Table Of ContentS T R E P T O M Y C E S
in Nature and Medicine
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S T R E P T O M Y C E S
in Nature and Medicine
The Antibiotic Makers
David A. Hopwood
John Innes Centre
1
2007
3
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Library of Congress Cataloging-in-Publication Data
Hopwood, D. A.
Streptomyces in nature and medicine / David A. Hopwood.
p. ; cm.
Includes bibliographical references and index.
ISBN-13 978–0–19–515066–7
ISBN 0–19–515066–X
1. Streptomyces—Genetics.
[DNLM: 1. Streptomyces—genetics. 2. Genetic Engineering.
QW 125.5.S8 H799s 2006] I. Title.
QR82.S8H57 2006
579.3'78—dc22 2006005669
9 8 7 6 5 4 3 2 1
Printed in the United States of America
on acid-free paper
To Joyce
for her companionship and encouragement
during more than four decades of marriage
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Preface
Everyone has heard of antibiotics, and most people, at least in the developed world,
have benefited from their curative powers. But how many of us know where they
come from and how they developed into a cornerstone of medicine? The mold that
famously contaminated Alexander Fleming’s culture dish and eventually gave us
penicillin is one of the icons of 20th century biology, but penicillin was just the first
antibiotic to become a medicine. Dozens of important compounds followed, revolu-
tionizing the treatment of infectious diseases. Most are made by a group of soil mi-
crobes, the actinomycetes, which were little known until their powers of antibiotic
production were revealed, starting some 60 years ago.
This book begins by describing how these microbes were discovered and how they
became an important source of antibiotics and moves on to an insider’s account of
how knowledge of their genetics developed over the second half of the 20th century.
These insights, culminating in the determination of the complete DNA sequence for
a model species at the start of the new millennium, have allowed us to understand
the intricacies of actinomycete biology and the incredible feats of microengineering
that go into building even a comparatively simple organism and adapting it superbly
to its habitat. I describe how techniques for manipulating the genes for antibiotic
production stemming from these studies are being applied to the challenge of mak-
ing new antibiotics to counter the threat posed by pathogens that have become resis-
tant to those in current use. Among these pathogens are other actinomycetes, relatives
of the useful soil inhabitants, which cause deadly and disfiguring diseases: tubercu-
losis and leprosy. I talk about them too.
In attempting to bring the wonders of the actinomycetes to a wider audience I have
tried to explain genetic concepts and fundamental biological principles in simple
viii PREFACE
language, but I have included a glossary of terms for separate reference, and this may
make some of the chapters intelligible in isolation.
I am indebted to the Leverhulme Trust for a grant to cover the costs of the project
and to many people for their help and advice in writing this book. First and foremost
my thanks go to my son, Nick Hopwood, who read two drafts and made innumerable
suggestions for improving the manuscript. I should have been lost without his input.
My wife, Joyce, made many valuable suggestions too, as did Jeffrey House of Oxford
University Press. Douglas Eveleigh hosted a visit to the Waksman Archive and pa-
tiently answered my many subsequent questions about Rutgers University; Lisa
Pontecorvo graciously gave me guided access to the archive of her father Guido; and
Marianna Jackson devoted much time and effort to providing her reminiscences of life
at Abbott during the Golden Age of antibiotic discovery. Many other colleagues gen-
erously responded to queries about specific topics: Boyd Woodruff for the early days
of antibiotic discovery in Waksman’s laboratory (Chapter 1); Liz Wellington for se-
lective isolation of actinomycetes from soil, and Peter Hawkey for comments on clini-
cally important antibiotic resistance (Chapter 2); Gilberto Corbellini for information
on the Istituto Superiore di Sanità (Chapter 3); Natasha Lomovskaya for insights into
science in Moscow before perestroika (Chapter 4); Stephen Bentley for many discus-
sions about genome sequencing and the Sanger Institute (Chapter 5); Liz Wellington
for spore dispersal, Geertje van Keulen for spore buoyancy, Jolanta Zakrzewska-
Czerwinska and Dagmara Jakimowicz for chromosome replication and partition, and
Carton Chen for chromosome transfer (Chapter 6); Marie-Joelle Virolle for amylase
production, Hildgund Schrempf for chitin and cellulose degradation, Mark Buttner for
vancomycin resistance, and Eriko Takano for signaling molecules (Chapter 7); Leonard
Katz and David Cane for comments on Chapter 8; Cammy Kao for microarrays, Andy
Hesketh for proteomics, and Kay Fowler for transposon mutagenesis (Chapter 9); and
the late Jo Colston for answering my many questions about tuberculosis and leprosy
(Chapter 10). I thank Keith Chater, Julian Davies, and Arny Demain for reading a draft
of the whole manuscript and providing many useful suggestions.
I am greatly indebted to Tobias Kieser for generously providing many photographs
and for teaching me the rudiments of Adobe Photoshop, and to Nigel Orme for imagi-
natively converting my rough sketches into the finished diagrams. I thank the many
people, acknowledged in the captions, who provided other photographs. I am espe-
cially grateful to Helen Kieser for a long professional partnership, without which my
own career would have been much less rewarding. I thank the many other colleagues
at the John Innes Centre and worldwide who joined in the quest for knowledge about
nature’s antibiotic makers. Collaboration in science is nearly always beneficial, but
in the Streptomycesfield it has been unusually wide and prolonged, embracing com-
mercial companies as well as universities and research institutes, and linking people
across the world in a strikingly harmonious “family” that has helped to make my
professional life both a happy and a satisfying one.
Contents
Introduction 3
1 Actinomycetes and Antibiotics 8
2 Antibiotic Discovery and Resistance 28
3 Microbial Sex 51
4 Toward Gene Cloning 81
5 From Chromosome Map to DNA Sequence 103
6 Bacteria That Develop 123
7 The Switch to Antibiotic Production 145
8 Unnatural Natural Products 165
9 Functional Genomics 193
10 Genomics Against Tuberculosis and Leprosy 211
Conclusion 226
Notes and References 229
Glossary 241
Index 245
Description:This is an insiders account of 50 years of genetic studies of the soil-inhabiting microbes that produce most of the antibiotics used to treat infections, as well as anti-cancer, anti-parasitic and immunosuppressant drugs. The book begins by describing how these microbes the actinomycetes were discov
