Efflux-Mediated Antimicrobial Resistance in Bacteria: Mechanisms, Regulation and Clinical Implications

850 Pages·2016·20.2 MB·English

by  Xian-Zhi Li

Xian-Zhi Li · Christopher A. Elkins
Helen I. Zgurskaya Editors
Effl ux-Mediated
Antimicrobial
Resistance in
Bacteria
Mechanisms, Regulation
and Clinical Implications
Effl ux-Mediated Antimicrobial
Resistance in Bacteria

Xian-Zhi Li • Christopher A. Elkins
Helen I. Zgurskaya
Editors
Effl ux-Mediated
Antimicrobial Resistance
in Bacteria
Mechanisms, Regulation and Clinical
Implications
Editors
Xian-Zhi Li Helen I. Zgurskaya
Health Products and Food Branch University of Oklahoma
Health Canada Norman
Ottawa Oklahoma
Ontario USA
Canada
Christopher A. Elkins
U.S. Food and Drug Administration
Laurel
Maryland
USA
ISBN 978-3-319-39656-9 ISBN 978-3-319-39658-3 (eBook)
DOI 10.1007/978-3-319-39658-3
Library of Congress Control Number: 2016952619
© Springer International Publishing Switzerland 2016
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Foreword
O ne of the greatest threats to the control of infectious diseases is universal drug
resistance; this is an increasing and apparently irreversible phenomenon. The disas-
trous failure of physicians, government, pharmaceutical companies, and the general
population to control the uses and misuses of antimicrobial agents is one of the most
tragic events of the twentieth century. Antibiotic resistance is now a worldwide
plague that shows no evidence of declining.
I t is essential that increased funding and commitment are devoted to studying the
origins of the biochemical mechanisms of drug resistance and their genetic dissemi-
nation. Resistance takes many forms and is often a complex process, as in the case
of multidrug resistance. However, the primary response of most pathogens to anti-
biotic exposure is drug effl ux, and a better understanding of this process with more
extensive studies would lead to improved therapeutic applications.
This collection of reviews on the above topic, edited by Drs. Xian-Zhi Li,
Christopher A. Elkins, and Helen I. Zgurskaya, is without question the “must-have”
book. Herein an expert group of specialists have covered all aspects of effl ux-medi-
ated drug resistance. Nothing has been left out, and notably, the last three chapters
of this book discuss the absolute necessity for encouraging novel approaches to the
prevention of drug effl ux processes in bacteria. Insuffi cient attention has been paid
to this essential aspect in the past, and more effort must be devoted to this vital
topic.
Julian E. Davies
Department of Microbiology and Immunology
University of British Columbia
Vancouver , BC , Canada

February 2016
v

Pref ace
A ntibiotics are vital to modern medicine. However, bacterial resistance constitutes
a growing threat to effective antimicrobial therapy worldwide. Indeed, antimicro-
bial resistance continues to be one of this century’s major public health threats
exemplifi ed by intra- and intergovernmental efforts and task forces. In 2014 and
2015, Canada published its Federal Action Plan and Framework on Antimicrobial
Resistance and Use, while an executive order was released in 2014 by the president
of the United States to establish a National Strategy to Combat Antibiotic-Resistant
Bacteria. The World Health Assembly also endorsed a global plan to tackle antimi-
crobial resistance in May 2015. Resistance takes many forms, and bacterial drug
effl ux pumps constitute a major mechanism for both natural and acquired resistance
to a diverse range of clinically used antibiotics and other toxic agents including
biocides. The latter insinuates that infection control may inadvertently link with
multidrug resistance through effl ux mechanisms. Drug effl ux pumps are ubiqui-
tously distributed in bacteria, and their role as a key mechanism of resistance and
other functions, including pathogenicity, cannot be overstated.
Initially recognized in the late 1970s for their role in drug-specifi c resistance,
bacterial effl ux pumps were further investigated in the early 1990s for their signifi -
cant contribution to multidrug resistance. Over the last two decades, a large number
of bacterial drug exporters have been characterized. In particular, in-depth studies
on prototypical pumps of various transporter families have greatly enhanced our
understanding of multidrug transporter structures and transport dynamics, as well as
their expression, regulation, and clinical ramifi cations. Effl ux-based phenomena
also interact synergistically with other resistance mechanisms including the mem-
brane permeability barrier, drug inactivation, and drug target alterations to enhance
resistance levels and cause clinically resistant profi les. These characteristics pose
major challenges to antimicrobial development and therapy. Effl ux pumps are can-
didate drug targets for therapeutic interventions and open the potential for combina-
tory products that may reinvigorate the current arsenal of decreasingly effective
drugs. This book describes our current understanding of the above advancements.
T he contributors of this book hail from various leading international scientifi c
groups. We are sincerely grateful to them for their efforts in the preparation of this
vii
viii Preface
outstanding work divided into four sections with a total of 30 chapters. The insights
of the authors on various aspects of drug effl ux-mediated resistance will be benefi -
cial to the future of research in this fi eld and provide a strong scientifi c argument in
promoting antimicrobial stewardship to minimize resistance threats. We also wish
to express our immense gratitude to Dr. Hiroshi Nikaido, not only for the opportu-
nity to work with him on the drug effl ux phenomena but also for his encouragement
on this book. We are also honored to have the support from Dr. Julian E. Davies in
writing the Foreword of this book. Xian-Zhi Li acknowledges the support from
Daniel Chaput. Finally, we especially thank Dene Peters at Springer for initiating
and guiding this project. We also deeply appreciate the help from other staff from
the publisher, Carole Pearson, Mahalakshmi Sethish Babu, Kalpana Venkataramani,
and Cameron Wright, during this entire process.
Ottawa , ON , Canada Xian-Zhi Li
Laurel , MD , USA Christopher A. Elkins
Norman , OK , USA Helen I. Zgurskaya
Contents
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
About the Editors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xix
Part I Bacterial Drug Efflux Pumps: Structures and Transport
Mechanisms
1 Structures and Transport Mechanisms of RND Efflux Pumps . . . . . 3
Satoshi Murakami
2 Structural and Functional Landscape of MFS and MATE
Efflux Pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Asha V. Nair, Kenneth W. Lee, and Hendrik W. van Veen
3 Small Multidrug Resistance Efflux Pumps. . . . . . . . . . . . . . . . . . . . . . 45
Denice C. Bay and Raymond J. Turner
4 Structures and Transport Mechanisms of the ABC
Efflux Pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Cédric Orelle and Jean-Michel Jault
5 Multidrug Efflux in the Context of Two- Membrane
Cell Envelopes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Helen I. Zgurskaya, Vassiliy N. Bavro, Jon W. Weeks,
and Ganesh Krishnamoorthy
ix