Development of the semi-synthetic penicillins and cephalosporins

doi:10.1016/j.ijantimicag.2007.11.010

International Journal of Antimicrobial Agents

Volume 31, Issue 3, March 2008, Pages 189-192

https://doi.org/10.1016/j.ijantimicag.2007.11.010 Get rights and content

Abstract

Semi-synthetic penicillins and cephalosporins both derive from their respective chemical nuclei, 6-aminopenicillanic acid (6-APA) and 7-aminocephalosporanic acid (7-ACA). Work leading to their isolation was being carried out in parallel, but following very different pathways, during the last half of the 1950s. The development of 6-APA was reviewed recently in this journal, and in the present article I take a closer look at early work on ‘penicillin amidase’ and revisit the steps that led to 7-ACA.

Introduction

Living history, as illustrated in the recent review in this journal by Rolinson and Geddes [1] on the discovery of 6-aminopenicillanic acid (6-APA) 50 years ago, is inspirational. Thus, memories are turned into history. The modern generation of microbiologists and medical practitioners take antibiotics for granted, and it is salutary for them to be able to read at first hand of the ingenuity, insight and hard work that went into the birth of the semi-synthetic penicillins.

I am grateful for the opportunity to be able to add some further memories to this story, in which I have personal interests. Some 40 years ago I undertook a comprehensive review of penicillin acylase [2], having been initially confused by the fact that this enzyme was also being called penicillin amidase in the early literature. (I subsequently discovered that there was indeed a genuine penicillin amidase, whose substrate was penicillinamide.) Shortly afterwards I started a postdoctoral fellowship at The Sir William Dunn School of Pathology with Edward Abraham. The latter, with Guy Newton, had isolated 7-aminocephalosporanic acid (7-ACA) and thus followed a path parallel to that of the semi-synthetic penicillins, but, as will be shown below, going by an entirely different route.

Section snippets

Work in Japan during the 1950s

Rolinson & Geddes [1] in section 4 of their review discuss some of the early reports from Japan suggesting that “penicillin nucleus” or “penicin” could possibly have been 6APA. This discussion can be amplified somewhat by considering some other papers by the same authors published in the Japanese literature (with complete or partial translation) before the definitive Beechams paper on 6APA in 1959 [12]. These early papers were concerned solely with aspects of the industrial production of

Work at Oxford towards 7-ACA

The isolation of 6-APA by scientists at Beecham Laboratories, which actually occurred in the summer of 1957 [1] but was not reported in the literature until 2 years later [13], preceded 7-ACA, isolated in 1959 by Abraham at Oxford [14], reported 2 years later [15]. Abraham was first and foremost a peptide chemist, and an extraordinarily skilled one. He showed his prowess on two separate spectacular but largely unreported occasions, by being right when two of the greatest organic chemists of the

Conclusion

As with all great scientific discoveries, there are not only stars that shine brightly in the firmament but also a host of background lights. The production of 6-APA and 7-ACA required great scientific ingenuity and much hard work; there is sufficient reward to be shared by all—as Sir Almroth Wright commented [29] about the discovery of penicillin: Palmam qui meruit ferat [‘Let the credit be given to those who deserve it’].

Acknowledgments

I am very grateful to Dr John Jones, Balliol College, Oxford University, for sight of reference [16] prior to publication as well as other helpful communications; to David Evans, Senior Librarian at Hampstead Campus, The Royal Free & University College Medical School, for his help in obtaining various papers; and to Graham Arnot for a patent search.

Funding: No funding sources.

Competing interests: None declared.

Ethical approval: Not required.

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Correspondingly, about two-thirds of the commercial cephalosporins are derived from 7ACA by either chemical or enzymatic deacylation [22]. As an important intermediate of antibiotics, 7ACA shares the nucleus with numbers of antibiotics [17,19,20]. The top ten antibiotics binding well with the non-N-terminal domain of HSP90β using a Biacore T200, contained 4 cephalosporins.
Hepatic steatosis is one of the most important causes of liver disease worldwide. Heat shock protein 90 (HSP90) is essential for numerous client proteins. Recently, more attention was focused on increased HSP90 levels in hepatic steatosis, especially HSP90β. Thus, great efforts have been made to develop HSP90β inhibitors, and most natural inhibitors are derived from microorganisms. In this study, using microarray chips and surface pasmon resonance (SPR) technology, we screened 189 antibiotics in order to obtain an inhibitor directly binding to the non-N-terminal domain of HSP90β. Finally, we discovered an antibiotic, 7-aminocephalosporanic acid (7ACA), with a K_D value of 6.201 μM between 7ACA and non-N-terminal domain of HSP90β. Besides, 7ACA was predicted to interact with the middle domain (MD) of HSP90β. In HepG2 cells, we found that 7ACA reduced cellular total cholesterol (TC) and triglyceride (TG) by decreasing sterol regulatory element-binding proteins (SREBPs). In HFD fed mice, administration of 7ACA (5, 10, and 25 mg kg⁻¹ d⁻¹, ig, for 12 weeks) dose-dependently decreased serum TC and TG and played an important role in protecting liver and adipose tissue from lipid accumulation. In conclusion, our study demonstrated that antibiotic 7ACA, as an HSP90β middle domain inhibitor, was promising for the development of lipid-lowering drugs.
Biosynthesis of β-lactam nuclei in yeast
2022, Metabolic Engineering
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From the structural point of view, β-lactam antibiotics can be divided into several subclasses, in which penicillins and cephalosporins contribute the two major ones. Due to the continuing emergence of bacterial resistance, exploiting new semisynthetic antibiotics with enhanced effectiveness are pressingly demanded in the pharmaceutical industry (Oshiro, 1999; Hamilton-Miller, 2008). In particular, semi-synthetic β-lactams are derived from the core nuclei, inter alia, 6-aminopenicillanic acid (6-APA) for penicillins, and 7-aminocephalosporanic acid (7-ACA) as well as 7-amino deacetoxycephalosporanic acid (7-ADCA) for cephalosporins (Supplementary Fig. 1).
We have engineered brewer's yeast as a general platform for de novo synthesis of diverse β-lactam nuclei starting from simple sugars, thereby enabling ready access to a number of structurally different antibiotics of significant pharmaceutical importance. The biosynthesis of β-lactam nuclei has received much attention in recent years, while rational engineering of non-native antibiotics-producing microbes to produce β-lactam nuclei remains challenging. Benefited by the integration of heterologous biosynthetic pathways and rationally designed enzymes that catalyze hydrolysis and ring expansion reactions, we succeeded in constructing synthetic yeast cell factories which produce antibiotic cephalosporin C (CPC, 170.1 ± 4.9 μg/g DCW) and the downstream β-lactam nuclei, including 6-amino penicillanic acid (6-APA, 5.3 ± 0.2 mg/g DCW), 7-amino cephalosporanic acid (7-ACA, 6.2 ± 1.1 μg/g DCW) as well as 7-amino desacetoxy cephalosporanic acid (7-ADCA, 1.7 ± 0.1 mg/g DCW). This work established a Saccharomyces cerevisiae platform capable of synthesizing multiple β-lactam nuclei by combining natural and artificial enzymes, which serves as a metabolic tool to produce valuable β-lactam intermediates and new antibiotics.
β-lactam antibiotics to tame down molecular pathways of Alzheimer's disease
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β-lactam antibiotics have been reported to inhibit neuroinflammatory pathways, inhibit these proteins JNK and p38 MAPK at post synaptic neurons and offer neuroprotection in various experimental models (Nath et al., 2020; Nizzardo et al., 2011; Yimer et al., 2019). Amoxicillin (Mehla, 2017), ceftriaxone (Muri et al., 2019), and cefazolin (Hamilton-Miller, 2008) exhibit their anti-inflammatory effects by activating survival kinase pathways (CAMK-II, pCREB) and inhibits stress kinase pathways (JNK, p38-MAPK) at post synaptic neurons (Fig. 6). Thus β-lactam antibiotic helps in decreasing neuro-inflammatory stress by decreasing the microglial action and release of pro-inflammatory cytokines.
Alzheimer's disease is a multifactorial disorder characterized by extracellular accumulation of amyloid-β (Aβ) and intracellular accumulations of neurofibrillary tangles. Numerous drug targets have been explored for therapeutic efficacy but failed to deliver successful treatments clinically. However, over the years our understanding of the disease pathophysiology increased significantly. Many of the novel targets which can cure or modify disease pathology are being explored preclinically as well as clinically. On contrarily, the drug discovery and development process is lengthy and the cost involved makes it difficult for faster translation of therapeutic outcomes. Therefore, repurposing existing drugs for a new therapeutic indication is considered a better approach and helps in the fast translation of therapeutic information. The existing drugs have well-proven records on their safety, pharmacokinetics, etc. In recent years, beta (β)-lactam antibiotics have been repurposed for the management of neurodegenerative pathologies. Here in the current review, we have explored β-lactam antibiotics, their target sites, molecular mechanisms, and their therapeutic potential in Alzheimer's disease.
Occurrence of antimicrobial resistance bacteria in the Yodo River basin, Japan and determination of beta-lactamases producing bacteria
2017, Ecotoxicology and Environmental Safety
Citation Excerpt :
The remarkable success of infectious disease therapy through the creation of new antimicrobials over the past half century has simultaneously led to the emergence of antimicrobial resistance in bacteria. Most currently used antimicrobials are chemically semisynthetic modifications of various natural compounds (Hamilton-Miller, 2008). These include, for example, the beta-lactams, which consist of the penicillins, the monobactams, the cephalosporins (the cephems), and the carbapenems.
Antimicrobial resistant bacteria are widespread in aquatic environments. The aim of the present study was to obtain information on the occurrence of bacteria with antimicrobial resistance and their multiple antimicrobial resistance (MAR) patterns in a river basin in Japan. In addition, the occurrence of fecal bacteria producing extended-spectrum beta-lactamases (ESBLs) and metallo-beta-lactamase (MBL) in the aquatic environment was determined. Among the Escherichia coli isolates recovered from river samples upstream, 55% isolates were resistant to at least one antimicrobial and 18% were MAR. Among the E. coli isolates recovered from wastewater treatment plant (WWTP) effluent samples, 74% isolates were resistant to at least one antimicrobial and 46% were MAR. These findings suggest that the presence of WWTP effluent will increase the degree of contamination with MAR in the aquatic environment. Among the ampicillin-resistant isolates recovered from river samples, 21% isolates were judged as ESBL-producing and none (0%) was judged as MBL-producing. Among the ampicillin-resistant isolates recovered from WWTP effluent samples, 21% were judged as ESBL-producing and 1% was judged as MBL-producing. As for the hospital wastewater samples, 48% were judged as ESBL-producing and 3% were judged as MBL-producing. The percentage of ESBLs and MBL production was highest in hospital wastewater samples. All of the ESBL-producing isolates detected had resistance to ampicillin, cephazolin, and cefpodoxime and many ESBL-producers had resistance not only to beta-lactams but also to other kinds of antimicrobials such as aminoglycosides and quinolones. The frequency of detection of MBL-producers was much lower than that of ESBL-producers and MBL-producers were not detected in the river samples. However, the detection in WWTP effluent samples indicated that bacteria with MBL were present downstream of the WWTP at low concentrations. Thus, ESBLs and MBL have already been spread around aquatic environments.
Synthesis and antimicrobial activities of new higher amino acid Schiff base derivatives of 6-aminopenicillanic acid and 7-aminocephalosporanic acid
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Citation Excerpt :
Therefore, the research has been focused toward development of new and effective antimicrobial agents. After the isolation of penicillin nucleus, 6-aminopenicillanic acid (6-APA) in 1957 [5] and the synthesis of cephalosporin nucleus, 7-aminocephalosporanic acid (7-ACA) in 1962 [6], the way was open for the preparation of semisynthetic penicillins and cephalosporins [7]. Since that time, it has been great interest to synthesize new semisynthetic penicillins which having various groups, like as α-aryloxyalkanoic acids, isocyanates, N'-substituted-phthalic acids [8–12], glucose, maltose and lactose [13], imidazolidine derivatives [14], N-carbamyl [15], alkyl, alkenyl, cyclopropylmethyl groups [16], benzalimino-arylthio group [17], (D)-[(2-amino-2-carboxy)ethylthio]-acetamido group [18], methoxy or thioalkyl groups [19], 4-substituted-3-(4,4-dimethyloxazolin-2-yl)-1,4-dihidropyridylasetic acid [20], lipidic amino acid chains [21], para-hydroxy-phenylglycine methyl ester [22], d-phenylglycine methyl ester [23], ferrocenyl [24] in the 6-side chain of 6-APA.
Novel β-lactam derivatives (1c-3c) (1d-3d) were produced by using 6-aminopenicillanic acid (6-APA), 7-aminocephalosporanic acid (7-ACA) and the higher amino acid Schiff bases. The synthesized compounds were characterized by elemental analysis, IR, ¹H/¹³C NMR and UV–vis spectra. Antibacterial activities of all the higher amino acid Schiff bases (1a-3a) (1b-3b) and β-lactam derivatives were screened against three gram negative bacteria (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Acinetobacter baumannii RSKK 02026), three gram positive bacteria (Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 07005, Bacillus subtilis ATCC 6633) and their drug-resistant isolates by using broth microdilution method. Two fungi (Candida albicans and Candida krusei) were used for antifungal activity.
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CommentaryDevelopment of the semi-synthetic penicillins and cephalosporins

Abstract

Introduction

Section snippets

Work in Japan during the 1950s

Work at Oxford towards 7-ACA

Conclusion

Acknowledgments

Int J Antimicrob Agents

Penicillinacylase

Bacteriol Rev

A preliminary report on a new enzyme ‘penicillin-amidase’

J Agric Chem Soc Jpn

Occurrence of penicillin-nucleus in culture broths

J Antibiot Ser A

Further notes on penicillin-nucleus

J Antibiot Ser A

Studies on penicillin-amidase. Part 2. Research on conditions of producing penicillin-amidase

J Agric Chem Soc Jpn

Studies on penicillin-amidase. Part 3. Researches of penicillin-amidase. Mechanism on Na-penicillin G

J Agric Chem Soc Jpn

Degradation of penicillins to 6-aminopenicillanic acid by Penicillium chrysogenum

Bact Proc

Specificity of penicillin amidases

Proc Soc Exp Biol Med

Penicillin acylase activity of Penicillium chrysogenum

Appl Microbiol

β-Lactam antibiotics and related substances

Jpn J Antibiot

Oxford, Howard Florey and World War II

Synthesis of penicillin: 6-aminopenicillanic acid in penicillin fermentations

Nature

Commentary
Development of the semi-synthetic penicillins and cephalosporins