Molecular Biotechnolgy of Fungal beta-Lactam Antibiotics and Related Peptide Synthetases: -/-

290 Pages·2004·3.72 MB·English

by  Esther K. Schmitt

88
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Preface
Preface
The concept ofone microorganism killing another was introduced by Pasteur
who coined the term antibiosis in 1877,but it was much later that this concept
was realised in the form of an actual antibiotic.In 1929,the microbiologist
Alexander Fleming published his observation about the inhibition ofthe gro-
wth ofStaphylococcus aureuson an agar plate contaminated with Penicillium
notatum.Three years later,it was shown that the growth inhibition was due to
penicillin.The work was taken up further at Oxford University by pathologist
Howard Florey and biochemist Ernst Chain.The first clinical trials with peni-
cillin were undertaken in 1941.During the late 1940s the fungus Cephalospo-
rium acremonium (now renamed Acremonium chrysogenum) was isolated
from the sea at Cagliari (Italy) by Guiseppi Brotzu.This fungus was found to
produce a b-lactam compound designated cephalosporin. The discovery of
antibiotics for clinical use started with a b-lactam compound and is perhaps
the most important discovery in the history of therapeutic medicine. The
application ofantibiotics to the therapy ofinfectious diseases may conceivab-
ly have saved more lives than any other medical therapy.The success ofb-lac-
tams in the treatment ofinfectious disease is due to their high specificity and
their low toxicity.Despite a growing number ofantibiotics and the incidence
of penicillin-resistant isolates,b-lactams are still by far the most frequently
used antibiotic.
In this volume,it was my aim to get together leading scientists in the area of
research on fungal b-lactam antibiotics who cover the most recent develop-
ments in all areas ofresearch on this important group ofcompounds.Both the
economic aspects and the industrial production offungal b-lactam antibiotics
are summarised in the chapter by Barber et al.
Because fungal b-lactam antibiotics are of great clinical importance, the
biochemistry and genetics of their biosyntheses are well elucidated which is
summarised in several chapters in this book.From an academic point ofview
the analysis of the regulation of b-lactam biosynthesis represents the most
advanced system for elucidating the regulation ofa fungal secondary metabo-
lism gene cluster.Furthermore,with regard to applied aspects,this knowledge
is ofgreat value to strategies for increasing production levels by the use ofgene
regulators. Because penicillin and cephalosporin are produced by different
fungi and differ in the later steps ofthe biosynthesis,the regulation ofpenicil-
X Preface
lin biosynthesis is described by Brakhage et al.and that ofcephalosporin bio-
synthesis by Schmitt et al.Data presented in these chapters show that we are
far from having a complete picture of the regulation of fungal b-lactam bio-
syntheses.Within the last few years,several studies have indicated that the fun-
gal b-lactam biosynthesis genes are controlled by a complex regulatory net-
work.A comparison with the regulatory mechanisms (regulatory proteins and
DNA elements) involved in the regulation ofgenes ofprimary metabolism in
lower eukaryotes is thus of great interest. Furthermore, such investigations
have contributed to the elucidation of signals leading to the production of
b-lactams,their physiological meaning for the producing fungi and can be
expected to have a major impact on rational strain improvement programs.
Recently,the knowledge ofthe whole cephalosporin biosynthesis was comple-
ted by cloning and characterisation of the missing isopenicillin N epimerase
system which is reported by Martin et al.
Investigations in recent years have shown that the various steps of b-lactam
biosynthesis occur in different compartments.This finding is important not only
for academic reasons but also for strategies to produce new compounds by meta-
bolic engineering.Therefore,the current knowledge is reviewed by Evers et al.
A major aspect of all biotechnological processes concerns their metabolic
basis which,for antibiotics, includes the control offluxes towards antibiotics
and the role ofprimary metabolism in production ofantibiotics.This impor-
tant area is covered by the chapter by Gunnarsson et al.
Among the constant challenges in managing bacterial infections are the
outbreak of new infectious diseases and the evolution of known commensal
and pathogenic bacteria to problem status by acquisition of new resistant
determinants. Therefore, there is increasing pressure to provide more and
superior antibiotics.A promising approach to identifying novel compounds is
based on combinatorial biosynthesis. Because the biosynthesis of b-lactam
antibiotics involves a non-ribosomal peptide synthetase (NRPS) which is rat-
her well characterised,this NRPS represents a good starting point for combi-
natorial biosynthesis offungal compounds.In addition to the biochemistry of
b-lactam biosynthesis,this aspect is discussed in detail in the chapter by Hans
von Döhren.
Because this book covers the current knowledge ofall main aspects offun-
gal b-lactam antibiotics,I hope it will be a useful reference source for both
applied investigators and basic research scientists.
I am deeply indebted to the authors ofthe chapters in this volume for their
intelligent and diligent efforts which made this joint project possible.The care
and energy with which they approached this work are gratefully acknowled-
ged.I thank the series editor Thomas Scheper for his enthusiasm for preparing
this volume and for his excellent scientific co-operation.The editorial and pro-
duction staff of Springer Verlag are gratefully acknowledged for the fruitful
and professional collaboration.
Hannover,August 2004 Axel A.Brakhage