Applied Microbiology and Biotechnology

, Volume 100, Issue 9, pp 3825–3839 | Cite as

A breakthrough in enzyme technology to fight penicillin resistance—industrial application of penicillin amidase

  • Klaus Buchholz


Enzymatic penicillin hydrolysis by penicillin amidase (also penicillin acylase, PA) represents a Landmark: the first industrially and economically highly important process using an immobilized biocatalyst. Resistance of infective bacteria to antibiotics had become a major topic of research and industrial activities. Solutions to this problem, the antibiotics resistance of infective microorganisms, required the search for new antibiotics, but also the development of derivatives, notably penicillin derivatives, that overcame resistance. An obvious route was to hydrolyse penicillin to 6-aminopenicillanic acid (6-APA), as a first step, for the introduction via chemical synthesis of various different side chains. Hydrolysis via chemical reaction sequences was tedious requiring large amounts of toxic chemicals, and they were cost intensive. Enzymatic hydrolysis using penicillin amidase represented a much more elegant route. The basis for such a solution was the development of techniques for enzyme immobilization, a highly difficult task with respect to industrial application. Two pioneer groups started to develop solutions to this problem in the late 1960s and 1970s: that of Günter Schmidt-Kastner at Bayer AG (Germany) and that of Malcolm Lilly of Imperial College London. Here, one example of this development, that at Bayer, will be presented in more detail since it illustrates well the achievement of a solution to the problems of industrial application of enzymatic processes, notably development of an immobilization method for penicillin amidase suitable for scale up to application in industrial reactors under economic conditions. A range of bottlenecks and technical problems of large-scale application had to be overcome. Data giving an inside view of this pioneer achievement in the early phase of the new field of biocatalysis are presented. The development finally resulted in a highly innovative and commercially important enzymatic process to produce 6-APA that created a new antibiotics industry and that opened the way for the establishment of over 100 industrial processes with immobilized biocatalysts worldwide today.


Immobilized enzymes Biocatalyst application Penicillin amidase Enzymatic penicillin hydrolysis Bioprocess development 



Valuable suggestions, corrections, and considerable improvement by Uwe Bornscheuer and John Collins are gratefully acknowledged.

Compliance with ethical standards

Conflict of interest

The author declares that he has no competing interests.

Human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.


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© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Institute for Chemical EngineeringTechnical University BraunschweigBraunschweigGermany

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