Aminoglycoside Antibiotics - From Chemical Biology to Drug Discovery - D. Arya (Wiley, 2007) WW

339 Pages·2007·9.54 MB·English

AMINOGLYCOSIDE
ANTIBIOTICS

AMINOGLYCOSIDE
ANTIBIOTICS

From Chemical Biology to Drug Discovery

DEV P. ARYA
Clemson University

WILEY-INTERSCIENCE
A John Wiley & Sons, Inc., Publication

Copyright © 2007 by John Wiley & Sons, Inc. All rights reserved.

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Library of Congress Cataloging-in-Publication Data:

ISBN 978-0-471-74302-6

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10 9 8 7 6 5 4 3 2 1

CONTENTS

Preface
vii

Contributors
ix

1. In the Beginning There Was Streptomycin
1
Julian Davies

2. The Biochemistry and Genetics of Aminoglycoside Producers
15
Wolfgang Piepersberg, Khaled M. Aboshanab, Heike Schmidt-Beißner,
and Udo F. Wehmeier

3. Mechanisms of Aminoglycoside Antibiotic Resistance
119
Tushar Shakya and Gerard D. Wright

4. Design, Chemical Synthesis, and Antibacterial Activity
of Kanamycin and Neomycin Class Aminoglycoside
Antibiotics
141
Jinhua Wang and Cheng-Wei Tom Chang

5. NMR Structural Studies of Aminoglycoside:
RNA Interaction
181
R. Andrew Marshall and Joseph D. Puglisi

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vi
CONTENTS

6. Structural Comparisons Between Prokaryotic and Eukaryotic
Ribosomal Decoding A Sites Free and Complexed with
Aminoglycosides
209
Jiro Kondo and Eric Westhof

7. Binding of Antibiotics to the Aminoacyl-tRNA Site of Bacterial
Ribosome
225
Dale Kling, Christine Chow, and Shahriar Mobashery

8. Metalloaminoglycosides: Chemistry and Biological Relevance
235
Nikhil Gokhale, Anjali Patwardhan, and J. A. Cowan

9. Adverse Effects of Aminoglycoside Therapy
255
Andra E. Talaska and Jochen Schacht

10. Targeting HIV-1 RNA with Aminoglycoside Antibiotics and
Their Derivatives
267
Lev Elson-Schwab and Yitzhak Tor

11. Novel Targets for Aminoglycosides
289
Dev P. Arya, Nicholas Shaw, and Hongjuan Xi

Index
315

PREFACE

Since Selman Waksman’s discovery of streptomycin in 1944, aminoglycosides
have been at the forefront of antibacterial drug treatment. Advances in carbohy-
drate chemistry and biochemistry, coupled with other technological advances in
nucleic acid synthesis, biochemistry and structure analysis have led to a substan-
tial increase in aminoglycoside research among both chemists and biochemists.
While by no means exhaustive, this endeavor attempts to chronicle the advances
made in aminoglycoside-related work over the last two decades to assist new
researchers in the field of aminoglycoside research while also offering a refer-
ence guide for the expert. Any omission of work is unintentional and due partly
to the time constraints always present in such a venture.
In the introduction, Dr. Davies’ narrative of aminoglycoside research provides
us with an elegant historical perspective on aminoglycoside discovery and the
mechanism of action over the past 50 years. Chapter 2 illustrates the progress
made in the elucidation of the biosynthetic pathways for aminoglycoside syn-
thesis. Piepersburg and coworkers have outlined the major pathways and their
work should serve as an important reference guide for years to come. A major
problem in aminoglycoside therapy has been drug resistance and in Chapter 3 are
the findings of Shakya and Wright regarding their articulation of the major mech-
anisms of aminoglycoside resistance and the possible methods for overcoming
these pathways. To get past the resistance mechanisms, chemistry and biology
must come together and in Chapter 4, Wang and Chang summarize the synthetic
advances made in aminoglycoside chemistry over the past decade and their uses
in the development of improved antibiotics.
A large interest among chemists and biochemists in aminoglycosides stems
also from the fact that their molecular RNA target of therapeutic action has
been identified. Chapters 5–7 provide a broad overview of the interaction of

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PREFACE

aminoglycoside with RNA focusing particularly on the A-site, their ribosomal
target. In Chapter 5, Marshall and Puglisi first summarize the advances made in
the NMR-based structural investigation of aminoglycosides with RNA, including
the A-site. In Chapter 6, Kondo and Westhof detail the progress made in the
crystallographic investigations of RNA–aminoglycoside interactions and how
that has been used to decipher the differences between eukaryotic and prokaryotic
ribosomal drug targets. Kling, Chow and Mobashery summarize the different
approaches regarding the further comprehension of this important nucleic-acid
interaction. Together, these accounts should provide an excellent reference guide
for students and established researchers interested in the field of aminoglycoside
biochemistry, biophysics, chemical biology or medicinal chemistry.
In Chapter 8, Cowan and coworkers review the state of the art on the metal-
mediated aminoglycoside research resulting in possible metallozymes that can be
developed as novel drugs and tools for DNA and RNA cleavage. A major issue
preventing the development of aminoglycoside therapies has to do with their tox-
icity. As the mechanisms causing these aminoglycoside toxicities (ototoxicity and
nephrotoxicity) become clearer, molecular mechanisms to circumvent the propa-
gation of these toxicities are being proposed. Talaska and Schacht discuss these
proposed mechanisms and the possible role of iron-mediated free radical damage
leading to oxidative stress. For other molecular mechanisms in the genetic basis
of aminoglycoside ototoxicity, the reader is advised to consult the references at
the end of Chapter 1. In Chapter 10, Elson-Schwab and Tor describe the use of
aminoglycosides in other medicinally relevant RNA targets, specifically those
involved in HIV therapy. The work elegantly illustrates how the congruence of
chemistry and biology can lead to novel paradigms in drug development. Finally,
Arya and coworkers summarize the recent work in some non-RNA targets dis-
covered for aminoglycoside-based recognition and how chemical manipulations
can be used to tailor aminoglycoside specificities.
Aminoglycoside research is now a legitimate aspect of scientific endeavor;
with much knowledge, yet unknown, that we can learn. Aminoglycosides have
brought together a number of different disciplines (and many more disciplines are
expected to be positively affected by aminoglycoside research). It is my hope that
this book will assist in both the continuing progress and expansion of aminoglyco-
side research into drug development, chemical biology, biophysics, microbiology,
toxicology, molecular recognition and carbohydrate chemistry. I wish to thank all
the authors for their wholehearted collaboration in this endeavor. Without them
this book would not have been possible.

Dev Priya Arya

Clemson

CONTRIBUTORS

Khaled M. Aboshanab, BU Wuppertal, Chemical Microbiology, D-42097 Wup-
pertal, Germany
Dev P. Arya, Laboratory of Medicinal Chemistry, Department of Chemistry,
Clemson University, Clemson, SC 29634
Cheng-Wei Tom Chang, Department of Chemistry and Biochemistry, Utah
State University, Logan, UT 84322
Christine Chow, Department of Chemistry, Wayne State University, Detroit, MI
48202
J. A. Cowan, Department of Chemistry, Ohio State University, Columbus, OH
43210
Julian Davies, Department of Microbiology and Immunology, University of
British Columbia1 Life Sciences Institute,2 Vancouver BC V6T 1Z3, Canada
Lev Elson-Schwab, Department of Chemistry and Biochemistry, University of
California, San Diego, La Jolla, CA 92093
Nikhil Gokhale, Department of Chemistry, Ohio State University, Columbus,
OH 43210
Dale Kling, Department of Chemistry and Biochemistry, University of Notre
Dame, Notre Dame, IN 46556
Jiro Kondo, Institut de Biologie Mol´eculaire et Cellulaire, UPR9002 CNRS,
Universit´e Louis Pasteur, 67084 Strasbourg, France
R. Andrew Marshall, Department of Chemistry, Stanford University, Stanford,
CA 94305
Shahriar Mobashery, Department of Chemistry and Biochemistry, University
of Notre Dame, Notre Dame, IN 46556

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