation derivatives and are used to treat urinary and tract infections, and skin and soft tissue infections. A variety of orally administered second-generation agents (cefaclor, cefprozil, loracarbef, cefpodoxime) are commonly used in the outpatient management of sinopulmonary infections and otitis media (Lin and Kück 2022).…”

“…Third generation cephalosporins are typically used for serious pediatric infections, including meningitis and sepsis (Lin and Kück 2022).…”

Oral third-generation cephalosporin cefpodoxime in the therapy of respiratory infections

“…Цефподоксим -полусинтетический цефалоспорин III поколения -был синтезирован еще в 1984 г. и достаточно широко применяется в различных странах мира для лечения респираторных и ряда других инфекций [2]. Цефподоксим входит в топ-5 препаратов, на долю которых приходится 90% всех цефалоспоринов, потребляемых населением в 28 странах Европейского Союза/ Европейской экономической зоны (ЕС/ЕЭЗ) по данным 2017 г., что также указывает на перспективы его применения в России [3]. Как и все бета-лактамные антибиотики, цефподоксим обладает бактерицидным действием за счет нарушения синтеза пептидогликана клеточной стенки бактерий, что приводит к нарушению роста и последующей гибели микробной клетки.…”