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Antibiotics. Actions Origins Resistance

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Actions, Origins,
By Christopher Walsh.
ASM Press, Washington DC 2003. 345 pp.,
hardcover $ 99.95.—
ISBN 1-55581-254-6
It is still less than 70 years since the first
antibiotics, the sulfonamides, were used
for the treatment of bacterial infections
in humans. Since then the discovery, in
rapid succession, of many other potent
classes of antibiotics has allowed us to
gain the confident impression that—at
least in developed countries, and for
patients with normal immune systems—most diseases caused by bacterial
infections can be cured. However,
recent reports about the spread of antibiotic-resistant strains and the appearance of pathogens with multiple resistance phenotypes demonstrate that the
certainty of controlling bacterial infections by means of antibiotics is a privilege that we must work at if we want it
to continue in the future. To search for
new classes of antibiotics that are effective against multiresistant bacterial
strains, we need a detailed understanding of the mechanisms of successful antibiotics, of the principles underlying the
development of resistant strains, and of
the origins of antibiotic agents.
Those three topic areas form the
basis for the structure of Christopher
Walsh's comprehensive survey of
recent literature on antibiotics. In the
first part of his book he describes the
mechanisms whereby the main established types of clinically successful antibiotics inhibit bacterial growth. Of the
Angew. Chem. Int. Ed. 2004, 43, 2879 – 2880
hundreds of compounds that are
known to show antibacterial activity,
only a few structural classes are effective
enough and therapeutically safe enough
for use in treating humans. If one considers the classic examples of successful
antibiotics, their mechanisms of action
affect only a few specific aspects of bacterial metabolism: cell-wall synthesis,
protein synthesis, DNA and RNA synthesis and repair, and folic acid metabolism. After introducing the reader to the
fundamental principles of these bacterial metabolic pathways, Walsh presents
the current state of knowledge about the
molecular mechanisms whereby the different classes of antibiotics achieve their
antibacterial effects, including data from
X-ray crystallographic analysis of the
targets and binding mechanisms of the
The second part of the book discusses how bacteria resist the effects of
antibiotics. Experience shows that
whenever a new class of antibiotics
comes into widespread use, sooner or
later resistant strains emerge from the
bacteria population by a selection process. As Walsh rightly observes with
regard to this effect: “Bacterial resistance to antibiotics is not a matter of if
but only a matter of when”. On the
basis of some prominent examples, he
discusses ways in which such bacterial
strains are able to resist the effects of
antibiotics: by destroying the antibiotic
molecules, by exporting the active
agent out of the cell, by limiting its penetration within the cell, or by modification of the target molecule. This is also
discussed in relation to the autoimmunity of organisms that produce antibiotics.
Since most of the known antibiotics are
natural products, and are themselves
synthesized by bacteria or fungi, a resistance principle is often already present
in the antibiotic-producing strain, and
can sometimes be transferred over
from this source to pathogens.
The third part of the work deals with
the origin of antibiotics. Apart from a
few exceptions (sulfonamides, trimethoprim, quinolones, and oxazolidinones),
all the antibiotics currently in clinical
use are derived from core structures
produced by microorganisms. Considering the structural complexity of many
antibiotic natural products, it is apparent
that the antibiotic-producing organisms
have impressive biosynthetic capabilities in their secondary metabolism.
Some of the most impressive bacterial
synthetic machineries are the enzyme
cascades that produce the polyketides
and non-ribosomal peptide antibiotics,
and these and other examples are discussed in detail in this section.
One of the strengths of the book is
undoubtedly its comprehensive, thoroughly detailed, yet also very clear
description of the present state of
knowledge about the molecular properties of the classes of antibiotics in current clinical use. In addition, Walsh
describes several structural classes that
have arrived on the market only
recently, or are at an advanced stage of
clinical development (e.g., Daptomycin,
Linezolid, Ramoplanin, Synerzid).
Another extensive topic area is concerned with sources and search strategies for new classes of antibiotics and
with new potential sites of antibiotic
action (targets). Based on knowledge
from bacterial genome analysis, Walsh
discusses strategies for identifying pharmaceutical targets, as well as many targets or metabolic processes that have
recently been investigated in the screening programs of pharmaceutical companies, or are being actively pursued (e.g.,
fatty acids biosynthesis, synthesis of isoprenoids, aminoacyl-tRNA synthetases,
peptide deformylase, methionin aminopeptidase, transglycosylases, sortase,
quorum sensing systems, two-component regulation systems). Other topics
discussed are the origin of new substance pools, strategies for combinatorial medicinal chemistry, targeted compound libraries, and combinatorial biosynthesis.
The great advantage of the book is
that the different areas of antibiotics
resistance development, and the search
for novel antibacterial compounds—
are compiled in a single work in a presentation that is up-to-date, comprehensive and detailed, but also clear and concise, and that it achieves the connection
between basic research and industrial
applications easily. Its topicality results
from presenting the latest knowledge
about molecular mechanisms alongside
the descriptions of new active agents
and targets. The monograph is written
in a relaxed and readable style and is
, 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
attractively illustrated. Details too
extensive for incorporating into the
text are presented in clear tables. Antibiotics: Actions, Origins, Resistance sets a
new standard for a general work of reference on the subject of antibiotics,
and can be thoroughly recommended.
Heike Brtz-Oesterhelt
Bayer HealthCare AG
Wuppertal (Germany)
DOI: 10.1002/anie.200385085
Catalytic Synthesis of Alkene–
Carbon Monoxide Copolymers and
Edited by Ayusman
Sen. Kluwer Academic/
Plenum Publishers,
New York 2003.
325 pp., hardcover
E 148.00.—ISBN
The finding that perfectly alternating
polyketones can be synthesized easily
under mild conditions of pressure and
temperature by using homogeneous palladium catalysts has given a strong
impulse to the field of catalysis and synthesis of new thermoplastics. The low
cost of the monomers and the good
materials properties of the polyketones
have generated academic and industrial
interest over the last two decades.
Application of this process on an industrial scale has led to commercialization
of terpolymers of carbon monoxide, ethylene, and propene as engineering thermoplastics.
Although several reviews have
appeared in the last few years concerning different aspects of the reaction,
this is the first book entirely devoted
to the subject, and is therefore a very
welcome initiative. It offers a complete
account of the catalytic reaction, written
by outstanding experts in the field. As
the title implies, the book focuses on
the catalytic polymer synthesis, with an
emphasis on mechanistic considerations
and catalyst design. The reader should
be aware that the properties of the
copolymers, their reactivity, and related
aspects are not covered.
After an introductory chapter where
the main achievements and future goals
of the reaction are briefly presented,
Chapter 2 gives a detailed explanation
of the investigations that led the authors
to state the requirements for a palladium catalyst to promote this reaction.
The versatility of these catalysts, which
can be fine-tuned to give a variety of
products, ranging from high-molecularweight polyketones to simple esters,
aldehydes, or ketones is presented. The
chapter is largely devoted to reviewing
the authors' own work, and thus has
the character of a personal account.
Related to this versatility, Chapter 3
shows different ways to turn the selectivity of the reaction towards the synthesis
of low-molecular-weight co-oligomers
by controlling the parameters that influence the different steps of the reaction.
The chapter takes a fresh look at the
role of the catalyst, by analyzing results
from several mechanistic studies.
The industrial approach to the synthesis of co- and terpolymers is reviewed
in Chapter 4. The commercial development of the process required the control
of a reaction taking place in a multiphase system. Thus, in this chapter the
reader finds a discussion of the reaction
from a different viewpoint, which provides an interesting complement to the
mechanistic chapters.
Chapter 5 again deals with mechanistic considerations, focusing on the
organometallic reactions that can be
responsible for the chain transfer using
palladium catalysts. The didactic style
of this chapter is very appropriate for a
textbook, since it addresses a broader
Overall, Chapters 2, 3, and 5 overlap
to some extent. However, this is acceptable for the reader, as the mechanism of
the copolymerization reaction is
approached from very different angles.
The synthesis of regio- and stereoregular polyketones by copolymerizing
1-alkenes, mainly propene and styrene,
with carbon monoxide is discussed in
Chapters 6 and 7 of the book. Since
these polyketones possess true stereogenic centers, enantioselective catalysis
, 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
can be used to obtain optically active
polymers starting from achiral monomers. Special attention is devoted to
understanding the factors that govern
the control of regiochemistry and stereochemistry of the polyketones produced, depending on the symmetry of
the catalytic system. The authors give
an exhaustive survey of the results
reported for the synthesis of stereoregular or irregular polyketones.
Chapter 8 is again concerned with
mechanistic aspects of alkene–carbon
monoxide copolymerization reactions
in a more general sense. This rather
short chapter does not add much to the
three previous chapters devoted to the
reaction mechanism (Chapt. 2, 3, and 5).
The book is completed by Chapter 9,
which reviews theoretical research in
the field of catalytic copolymerization
of alkenes with polar monomers.
Throughout the chapter, theoretical
results are compared with independently obtained experimental data,
which is in good agreement between
theory and experiment.
It is somewhat disappointing that
nickel(ii)-catalyzed CO/alkene copolymerizations are largely neglected
throughout the book, especially since
those reactions have been very important for the historical development of
the field. Furthermore, such catalysts
have been investigated intensively as
an alternative to the costly palladium
systems. Especially in view of the
book's focus on mechanistic aspects,
and also the emphasis on commercial
applications, a detailed consideration
of the reasons for the failure of nickel(ii)-catalyzed CO/alkene copolymerization to be widely used up to now
would have been attractive.
This book offers a very good overview of the work performed in the
field of CO/alkene copolymerization,
and is of interest both for researchers
working in the area and for scientists
wishing to get a fundamental understanding of the reaction.
Amaia Bastero
Institut f?r Makromolekulare Chemie
UniversitAt Freiburg
Freiburg im Breisgau (Germany)
Angew. Chem. Int. Ed. 2004, 43, 2879 – 2880
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antibiotics, resistance, action, origin
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