Table Of ContentSadhana Sagar · Shilpa Kaistha
Amar Jyoti Das · Rajesh Kumar
Antibiotic
Resistant Bacteria:
A Challenge to
Modern Medicine
Antibiotic Resistant Bacteria: A Challenge
to Modern Medicine
Sadhana Sagar • Shilpa Kaistha
Amar Jyoti Das • Rajesh Kumar
Antibiotic Resistant
Bacteria: A Challenge
to Modern Medicine
Sadhana Sagar Shilpa Kaistha
Department of Microbiology Department of Microbiology
Rani Lakshmi Bai Central Agricultural Chhatrapati Sahu Ji Maharaj University
University Kanpur, Uttar Pradesh, India
Jhansi, Uttar Pradesh, India
Rajesh Kumar
Amar Jyoti Das Department of Environmental Microbiology
Department of Environmental Microbiology Babasaheb Bhimrao Ambedkar University
Babasaheb Bhimrao Ambedkar University Lucknow, Uttar Pradesh, India
Lucknow, Uttar Pradesh, India
ISBN 978-981-13-9878-0 ISBN 978-981-13-9879-7 (eBook)
https://doi.org/10.1007/978-981-13-9879-7
© Springer Nature Singapore Pte Ltd. 2019
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, expressed or implied, with respect to the material contained herein or for any
errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721,
Singapore
Preface
Bacteria are beautifully designed by nature and have potential to challenge the most
intelligent creature (human) of Earth. They are dynamic and versatile and can adapt
to any type of environmental condition. They have acquired various mechanisms to
challenge the currently available antibiotics. They have acquired various antibiotic-
resistant mechanisms, some of these are discussed in this book such as efflux pumps,
alteration of membrane permeability, the formation of membrane vesicles, SOS
response, etc.. Life-threatening diseases are the consequences of such dynamic tiny
organisms. They have entrapped the public health in their claws, and challenged
modern medicines, as we know multiple drug resistance is currently the burning
issue infront of medical practitioners. It is well accepted by them that the currently
available antibiotics are not able to limit the multiple drug-resistant bacteria. There
was a time when penicillin earned a name as a lifesaving drug, but very soon, the
name was blemished by multiple drug-resistant bacteria. As per the UN secretary-
general, antimicrobial resistance is a “fundamental threat” for the public health,
although, to challenge such drug-resistant pathogens, many initiatives have been
taken up. In this regard, the present book describes various aspects of medical prac-
tices from the pre-antibiotic era to the present time. The chapters of this book also
discusses the horrible ancient medical practices such as cupping and bloodletting
techniques and challenging infectious bacterial pathogens. Nevertheless, the dis-
covery of magic bullet replaced that panic therapies from the medical history for-
ever and enlighten the path for modern medicine, the emergence of antibiotic-resistant
strains further created havoc conditions. Hence, within this book, all the informa-
tion regarding the discovery of antibiotics, currently available antibiotics, and those
which are under clinical trials have been described. Some modern approaches such
as phage therapy, nanomedicine, and CRISPR gene-editing technology have also
been elaborated.
Jhansi, Uttar Pradesh, India Sadhana Sagar
Kanpur, Uttar Pradesh, India Shilpa Kaistha
Lucknow, Uttar Pradesh, India Amar Jyoti Das
Rajesh Kumar
v
Acknowledgments
The authors would like to thank Springer Nature who has given this wonderful
opportunity to write a book on the current global health issues. They would also like
to thank Anita Puyam and Sunaina who helped them a lot during the writing of this
book. Sunaina has given excellent ideas for creating a cartoon diagram for this
book. We have discussed so many things regarding animal pathogens and antimicro-
bials to address the issue. Thank you, dear Anita and Sunaina for building a condu-
cive environment for a healthy discussion on untouched aspects of the microbial
world. Thank you all for your undeniable efforts and support.
Sadhana Singh Sagar I would like to thank my mother for her support and love.
This was a stressful time, but she has done a wonderful job in keeping me focused
during turmoil.
Shilpa Kaistha I would like to appreciate Springer Nature Singapore Pvt. Ltd. for
providing me the opportunity to write a book on topic of high importance.
Amar Jyoti Das I thankfully acknowledge my family and friends. Lastly, I would
highly appreciate the help which has been received from the editorial board,
Springer Nature Singapore Pvt. Ltd., Singapore.
Rajesh Kumar I would highly appreciate the help constantly received from the
editorial board, Springer Nature Singapore Pvt. Ltd., Singapore.
vii
Contents
1 Era of Antibiotic Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Horrible Medical History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.3 Bloodletting and Cupping Techniques of Ancient Medicine . . . . . . . 2
1.4 Vague Chemotherapeutics of Ancient Medicine . . . . . . . . . . . . . . . . 3
1.5 Glimpse of First World War . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.6 Foundation of Modern Medical Practices . . . . . . . . . . . . . . . . . . . . . 5
1.7 World War II and Implementation of Antibiotic
in the Modern Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.8 Discovery of Antibiotic and Its Role in Combating Pathogens . . . . . 7
1.9 Supremacy of Bacterial Pathogens over Mankind . . . . . . . . . . . . . . . 11
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2 Emergence of Antibiotic-Resistant Microbes Immediately After
the Discovery of Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.2 Challenging History: When Microbes Introduced Us with Their
Supremacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.3 Emergence and Dissemination of Vector-Borne Disease . . . . . . . . . . 16
2.4 Penicillin’s Working Mechanism and Emergence
of Penicillin-Resistant Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.5 Emergence of Penicillin-Resistant Bacteria . . . . . . . . . . . . . . . . . . . . 18
2.6 Emergence of Resistance in Bacteria to Different
Classes of Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.7 Introduction of Polypeptides in Modern Clinical Practices . . . . . . . . 20
2.8 Popularity of Aminoglycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.9 Tetracyclines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.10 Amphenicols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.11 Lipopeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.12 Macrolides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.13 Oxazolidinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.14 Glycopeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.15 Streptogramins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
ix
x Contents
2.16 Ansamycins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.17 Quinolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.18 Lincosamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3 Advance Class of Antibiotics of the Twenty-First Century . . . . . . . . . . 31
3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.2 Evolution of Microbes from Nonpathogenic to Pathogenic . . . . . . . 32
3.3 Pathogens Dynamicity and Versatility . . . . . . . . . . . . . . . . . . . . . . . . 33
3.4 Need for the Discovery of Twenty-First-Century Antibiotic . . . . . . . 34
3.5 Cephalosporins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3.6 Bedaquiline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
3.7 Linezolid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.8 Nitazoxanide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.9 Carbapenems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.10 Old Drugs with Advance Version . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.11 New β-Lactam Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
4 Antibiotic Resistance: Role and Pattern in Different
Class of Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
4.2 Antibiotic Resistance Pattern in Gram-Positive
and Gram-Negative Bacteria and Various Modes of Action
of Antibiotics for Intervention with Bacterial Cell Membrane . . . . . 47
4.2.1 Intervention with Peptidoglycan . . . . . . . . . . . . . . . . . . . . . . 47
4.2.2 Intervention with Teichoic Acids . . . . . . . . . . . . . . . . . . . . . . 48
4.2.3 Intervention with Lipopolysaccharides . . . . . . . . . . . . . . . . . 51
4.2.4 Intervention with Phospholipids . . . . . . . . . . . . . . . . . . . . . . 51
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
5 Effect of Drug-Resistant Bacteria on Agriculture, Livestock,
and Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
5.2 Sources of Antibiotics in Environment and Agricultural Land . . . . . 58
5.3 Persistent Nature of Antibiotics in the Soil and Environment
and Their Influence on the Soil Microbial Population . . . . . . . . . . . . 59
5.4 Effects of Antibiotics on Livestocks and Agriculture . . . . . . . . . . . . 59
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
6 Intrinsic Antibiotic Resistance Mechanism in Bacteria . . . . . . . . . . . . 69
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
6.2 Alteration of Outer Membrane Permeability . . . . . . . . . . . . . . . . . . . 70
6.3 Outer Membrane Vesicles for Antibiotic Resistance . . . . . . . . . . . . . 72
6.4 Role of Efflux Pumps in Drug Resistance . . . . . . . . . . . . . . . . . . . . . 73
6.5 Role of Small Multidrug Resistance (SMR) Transporters . . . . . . . . . 73
6.6 Role of Major Facilitator Superfamily (MFS) Transporter . . . . . . . . 75
Contents xi
6.7 Drug Resistance by Multi-antimicrobial Extrusion (MATE)
Transporter of Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
6.8 ATP Binding Cassette (ABC) Transporter . . . . . . . . . . . . . . . . . . . . . 78
6.9 RND Transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
6.10 Proteobacterial Antimicrobial Compound Efflux (PACE)
Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
7 Extrinsic Antibiotic-Resistant Mechanism in Bacteria . . . . . . . . . . . . . 87
7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
7.2 Targeting Gene Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
7.3 Horizontal Gene Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
7.3.1 Transformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
7.3.2 Conjugation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
7.4 Homologous Recombination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
7.5 Integrons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
7.6 Site-Specific Recombination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
7.7 Targeting SOS Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
7.8 Emergence of Antibiotic Resistance Through Mutation . . . . . . . . . . 94
7.9 Mobile DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
7.10 Plasmids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
7.11 Conjugative Transposons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
7.12 Gene Cassettes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
7.13 ISCR-Promoted Gene Mobilization . . . . . . . . . . . . . . . . . . . . . . . . . . 98
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
8 Chemical-Mediated Alteration of Antibiotics . . . . . . . . . . . . . . . . . . . . . 105
8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
8.2 Mechanisms of Antibiotic Resistance . . . . . . . . . . . . . . . . . . . . . . . . 106
8.3 Modifications of the Antibiotic Molecule . . . . . . . . . . . . . . . . . . . . . 106
8.4 Chemical Alterations of the Antibiotic . . . . . . . . . . . . . . . . . . . . . . . 106
8.4.1 Alteration Through Aminoglycoside-Modifying
Enzymes (AMEs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
8.4.2 Aminoglycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
8.4.3 Aminoglycoside-Modifying Enzymes . . . . . . . . . . . . . . . . . . 108
8.4.4 Mechanisms of Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
8.5 Destruction of the Antibiotic Molecule . . . . . . . . . . . . . . . . . . . . . . . 112
8.5.1 β-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
8.5.2 Mode of Action of β-Lactamases . . . . . . . . . . . . . . . . . . . . . . 114
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
9 Collapse of Antibiotic Resistance with the Help
of Genetic Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
9.2 Molecular Strategy for the Control of Antibiotic- Resistant Bacteria 128
9.3 What Is CRISPR? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
xii Contents
9.4 Discovery of CRISPR Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
9.5 What Does CRISPR/Cas System Contain? . . . . . . . . . . . . . . . . . . . . 129
9.6 Implementation of CRISPR/Cas Triumph over Antibiotic
Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
9.7 Overcoming Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
9.8 Mechanism of CRISPR/Cas9 System in the Reversal of Drug
Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
10 Nanotechnology: A Twenty-First- Century Approach Towards
the Control of Antibiotic-Resistant Bacteria . . . . . . . . . . . . . . . . . . . . . 135
10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
10.2 Irreplaceable Properties of Nanomaterials . . . . . . . . . . . . . . . . . . . . 136
10.3 Electrical Properties of Nanomaterials . . . . . . . . . . . . . . . . . . . . . . 137
10.4 Mechanical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
10.5 Classification of Nanomaterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
10.6 Importance of Nanomaterials in Medical Field . . . . . . . . . . . . . . . . 139
10.7 Biodetection of Pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
10.8 Probing of DNA Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
10.9 Nanomaterial as Therapeutics Against Bacterial Infection . . . . . . . 141
10.10 Mechanisms of Nanomaterials for Combating
Drug Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
10.10.1 Interaction with Cell Wall . . . . . . . . . . . . . . . . . . . . . . . . . . 142
10.10.2 Nanomaterial-Mediated Generation of Reactive
Oxygen Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
10.10.3 Disruption of Cell Membrane . . . . . . . . . . . . . . . . . . . . . . . 145
10.10.4 Intrusion of Electron Transportation . . . . . . . . . . . . . . . . . . 146
10.10.5 Alteration in Membrane Permeability . . . . . . . . . . . . . . . . . 146
10.10.6 Penetration of the Cell Envelope and Ribosome
Destabilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
11 Bacteriophage: A New Hope for the Control
of Antibiotic-Resistant Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
11.2 Properties of Bacteriophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
11.3 History of Phage Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
11.4 Conflicts Headed on Phage Therapy . . . . . . . . . . . . . . . . . . . . . . . . 155
11.5 Why Did Medical Researcher Hunt for Phages? . . . . . . . . . . . . . . . 155
11.6 Implementation of Phage Therapy in Medical Practices . . . . . . . . . 157
11.7 FDA-Approved Phage Therapies for Mitigation
of Human Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
11.8 Limitation of Phage Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
