Functionalized Nanomaterials for the Management of Microbial Infection Functionalized Nanomaterials for the Management of Microbial Infection A Strategy to Address Microbial Drug Resistance Edited by Rabah Boukherroub CNRS, Lille University of Science and Technology, Villeneuve d’Ascq, France Sabine Szunerits Lille University of Science and Technology, Villeneuve d’Ascq, France Djamel Drider Lille University of Science and Technology, Villeneuve d’Ascq, France AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD PARIS • SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford, OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright © 2017 Elsevier Inc. All rights reserved. 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British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-323-41625-2 For Information on all Elsevier publications visit our website at https://www.elsevier.com Publisher: Matthew Deans Acquisition Editor: Simon Holt Editorial Project Manager: Sabrina Webber Production Project Manager: Caroline Johnson Designer: Greg Harris Typeset by MPS Limited, Chennai, India List of Contributors A. Alvarez-Ordóñez University of León, León, Spain P.C. Balaure University Politehnica of Bucharest, Bucharest, Romania Y. Belguesmia Lille University of Science and Technology, Villeneuve d’Ascq, France R. Boukherroub CNRS, Lille University of Science and Technology, Villeneuve d’Ascq, France K. Braeckmans Ghent University, Ghent, Belgium; Centre for Nano- and Biophotonics, Ghent, Belgium T. Coenye Ghent University, Ghent, Belgium L.M.T. Dicks Stellenbosch University, Stellenbosch, South Africa D. Drider Lille University of Science and Technology, Villeneuve d’Ascq, France A. Friedman George Washington School of Medicine and Health Sciences, Washington, DC, United States D. Gudovan University Politehnica of Bucharest, Bucharest, Romania I. Gudovan University Politehnica of Bucharest, Bucharest, Romania I. Kempf Unité Mycoplasmologie-Bactériologie, Ploufragan, France B. Klumperman Stellenbosch University, Stellenbosch, South Africa B. Mordorski Albert Einstein College of Medicine, Bronx, NY, United States K. Naghmouchi Université de Tunis El Manar, Tunis, Tunisia L. Ruiz Complutense University of Madrid, Madrid, Spain S.K. Samal Ghent University, Ghent, Belgium; Centre for Nano- and Biophotonics, Ghent, Belgium ix x List of Contributors N. Škalko-Basnet Drug Transport and Delivery Research Group, Department of Pharmacy, Faculty of Health Sciences, University of Tromsø The Arctic University of Norway, Tromsø, Norway S. Szunerits Lille University of Science and Technology, Villeneuve d’Ascq, France E. Teirlinck Ghent University, Ghent, Belgium; Centre for Nano- and Biophotonics, Ghent, Belgium N. Tison Lille University of Science and Technology, Villeneuve d’Ascq, France; Haute École Louvain en Hainaut, HELHa, Mons, Belgium A.D.P. van Staden Stellenbosch University, Stellenbosch, South Africa Ž. Vanić Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, A Kovačića 1, Zagreb, Croatia Preface Bacteria usually must adhere to a cellular surface in order to cause disease. In some settings, the adherent microbe physically invades the cellular layer and gains access to inner milieu, as Salmonella or Shigella would in the intestine. In other scenarios, such as the airway of an individual with cystic fibrosis, adherent Pseudomonas aeruginosa establishes a colony (a “bio- film”) on the surface of the bronchial epithelium that resists antimicrobial therapy. Its presence provokes a chronic inflammatory process that gradually destroys the airway. Similarly, infec- tions of the urinary tract usually occur when a strain of Escherichia coli attaches to the surface of the bladder, increases in number, and migrates upwards toward the kidneys. Furthermore, the surfaces of medical devices that come into contact with bacteria generally become colo- nized, be they catheters that are placed in a vein or artery, the urinary tract, or the airway. Bacteria seem to love to grow on surfaces. To treat bacterial infections we almost universally administer antibiotics, which are physically quite small, relative to the size of the microbe. The antibiotic we introduce swarms around the bacterial cell. If the concentration of the antibiotic in the blood, or in the urinary tract, or on the surface of the airway is high enough, sufficient numbers of antibiotic molecules will pen- etrate the bacterial cell and disable it, the sooner the better. In this volume, Functionalized Nanomaterials for the Management of Microbial Infection, Drs. Boukherroub, Szunerits, and Drider suggest that we ought to consider exploiting the pre- dilection that microbes have for surfaces in our design of antibiotic therapeutics. The basic idea is to use nanoparticles, which present a small but discrete surface that can physically con- tact the bacterial cell. If the surface properties of the nanoparticle are optimal for the pur- pose intended, the particle and bacterial cell will adhere to one another. If the nanoparticle is decorated with antibiotics that can act despite being tethered to a surface, then the bacterial cell will find itself facing a wall of deadly agents. (Antimicrobial peptides, including many of the bacteriocins described in this volume, can inflict damage on the bacterial membrane and/ or proteoglycan wall, even when covalently bound to a surface). We learn in this volume that lipids, various polymers, and even graphene, can be exploited as the nanoparticle carrier. The development of nanoparticle antibiotics is very exciting. We all await the outcome of their safety and efficacy in appropriate clinical trials. M. Zasloff Georgetown University Hospital, Washington, DC, United States xi 1 Chapter Resistance to Antibiotics and Antimicrobial Peptides: A Need of Novel Technology to Tackle This Phenomenon Y. Belguesmia1, I. Kempf2, N. Tison1,3, K. Naghmouchi4 and D. Drider1 1Lille University of Science and Technology, Villeneuve d’Ascq, France 2Unité Mycoplasmologie-Bactériologie, Ploufragan, France 3Haute École Louvain en Hainaut, HELHa, Mons, Belgium 4Université de Tunis El Manar, Tunis, Tunisia CHAPTER OUTLINE 1.1 Resistance to Antibiotics 1 1.2 Resistance to Bacteriocins Produced by Gram-Positive Bacteria (GPB) 8 1.3 Conclusion and Prospects 14 Acknowledgements 15 References 15 1.1 RESISTANCE TO ANTIBIOTICS Antimicrobials used for human or animal health include many different families, such as β-lactams, aminoglycosides, macrolides, tetracyclines, and polypeptides, which differ according to their chemical structures, mechanisms of action, and spectra. Antibiotics are drugs of natural, syn- thetic, or semi-synthetic origin that have, at low concentrations, the capac- ity to kill or to inhibit the growth of bacteria whilst causing little or no damage to the host. They can target the bacterial cell wall (β-lactam anti- biotics, vancomycin, and bacitracin), the protein synthesis (macrolides, aminoglycosides, tetracyclines, and chloramphenicol), affect nucleic acid function (quinolones, rifampicin, and nitrofurans), or acid folic synthe- sis (trimethoprim and sulfonamides). Bacteria can be inherently resistant to a specific family of antimicrobials for various reasons: for example, mycoplasmas are naturally resistant to β-lactam antibiotics because they have no cell wall, and Gram-negative bacteria are intrinsically resistant to Functionalized Nanomaterials for the Management of Microbial Infection.DOI:http://dx.doi.org/10.1016/B978-0-323-41625-2.00001-6 1 © 2017Elsevier Inc. All rights reserved. 2 CHAPTER 1 Resistance to Antibiotics and Antimicrobial Peptides macrolides as these molecules are too large to enter the bacteria through their cell wall. Antimicrobial resistance can be acquired in previously sus- ceptible species, either by mutations, such as modifications of the target DNA-gyrase which renders Enterobacteriaceae resistant to quinolones or fluoroquinolones. Mutations can also result in the increased expression of efflux pumps able to export one or several classes of antimicrobials. Bacteria can also acquire resistance genes from other bacteria, by conju- gation, transformation, or transduction. The acquired genes can encode antibiotic-inactivating enzymes (e.g., β-lactamases and aminoglycosides- hydrolyzing enzymes) or modified molecules which are no longer the target of the antibiotic (e.g., altered penicillin-binding-protein PBP2a encoded by the mecA gene in Staphylococcus aureus resistant to methicil- lin), protect the target (e.g., tet(O) gene in Campylobacter spp. encoding a protein protecting the ribosome against tetracycline) or a new efflux pump (e.g., tet(A) gene in Escherichia coli encoding a tetracycline efflux pump). The polypeptide antibiotics belonging to the polymyxin group were dis- covered in the 1940s and were first used in both human and animal medi- cines. Polymyxins are non-ribosomal cyclic lipopeptides mainly used from the late 1950s as a topical treatment in human medicine. The polymyxin E (colistin) has been used particularly for the treatment of Gram-negative bacterial infections. However, in the 1970s, clinical use of these molecules was limited due to their serious nephrotoxicity and neurotoxicity after par- enteral administration under systematic use [1]. Because of this toxicity, the use of polymyxins soon decreased, but colistin remained in frequent use in animals, mainly for the control of enteric infections [2]. Recently the emergence of bacteria resistant to most antibiotic families, including carbapenems, renewed the interest for colistin as a last-resort treatment option for infections caused by multidrug-resistant Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii [3]. The basic structure of polymyxins is composed of a cyclic decapeptide bound to a fatty acid chain at amino terminus. Polymyxin B and poly- myxin E have almost identical primary sequence with difference at posi- tion 6 where D-Phe (D-phenylalanine) in polymyxin B is replaced by d-Leu (d-leucine) in polymyxin E (Fig. 1.1) [4]. The biosynthetic gene cluster of polymyxin is called pmx cluster, including five open reading frames, namely, pmxA, pmxB, pmxC, pmxD, and pmxE. Synthesis of poly- myxin implies three polymyxin synthetases, PmxA, PmxB, and PmxE, and transported by two membrane transport proteins, PmxC and PmxD. The polymyxin structure determines its activity, the assembly order of modules for amino acid during biosynthesis of polymyxin is PmxE–PmxA–PmxB, the fatty acid: 6-methyloctanoic acid or isooctanoic acid; Thr, threonine; 1.1 Resistance to Antibiotics 3 (A) 6 R O H 5 7 N O L-Leu L-Dab 3 NH 1 NH2 L-Dab 2 L-Dab H3HC3C NH O HN NHH2 O HN O CH3 R NH N N O N H H O NH2 O HO CH3 L-Dab O NH L-Dab L-Thr 8 OO NH 4 2 L-Dab HN CH 9 H 3 HN 2 Polymyxin B: R6= D-Phe L-Thr OH Polymyxin E: R6= D-Leu 10 (B) Inner membrane Polymyxin PmxE synthetase 5 C-domain γ-NH2 γ-NH2 γ-NH2 6 7 (α)L-Dab R L-Leu Fatty acid (α)L-Dab L-Thr (α)L-Dab (α,γ)L-Dab 1 2 3 4 L-Thr (α)L-Dab (α)L-Dab 10 T-domain C-domainγ-N9H2 γ-N8H2 PmxB synthetase PmxA synthetase Membrane transport proteins; PmxC and PmxD Polymyxin B: R6=D-Phe Polymyxin E: R6=D-Leu ■■FIGURE 1.1 Chemical structure of polymyxin (A); polymyxin biosynthesis in Paenibacillus polymyxa (B). Adapted from Yu Z, Qin W, Lin J, Fang S, Qiu J. Antibacterial mechanisms of polymyxin and bacterial resistance. BioMed Res Int 2015;679109. doi:10.1155/2015/679109. Phe, phenylalanine; Leu, leucine; Dab, α,γ-diaminobutyric acid, α and γ refer to the respective—NH involved in peptide linkage (Fig. 1.1). 2 Colistin is a bactericidal drug that binds to phospholipids in the outer cell membrane of Gram-negative bacteria and to lipopolysaccharide (LPS), by a hydrophobic interaction between the nine-carbon fatty acid side chain of colistin and the fatty acid portion of lipid A. It competitively displaces divalent cations from the phosphate groups of membrane lipids, which leads to disruption of the outer cell membrane, leakage of intracellular contents, and bacterial death (Fig. 1.2). 4 CHAPTER 1 Resistance to Antibiotics and Antimicrobial Peptides ■■FIGURE 1.2 Antimicrobial mode of action of polymyxin against Gram-negative bacterial membranes. LPS, Lipopolysaccharide. Adapted from [5] Biswas S, Brunel JM, Dubus JC, Reynaud-Gaubert M, Rolain JM. Colistin: an update on the antibiotic of the 21st century. Expert Rev Anti-infect Ther 2012;10(8):917–34. Resistance to polymyxins has been investigated in intrinsically resistant bacterial species, in vitro mutants and in clinical isolates. The electrostatic interaction between positively charged Dab residues, on polymyxin, and negatively charged phosphate groups, on lipid A of LPS, represents the critical step of bactericidal activity of polymyxins. Reduction of this ini- tial electrostatic attraction can occur when net negative charge of the bac- terial outer membrane (OM) is reduced via lipid A modification, implying