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18 CONTENTS 0-8493-1141-1/02/$0.00+$1.50 © 2002 by CRC Press LLC Microbial Membrane- Permeating Peptides and Their Applications K. R. Gunaratna, Mats Andersson, and Liam Good 18.1 Introduction ..................................................................................................378 18.2 Background ..................................................................................................378 18.2.1 Microbial and Mammalian Cell Barriers ........................................378 18.2.2 Origins and Discovery of Microbial Cell-Permeating Peptides .....380 18.2.3 Composition and Structure of Microbial Cell-Permeating Peptides ............................................................................................380 18.3 Mechanisms of Action .................................................................................382 18.3.1 Cell Uptake ......................................................................................382 18.3.1.1 Cell Permeation by Cationic Peptides..............................382 18.3.1.2 Receptor-Mediated Transport of Peptides and Endocytosis ................................................................383 18.3.2 Cell-Killing Mechanisms .................................................................383 18.3.2.1 Membrane Leakage ..........................................................383 18.3.2.2 Intracellular Target Inhibition...........................................384 18.3.2.3 Dual Activities of Microbial Cell-Permeating Peptides.............................................................................384 18.3.3 Cell Type-Specific Activities ...........................................................385 18.4 Methods........................................................................................................385 18.4.1 Antimicrobial Activity Assays .........................................................385 18.4.2 Cell Uptake Assays ..........................................................................386 18.4.2.1 Fluorescence Microscopy and FACS Analysis ................386 18.4.2.2 Cell Permeabilization Assays ...........................................386 18.5 Applications .................................................................................................388 18.5.1 Antimicrobial Peptides as a New Source of Anti-Infective Agents for Medicine ........................................................................388 18.5.2 Microbial Cell-Permeating Peptides as Carriers for Foreign Substance Delivery...........................................................................389 Acknowledgments..................................................................................................392 References..............................................................................................................392 377
378 Cell-Penetrating Peptides: Processes and Applications 18.1 INTRODUCTION This chapter reviews peptides that are able to permeate microbial cell membranes and enter cells. The existence of microbial-permeating peptides is surprising because peptides are generally considered too large to pass microbial cell barriers, which are typically more stringent than mammalian cells. Nevertheless, there are many clear examples of peptides able to permeate microbial cells without damage to host cells. Indeed, most of our knowledge of cell-permeating peptides and their potential practical applications stems from the discovery that the innate immune response in animals, plants, and insects involves the release of antimicrobial peptides. Antimicrobial peptides have been shown to kill microbes with im<strong>press</strong>ive potency and specificity and many research groups have sought to develop them as therapeutic agents for infectious disease treatment. In related applications, antimicrobial peptides could provide pathogen resistance to agricultural crops or be used in post harvest food preservation. 1 In all such cases, the objective is to develop peptides to augment the host’s own defense mechanisms against pathogenic microorganisms. The need is increasing for more prudent antibiotic usage and new strategies to fight antibiotic-resistant strains. 2 Despite early warnings during the 1940s, drug resistance has increased into a serious problem that can extend to “stand-by” antibiotics and even the newly introduced oxazolidinones. 3,4 To overcome this problem, antimicrobial peptides or their derivatives offer some exciting possibilities and “antibiotic peptides” may prove to be less susceptible to resistance mechanisms. 5 Effective antimicrobial peptides brought to market would lower our reliance on conventional antibiotics and help to overcome resistant strains. A second possible application is to use permeating peptides as carriers for delivery of foreign substances into microorganisms. 6 The idea seems reasonable, given that many antimicrobial peptides appear to enter cells and act on intracellular targets. 1,7,8 Therefore, it should be possible to use permeating peptides to deliver foreign substances that otherwise would enter microbes only poorly. This application has the same objective as earlier efforts to use receptor-mediated oligopeptide transport mechanisms for antimicrobial delivery, but the cellular uptake mechanism is different. 9-11 The microbialpermeating peptides described here enter cells independent of classical receptor-mediated uptake, as is also the case for the eukaryotic cell-permeating peptides described in earlier chapters in this book (see Chapters 1 to 7, 16, and 17). In this chapter, we first briefly describe microbial membranes and how they differ from mammalian cell membranes. Second, the chapter describes the origin and structures of antimicrobial peptides and their ability to permeate microbial cells. The chapter then focuses on practical applications for cell-permeating peptides in antimicrobial development and cellular delivery. Finally, we describe several research strategies to characterize the uptake of microbial cell-permeating peptides. 18.2 BACKGROUND 18.2.1 MICROBIAL AND MAMMALIAN CELL BARRIERS The cell membrane is formed by a phospholipid bilayer that is generally impermeable to fluids, ions, and most foreign substances. This would seem to isolate the cell from
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CELL- PENETRATING PEPTIDES Processe
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Pharmacology and Toxicology: Basic
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Library of Congress Cataloging-in-P
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to the handbook are prominent resea
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REFERENCES 1. Green, M. and Loewens
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Contributors Mats Andersson Microbi
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Erin T. Pelkey Department of Chemis
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Contents Section I Classes of Cell-
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Chapter 16 Cell-Penetrating Peptide
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The Tat-Derived Cell-Penetrating Pe
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24 Cell-Penetrating Peptides: Proce
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3 Transportans Margus Pooga, Mattia
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Transportans 55 Indeed, galparan is
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Transportans 57 especially the endo
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Transportans 59 In the penetration
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Transportans 61 A 21-mer antisense
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Transportans 63 Commonly, the prote
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Transportans 65 antibiotin antibodi
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Transportans 67 For cross-linking o
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Transportans 69 and still retain ef
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Model Amphipathic Peptides 73 its D
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Model Amphipathic Peptides 75 pmol/
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TABLE 4.1 Internalization of Peptid
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TABLE 4.2 Internalization of Peptid
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Model Amphipathic Peptides 81 relat
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Model Amphipathic Peptides 87 A cat
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Model Amphipathic Peptides 89 At th
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Model Amphipathic Peptides 91 16. H
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Signal Sequence-Based Cell-Penetrat
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Interactions of Cell-Penetrating Pe
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Structure Prediction of CPPs and It
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FIGURE 9.7 (Color Figure 9.7 follow
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FIGURE 9.8 The center of the figure
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Biophysical Studies of Cell-Penetra
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Toxicity and Side Effects of Cell-P
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Kinetics of Uptake of Cell-Penetrat
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Page 350 and 351: Cell-Penetrating Peptide Conjugatio
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Page 370 and 371: Cell-Penetrating Peptides as Vector
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