Novel Antimicrobial Agents and Strategies E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 901

Veröffentlichungsjahr: 2014

Beschreibung

By integrating knowledge from pharmacology, microbiology, molecular medicine, and engineering, researchers from Europe, the U.S. and Asia cover a broad spectrum of current and potential antimicrobial medications and treatments.
The result is a comprehensive survey ranging from small-molecule antibiotics to antimicrobial peptides and their engineered mimetics, from enzymes to nucleic acid therapeutics, from metallic nanoparticles to photo- and sonosensitizers and to phage therapy. In each case, the therapeutic approaches are compared in terms of their mechanisms, likelihood to induce resistance, and their efficiency in a global healthcare context.
Unrivaled knowledge for professionals in fundamental research, pharmaceutical development and clinical practice.

Leseprobe

Table of Contents

Cover

Related Titles

Title Page

Copyright

List of Contributors

Preface

Reference

Chapter 1: The Problem of Microbial Drug Resistance

1.1 Introduction

1.2 History of the Origins, Development, and Use of Conventional Antibiotics

1.3 Problems of Antibiotic Resistance

1.4 Multiple Drug-Resistant (MDR), Extensively Drug-Resistant (XDR), and Pan-Drug-Resistant (PDR) Organisms

1.5 MDR Mechanisms of Major Pathogens

1.6 Antimicrobial Stewardship Programs

1.7 Discussion

Acknowledgment

References

Chapter 2: Conventional Antibiotics – Revitalized by New Agents

2.1 Introduction

2.2 Conventional Antibiotics

2.3 The Principles of Combination Antibiotic Therapy

2.4 Antibiotic Resistance Breakers: Revitalize Conventional Antibiotics

2.5 Discussion

Acknowledgments

References

Chapter 3: Developing Novel Bacterial Targets: Carbonic Anhydrases as Antibacterial Drug Targets

3.1 Introduction

3.2 Carbonic Anhydrases

3.3 CA Inhibitors

3.4 Classes of CAs Present in Bacteria

3.5 Pathogenic Bacterial CAs

3.6 α-CAs in Pathogenic Bacteria

3.7 β-CAs in Pathogenic Bacteria

3.8 γ-CAs from Pathogenic Bacteria

3.9 Conclusions

References

Chapter 4: Magainins – A Model for Development of Eukaryotic Antimicrobial Peptides (AMPs)

4.1 Introduction

4.2 Magainins and Their Antimicrobial Action

4.3 Magainins as Antibiotics

4.4 Other Antimicrobial Uses of Magainins

4.5 Future Prospects for Magainins

References

Chapter 5: Antimicrobial Peptides from Prokaryotes

5.1 Introduction

5.2 Bacteriocins

5.3 Applications of Prokaryotic AMPs

5.4 Development and Discovery of Novel AMP

References

Chapter 6: Peptidomimetics as Antimicrobial Agents

6.1 Introduction

6.2 Antimicrobial Peptidomimetics

6.3 Discussion

Acknowledgments

References

Chapter 7: Synthetic Biology and Therapies for Infectious Diseases

7.1 Current Challenges in the Treatment of Infectious Diseases

7.2 Introduction to Synthetic Biology

7.3 Vaccinology

7.4 Bacteriophages: A Re-emerging Solution?

7.5 Isolated Phage Parts as Antimicrobials

7.6 Predatory Bacteria and Probiotic Bacterial Therapy

7.7 Natural Products Discovery and Engineering

7.8 Summary

Acknowledgments

References

Chapter 8: Nano-Antimicrobials Based on Metals

8.1 Introduction

8.2 Silver Nano-antimicrobials

8.3 Copper Nano-antimicrobials

8.4 Zinc Oxide Nano-antimicrobials

8.5 Conclusions

References

Chapter 9: Natural Products as Antimicrobial Agents – an Update

9.1 Introduction

9.2 Antimicrobial Natural Products from Plants

9.3 Antimicrobial Natural Products Bearing an Acetylene Function

9.4 Antimicrobial Carbohydrates

9.5 Antimicrobial Natural Chromenes

9.6 Antimicrobial Natural Coumarins

9.7 Antimicrobial Flavonoids

9.8 Antimicrobial Iridoids

9.9 Antimicrobial Lignans

9.10 Antimicrobial Phenolics Other Than Flavonoids and Lignans

9.11 Antimicrobial Polypeptides

9.12 Antimicrobial Polyketides

9.13 Antimicrobial Steroids

9.14 Antimicrobial Terpenoids

9.15 Miscellaneous Antimicrobial Compounds

9.16 Platensimycin Family as Antibacterial Natural Products

References

Chapter 10: Photodynamic Antimicrobial Chemotherapy

10.1 Introduction

10.2 The Administration and Photoactivation of PS

10.3 Applications of PACT Based on MB

10.4 The Applications of PACT Based on ALA

10.5 Future Prospects

References

Chapter 11: The Antimicrobial Effects of Ultrasound

11.1 Introduction

11.2 The Antimicrobial Activity of Ultrasound Alone

11.3 The Antimicrobial Activity of Assisted Ultrasound

11.4 Future Prospects

References

Chapter 12: Antimicrobial Therapy Based on Antisense Agents

12.1 Introduction

12.2 Antisense Oligonucleotides

12.3 First-Generation ASOs

12.4 Second-Generation ASOs

12.5 Third-Generation ASOs

12.6 Antisense Antibacterials

12.7 Broad-Spectrum Antisense Antibacterials

12.8 Methicillin-Resistant

Staphylococcus aureus

(MRSA)

12.9 RNA Interference (RNAi)

12.10 Progress Using siRNA

12.11 Discussion

References

Chapter 13: New Delivery Systems – Liposomes for Pulmonary Delivery of Antibacterial Drugs

13.1 Introduction

13.2 Pulmonary Drug Delivery

13.3 Liposomes as Drug Carriers in Pulmonary Delivery

13.4 Present and Future Trends of Liposome Research in Pulmonary Drug Delivery

13.5 Conclusions

References

Index

End User License Agreement

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Guide

Cover

Table of Contents

Preface

Chapter 1: The Problem of Microbial Drug Resistance

List of Illustrations

Figure 3.1

Figure 4.1

Figure 5.1

Figure 5.2

Figure 6.1

Figure 6.2

Figure 6.3

Figure 6.4

Figure 6.5

Figure 6.6

Figure 6.7

Figure 6.8

Figure 6.9

Figure 7.1

Figure 7.2

Figure 7.3

Figure 7.4

Figure 7.5

Figure 7.6

Figure 7.7

Figure 7.8

Figure 7.9

Figure 7.10

Figure 7.11

Figure 7.12

Figure 7.13

Figure 8.1

Figure 8.2

Figure 8.3

Figure 8.4

Figure 8.5

Figure 8.6

Figure 8.7

Figure 10.1

Figure 10.2

Figure 10.3

Figure 11.1

Figure 11.2

Figure 12.1

Figure 12.2

Figure 12.3

Figure 12.4

Figure 13.1

Figure 13.2

Figure 13.3

Figure 13.4

Figure 13.5

Figure 13.6

Figure 13.7

Figure 13.8

Figure 13.9

Figure 13.10

List of Tables

Table 1.1

Table 1.2

Table 1.3

Table 2.1

Table 3.1

Table 4.1

Table 4.2

Table 4.3

Table 4.4

Table 5.1

Table 8.1

Table 10.1

Table 10.2

Table 10.3

Table 10.4

Table 10.5

Table 11.1

Table 12.1

Table 12.2

Table 12.3

Table 12.4

Related Titles

Gualerzi, C.O., Brandi, L., Fabbretti, A., Pon, C.L. (eds.)

Antibiotics

Targets, Mechanisms and Resistance

2013

Print ISBN: 978-3-527-33305-9, also available in digital formats

Phoenix, D. A., Dennison, S. R., Harris, F.

Antimicrobial Peptides

2013

Print ISBN: 978-3-527-33263-2, also available in digital formats

Anderson, R.R., Groundwater, P.P., Todd, A.A., Worsley, A.A.

Antibacterial Agents - Chemistry, Mode of Action, Mechanisms of Resistance and Clinical Applications

2012

Print ISBN: 978-0-470-97244-1, also available in digital formats

Skold, O.

Antibiotics and Antibiotic Resistance

2011

Print ISBN: 978-0-470-43850-3, also available in digital formats

Chen, L., Petersen, J., Schlagenhauf, P. (eds.)

Infectious Diseases - A Geographic Guide

2011

Print ISBN: 978-0-470-65529-0, also available in digital formats

De Clercq, E. (ed.)

Antiviral Drug Strategies

2011

Print ISBN: 978-3-527-32696-9, also available in digital formats

Edited by David A. Phoenix, Frederick Harris, and Sarah R. Dennison

Novel Antimicrobial Agents and Strategies

The Editors

Prof. David A. Phoenix

London South Bank University

Borough Road 103

London

SE1 0AA

United Kingdom

Dr. Frederick Harris

University of Central Lancashire

Forensic & Investigative Science

Preston, Lancashire

PR1 2HE

United Kingdom

Dr. Sarah R. Dennison

University of Central Lancashire

Pharmacy and Biomedical Science

Preston, Lancashire

PR1 2HE

United Kingdom

Cover design

The cover shows beta-lactamase, an enzyme produced by some bacteria, which provide bacterial resistance to beta-lactam antibiotics in the presence of a lipid bilayer. The image was created by Dr. Manuela Mura, University of Central Lancashire, UK.

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library.

Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at <http://dnb.d-nb.de>.

© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

Print ISBN: 978-3-527-33638-8

ePDF ISBN: 978-3-527-67614-9

ePub ISBN: 978-3-527-67615-6

Mobi ISBN: 978-3-527-67616-3

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List of Contributors

Waqar Ahmed

University of Central Lancashire

Institute of Nanotechnology and Bioengineering

School of Medicine and Dentistry

Corporation street

Preston

PR1 2HE

UK

Hiroki Ando

Department of Electrical Engineering and Computer Science and Department of Biological Engineering

Massachusetts Institute of Technology

Massachusetts Avenue

Cambridge, MA 02139

USA

and

Massachusetts Institute of Technology

MIT Synthetic Biology Center

Technology Square

Cambridge, MA 02139

USA

Glenda M. Beaman

University of Central Lancashire

School of Forensic and Investigative Sciences

Corporation Street

Preston

PR1 2HE

UK

Jianfeng Cai

University of South Florida

Department of Chemistry

E. Fowler Avenue

Tampa, FL 33620

USA

Clemente Capasso

Istituto di Biochimica delle Proteine-CNR

via Pietro Castellino

- 80131 Napoli

Italy

and

Istituto di Bioscienze e Biorisorse-CNR

via Pietro Castellino

- 80131 Napoli

Italy

Nicola Cioffi

Università degli Studi di Bari Aldo Moro

Dipartimento di Chimica

via Orabona 4

Bari

Italy

Robert Citorik

Department of Electrical Engineering and Computer Science and Department of Biological Engineering

Massachusetts Institute of Technology

Massachusetts Avenue

Cambridge, MA 02139

USA

and

Massachusetts Institute of Technology

MIT Synthetic Biology Center

Technology Square

Cambridge, MA 02139

USA

and

Massachusetts Institute of Technology

MIT Microbiology Program

Massachusetts Avenue

Cambridge, MA 02139

USA

Sara Cleto

Department of Electrical Engineering and Computer Science and Department of Biological Engineering

Massachusetts Institute of Technology

Massachusetts Avenue

Cambridge, MA 02139

USA

and

Massachusetts Institute of Technology

MIT Synthetic Biology Center

Technology Square

Cambridge, MA 02139

USA

Anthony Coates

St George's University of London

Medical Microbiology

Institute of Infection and Immunity

Cranmer Terrace

London

SW17 0RE

UK

Sarah R. Dennison

University of Central Lancashire

Institute of Nanotechnology and Bioengineering

School of Pharmacy and Biomedical Sciences

Corporation Street

Preston

PR1 2HE

UK

Dzung B. Diep

Norwegian University of Life Sciences

Laboratory of Microbial Gene Technology

Department of Chemistry

Biotechnology and Food Science

P.O Box 5003

Å s

Norway

Abdelbary M.A. Elhissi

University of Central Lancashire

Institute of Nanotechnology and Bioengineering

School of Pharmacy and Biomedical Sciences

Corporation street

Preston

PR1 2HE

UK

Frederick Harris

University of Central Lancashire

School of Forensic and Investigative Science

Corporation street

Preston

PR1 2HE

UK

Maryam Hassan

Zanjan University of Medical Sciences

Pharmaceutical Biotechnology Research Center

Zanjan

Iran

David Hill

University of Wolverhampton

School of Biology, Chemistry, and Forensic Science

Faculty of Science and Engineering

Wulfruna Street

Wolverhampton

WV1 1LY

UK

Yanmin Hu

St George's University of London

Medical Microbiology

Institute of Infection and Immunity

Cranmer Terrace

London

SW17 0RE

UK

Morten Kjos

Norwegian University of Life Sciences

Laboratory of Microbial Gene Technology

Department of Chemistry

Biotechnology and Food Science

P.O Box 5003

Å s

Norway

and

University of Groningen

Molecular Genetics Group

Groningen Biomolecular Sciences and Biotechnology Institute

Centre for Synthetic Biology

Nijenborgh 7

AG Groningen

The Netherlands

Sebastien Lemire

Department of Electrical Engineering and Computer Science and Department of Biological Engineering

Massachusetts Institute of Technology

Massachusetts Avenue

Cambridge, MA 02139

USA

and

Massachusetts Institute of Technology

MIT Synthetic Biology Center

Technology Square

Cambridge, MA 02139

USA

Farzaneh Lotfipour

Tabriz University of Medical Sciences

Hematology & Oncology Research Center and Faculty of Pharmacy

Tabriz

51664

Iran

Timothy Lu

Department of Electrical Engineering and Computer Science and Department of Biological Engineering

Massachusetts Institute of Technology

Massachusetts Avenue

Cambridge, MA 02139

USA

and

Massachusetts Institute of Technology

MIT Synthetic Biology Center

Technology Square

Cambridge, MA 02139

USA

and

Massachusetts Institute of Technology

MIT Microbiology Program

Massachusetts Avenue

Cambridge, MA 02139

USA

Claire Martin

University of Wolverhampton

School of Pharmacy

Faculty of Science and Engineering

Wulfruna Street

Wolverhampton

WV1 1LY

UK

Mark Mimee

Department of Electrical Engineering and Computer Science and Department of Biological Engineering

Massachusetts Institute of Technology

Massachusetts Avenue

Cambridge, MA 02139

USA

and

Massachusetts Institute of Technology

MIT Synthetic Biology Center 500 Technology Square

Cambridge, MA 02139

USA

and

Massachusetts Institute of Technology

MIT Microbiology Program

Massachusetts Avenue

Cambridge, MA 02139

USA

Ingolf F. Nes

Norwegian University of Life Sciences

Laboratory of Microbial Gene Technology

Department of Chemistry

Biotechnology and Food Science

P.O Box 5003

Å s

Norway

David A. Phoenix

London South Bank University

Office of the Vice Chancellor

Borough Road

London

SE1 0AA

UK

Rosaria Anna Picca

Università degli Studi di Bari Aldo Moro

Dipartimento di Chimica

via Orabona 4

Bari

Italy

Iza Radecka

University of Wolverhampton

School of Biology

Chemistry and Forensic Science

Faculty of Science and Engineering

Wulfruna Street

Wolverhampton

WV1 1LY

UK

Muhammad Saleem

The Islamia University of Bahawalpur

Department of Chemistry

Baghdad-ul-Jadeed Campus

Bahawalpur, 63100

Pakistan

Maria Chiara Sportelli

Università degli Studi di Bari Aldo Moro

Dipartimento di Chimica

via Orabona 4

Bari

Italy

Claudiu T. Supuran

Università degli Studi di Firenze

Dipartimento di Scienze Farmaceutiche

Via della Lastruccia

3, Polo Scientifico

Sesto Fiorentino (Florence)

Italy

and

Sezione di Scienze Farmaceutiche e Nutraceutiche, Neurofarba Department

Università degli Studi di Firenze

Via Ugo Schiff 6

Sesto Fiorentino (Florence)

Italy

Kevin M.G. Taylor

University College London

Department of Pharmaceutics School of Pharmacy

29-39 Brunswick Square

London

WC1N 1AX

UK

and

Department of Pharmaceutics

UCL School of Pharmacy

29-39 Brunswick Square

London

WC1N 1AX

UK

Peng Teng

University of South Florida

Department of Chemistry

E. Fowler Avenue

Tampa, FL 33620

USA

Haifan Wu

University of South Florida

Department of Chemistry

E. Fowler Avenue

Tampa, FL 33620

USA

Preface

The “Golden age of antibiotics” was between 1929 and the 1970s when over 20 antibiotic classes were marketed [1, 2]. Since the 1960s, the rise in the emergence of microbial pathogens with multiple drug resistance (MDR) has led to the realization that the “Golden age” had ended. The pharmaceutical industry has been constantly battling with MDR because of the overprescription and misuse of antibiotics [3–5]. In Chapter 1, Radecka and coworkers give an insight into bacterial resistance being a major threat to public health. They also discuss the implications arising from the threat posed by MDR pathogens in relation to factors such as medical practice and economics, along with an overview of recent practices and measures proposed to contain this threat, such as the introduction of stewardship programs. Concern regarding our future ability to combat infection has been further intensified by the decreasing supply of new agents [3, 6–8], and in the remainder of the book we review approaches being taken to identity and develop the antimicrobials of the future.

In response to the challenges outlined, in this book there has been increasing research into maximizing opportunities to develop and revitalize established classes of antibiotics. Coates and Hu consider this area in Chapter 2 where they look at opportunities to extend the life of old antibiotics such as β-lactams by the addition of agents that can overcome drug resistance factors, such as β-lactamase inhibitors. Identification of new, effective derivatives remains a challenge, and another approach in the search for new antibiotics has been to seek out new targets that would enable new classes of antibacterials to be developed. In Chapter 4, Capasso and Supuran review the cloning and characterization of carbonic anhydrases (CAs). In this chapter, they make reference to the impact of inhibitors that target the α-, β-, and γ-CAs from many pathogenic bacteria and suggest that this provides evidence that these proteins could provide novel antibacterial targets for the development of new antimicrobial compounds.

There remain concerns, though, that only a small number of drugs are currently under research and development as antibacterial agents [9]. It has been suggested that a further approach could be to revisit naturally occurring compounds with antibacterial potential. Due to the arrival of antibiotics, there has been a rapid loss of interest in the therapeutic potential of natural host antibiotics such as lysozyme [3, 4]. However, more recently, there has been an awakened interest in host defense molecules, such as antimicrobial peptides (AMPs) [10, 11]. Since the early 1990s, the potential of AMPs has been investigated using, for example, magainins isolated from the African clawed frog Xenopus laevis, to investigate the effect of the structural and physiochemical properties of these peptides on their antimicrobial action. These AMPs have the potency to target and kill a wide range of Gram-negative and Gram-positive bacteria, fungi, viruses, and some tumor cells [12]. Based on this ability, AMPs are attractive propositions for development as therapeutically useful antimicrobial and anticancer agents [13]. The first clinical trials of these AMPs as potential novel antibiotics have been for topical treatments [14], and Dennison et al. review this area in Chapter 4. AMPs are not only produced by eukaryotes but are also generated by prokaryotes, and Lotfipour and coworkers review this class of peptides, generally known as bacteriocins, in Chapter 5. These prokaryotic peptides are produced by gene-encoded or ribosome-independent pathways [15]. Non-ribosomal prokaryotic AMPs generally include examples such as vancomycin and daptomycin, which are assembled by large multifunctional enzyme complexes. Gene-encoded AMPs from prokaryotes include microcins from Gram-negative bacteria, lantibiotics, and nonmodified bacteriocins from Gram-positive bacteria. The potential uses of these molecules are reviewed for their potential in food biopreservation and healthcare. However, both eukaryotic and prokaryotic AMPs have a range of challenges to overcome, such as the cost of production and design complexity of these molecules. For this reason, work has been under way to design mimics and peptidomimetics of these peptides, which is reviewed in Chapter 6 by Cai and coworkers. Major examples of these molecules include : peptoids [16], β-peptides [17], arylamide oligomers [18], AApeptides [19, 20], and other compounds [21–25], which may be considered second-generation AMPs. These molecules are designed to possess properties conducive to therapeutic application and retain key structural characteristics of naturally occurring AMPs, such as positive charge, hydrophobicity, and amphiphilicity, which facilitate their membranolytic and antimicrobial activity. Tuning these properties has led to superior levels of microbial selectivity and antimicrobial activity as compared to both natural AMPs and conventional antibiotics. This Chapter considers the recent development of these synthetic mimics of AMPs based on a variety of peptide backbones other than canonical peptides, including β-peptides, peptoids, and AApeptides.

It is interesting to note that, in addition to direct action, AMPs are part of more complex innate immune systems and a further approach to developing treatments for the future has involved review of how aspects of such immune systems could be adapted to support treatment of infections. Prior to the discovery and widespread use of antibiotics, it was believed that bacterial infections could be treated by the administration of bacteriophages, which are viruses that infect and kill bacteria via lytic mechanisms but have no effect on humans. With the advent of penicillins and other antibiotics, clinical studies with bacteriophages were not vigorously pursued in the United States and Western Europe, but phage therapy was extensively used in Eastern European countries mainly in the former Soviet Union and Georgia. However, with the current rise of antibiotic-resistant bacteria, there has been a revitalization of interest in phage therapy in Western countries. In Chapter 7, Lu and coworkers discuss the use of synthetic biology and whether bacteriophages are a re-emerging solution to the current problem of pathogenic microbes. Bacteriophage therapy has a number of potential advantages over the use of conventional antibiotics, such as high bacterial specificity and efficacy against bacteria with MDR, although there are concerns over its use, such as the possibility of inducing immunological responses. Nonetheless, phage therapy is generally regarded as one of the most promising strategies to provide antimicrobial alternatives for fighting antibiotic-resistant bacteria and could lead to the development of new and improved therapies and diagnostics to combat infectious threats of the present and the future.

In addition to the above approaches, there is a wide range of additional natural compounds that have the potential in the treatment of infection. The antimicrobial properties of metals such as copper and silver have been known for centuries especially in use for the treatment of burns and chronic wounds [26]. Recently, the confluence of nanotechnology and the search for new agents in the fight against microbes with MDR has brought metals in the form of nanoparticles to the fore as potential antimicrobial agents. In Chapter 8, Sportelli and coworkers present several examples of nanomaterials based on three of the main inorganic materials with known antimicrobial action (i.e., silver, copper, and zinc oxide) along with the mechanisms underlying their antimicrobial action. The potential applications of these nanoparticles as antimicrobials in areas such as prophylaxis and therapeutics, medical devices, the food industry, and textile fabrics are discussed in more detail. In addition, there are numerous examples of naturally produced organic compounds with antibacterial properties. In the period 2000–2008, over 300 natural metabolites with antimicrobial activity were reported, and in Chapter 9, Saleem reviews these compounds and describes candidates with potentially useful antimicrobial activity with reference to a variety of molecules, including : alkaloids, acetylenes, coumarins, iridoids, terpenoids, and xanthones.

A range of organic compounds with the potential to serve as anti-infectives are those that are known to sequester within bacterial cells and can be light-activated to induce antimicrobial activity. For example, phenothiazinium-based molecules [27, 28], whose antimicrobial properties were first noted in dyes that were used for the histological staining of cellular components, have been shown to be more efficacious than conventional antibiotics [28, 29]. These dyes photoinactivate bacteria, viruses, yeasts, fungi, and protozoa via the production of reactive oxygen species (ROS) such as such as hydroxyl radicals and hydrogen peroxide. Over the last few decades, photosensitizers (PS) have attracted increasing attention as antimicrobial agents with therapeutic potential, and, when applied in this context, the use of PS is known as photodynamic antimicrobial chemotherapy (PACT). Phoenix co-workers provide an overview of the photophysics and photochemistry involved in PACT, and illustrate the therapeutic uses of this action with reference to a variety of PACT agents such as methylene blue and 5-aminolevulinic acid. Whilst this area has clear potential, there are also challenges that need to be overcome if the use of such compounds is to become more widespread. One such limitation is the challenge of ensuring effective light penetration of tissue and in this respect, it has been suggested that ultrasound could be used as part of a new antimicrobial strategy that addresses this limitation based on its superior capacity for tissue penetration. Ultrasound has been shown to have an antibacterial effect comparable to some conventional antibiotics as recently reported in the case of rhinosinusitis. It has also been shown that the application of ultrasound in conjunction with conventional antibiotics such as gentamycin is able to synergize the effects of these drugs when applied to both planktonic and sessile bacteria. More recently, it has been shown that irradiation with ultrasound can activate some PS, which are generally termed sonosensitizers (SS) in this capacity, and based on these observations it was hypothesized that ultrasound and SS may be exploited for the treatment of infectious diseases. This system has been designated sonodynamic antimicrobial chemotherapy (SACT) and most recently has been shown to be able to eradicate both Gram-positive and Gram-negative bacteria. In Chapter 11, Harris coworkers provides an overview of the impact of SACT.

In considering approaches to combat growing drug resistance and to identify new means of treatment, the potential of oligonucleotides as antibacterial agents has been investigated. Such molecules are able to act as antisense agents to prevent translation, or, alternatively, can be designed to bind DNA to prevent gene transcription: these approaches are reviewed in Chapter 12 by Beaman coworkers. In this area, a range of new and exciting approaches are being developed. For example, it may be that such agents can inhibit microbial resistance mechanisms by interrupting the expression of resistance genes and hence restore susceptibility to key antibiotics, which would be co-administered with the antisense compound. Such an approach will clearly have significant applications.

Finally, it is worth considering whether antibiotic efficacy can be increased by enhancing the targeting of such molecules to their site of action. In the final chapter, Ehlissi coworkers review an example of such an approach by looking at targeting via the development of antimicrobial agent carrier systems such as the use of nanoparticle constructs. Here, the authors discuss the development of nanostructures for the entrapment and delivery of antimicrobials as an alternative to the direct application of these substances. Specific reference is made to structures formed from liposomes and the effects of the carrier on the activity of the compound are discussed.

In conclusion, it is clear that new approaches are needed if we are to maintain our ability to deal with infection. These approaches have to be holistic and integrated and must involve consideration of stewardship programs as well as the development of new antibiotics and novel approaches to enhancing activity through improved targeting or combination therapies. The need for the development of new antibiotics and antibacterial design strategies has never been greater.

March 2014

David A. Phoenix, Frederick Harris, and Sarah R. Dennison

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1The Problem of Microbial Drug Resistance

Iza Radecka, Claire Martin and David Hill

1.1 Introduction

Microbial colonization, where it is not wanted, can lead to disease, disability, and death. Therefore, control and/or destruction of pathogenic microorganisms is crucial for the prevention and treatment of disease. Modern medicine is dependent on antimicrobial/chemotherapeutic agents such as antibiotics (Greek anti, against, bios life). Antibiotics can either destroy pathogens or inhibit their growth and avoid damage to the host. In the nineteenth century, infections such as diarrhea, pneumonia, or post-surgical infections were the main causes of death. Therefore, the discovery of antibiotics was of great importance to society and impacted on the prevention and treatment of disease. Antibiotics can be defined as compounds produced by microorganisms that are effective against other microorganisms but nowadays also include microbial compounds that have been synthetically altered. The classification of antibiotics is based not only on the cellular components or systems they affect but also on whether they inhibit cell growth (bacteriostatic drug) or kill the cells (bactericidal drug) [1]. Other chemotherapeutic synthetic drugs, not originating from microbes, such as sulfonamides, are also sometimes called antibiotics [2].