Infectious Diseases, 3d Edition Elsevier/Mosby, 2010 Available on line at http://www.expertconsultbook.com/ Chapter 130: Mechanisms of Action Françoise Van Bambeke,1 Youri Glupczynski,2 Marie-Paule Mingeot-Leclercq1 & Paul M Tulkens1 1 Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium 2 Laboratoire de microbiologie, Cliniques universitaires UCL de Mont-Godinne, Yvoir, Belgium MOSBY is an imprint of Elsevier Limited. © 2010, Elsevier Limited. All rights reserved. First published 1999, Second edition 2004, Third edition 2010 ISBN: 978-0-323-04579-7 British Library Cataloguing in Publication Data Infectious diseases.-3rd ed. 1. Communicable diseases2. Communicable diseases - Diagnosis3. Communicable diseases - Treatment I. Cohen, J. (Jon), 1949-616.9 ISBN-13: 9780323045797 Infectious diseases.-3rd ed., Expert consult premium ed. Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress Françoise Van Bambeke Youri Glupczynski Marie-Paule Mingeot- Chapter |130 | Leclercq Paul M Tulkens Mechanisms of action the cyclic amide is similar, and act as a false substrate for D -alanyl- D - ANTIBIOTICS THAT ACT ON THE CELL WALL alanyl transpeptidases. The carbonyl of the beta-lactam ring reacts with a serine residue of the transpeptidases (also called penicillin-binding proteins, PBPs) to give an inactive acyl enzyme (‘suicide inhibition’ by The basis of the bacterial cell wall is peptidoglycan, containing alter- 2 nating residues of N -acetyl-glucosamine and muramic acid in β -1 →4 formation of a covalent bond; Fig. 130.3 ). Transpeptidases, located linkage. The carboxyl groups of muramyl residues are substituted by in the periplasmic space, are directly accessible in Gram-positive bac- teria but protected by the outer membrane in Gram-negative bacteria, short peptides (usually pentapeptides) terminated by a D -Asp- D -Ala- D - which β -lactams must cross (mainly via porin channels). Ala sequence. Cell-wall active antibiotics act by inhibiting the activity β of enzymes involved in the synthesis of the precursors or in the reticu- The impairment of cell wall formation by -lactams explains the lation of peptidoglycan. inhibition of the growth of bacteria, but the bactericidal effect results from indirect mechanisms (mostly the activation of autolytic enzymes). β -Lactams are usually active against rapidly dividing bacteria only. b -Lactams The β -lactam nucleus is the basic building block of an exceptionally Resistance large class of antibiotics that all share a common mode of action but Resistance to β -lactams occurs by three main different mechanisms. have quite distinct properties in terms of spectrum, pharmacokinetics • First, access to the PBPs in Gram-negative bacteria might be and, to some extent, activity against resistant strains. abolished by alteration of porin channels, which affects highly water-soluble β -lactams. • Second, resistance can be conferred through modification of PBPs, Chemical structure in particular PBP2 which is essential for the ‘shaping’ of bacteria. The All antibiotics in this class contain a cyclic amide called β -lactam. With most typical example is found in methicillin-resistant Staphylococcus the exception of the monobactams, this cycle is fused with a five- or aureus (MRSA) that produces an altered protein (called PBP2′ or six-membered cycle. According to the nature of the four-membered PBP2a) with a very low affinity for β -lactams. This makes the bacteria latter and/or of the heteroatom included, the following classes have resistant to all conventional β -lactams. Recent research has shown been described ( Fig. 130.1 ): that PBP2a is insensitive to β -lactams because the protein is in ‘closed’ • penams – β -lactams with a five-membered ring containing a conformation, preventing access of the drug to the reactive serine. This sulfur atom (penicillins); is circumvented if bacteria are exposed to acidic pH, which causes • clavams – β -lactamase inhibitors that contain a five-membered an opening of the enzymatic cavity. 3 This can also occur if β -lactams ring with an oxygen as the heteroatom (e.g. clavulanic acid; have a bulky hydrophobic substituent attached to the molecule in sulfur analogues have also been reported); the vicinity of the carboxylate (see Fig. 130.4 for cephalosporins). • carbapenems – five-membered rings without heteroatom and These molecules typically show a loss of activity towards MRSA of with a double bond (e.g. thienamycin, imipenem); only one to eight dilutions (corresponding to the energy needed to • cephems – six-membered unsaturated rings with a sulfur atom open the PBP2a) compared to fully susceptible S. aureus (in contrast (cephalosporins); with often more than 256-fold for conventional β -lactams). Two • oxacephems – the oxygen analogues of cephems (latamoxef); anti-MRSA β -lactam antibiotics (ceftobiprole and ceftaroline) 4 have • monobactams – cyclic amides in a four-membered ring been clinically developed. Penicillin-binding proteins in staphylococci (azetidine) with a methylcarboxylate function in the case or in other organisms (e.g. streptococci) can also show decreased of nocardicins and a sulfonate in the case of the other affinity; in such cases resistance is more specific to some β -lactams monobactams (e.g. aztreonam). but can also be only partial (decreased susceptibility). Other β -lactams include thiacephems, dethiacephems, dethiacephams, • The third and for many years the most frequent mechanism heterocephems and cephams, as well as diverse bicyclic systems. of resistance is the production of hydrolyzing enzymes called β -lactamases. 5 The corresponding genes may be carried either on chromosomes (where their expression may be constitutive or Mode of action inducible) or on plasmids, and their products are secreted out β -Lactams act primarily as inhibitors of transpeptidases (specialized of the cell wall in Gram-positive bacteria and in the periplasmic acyl serine transferases), thereby impairing the synthesis of the cell wall space in Gram-negative bacteria. β -Lactamases are serine proteases ( Fig. 130.2 ). 1 β -Lactams mimic the D -Ala- D -Ala sequence in that the that have a high affinity for β -lactams and cleave the amide bond. distance between the carboxylate or the sulfonate (monobactams) and Although most β -lactamases open the β -lactam ring in the same way 1288 Mechanisms of action Chapter | 130 | to five times the MIC provides little gain in activity, so that frequent Diversity of b-lactam antibiotics dosing is more appropriate than infrequent administration of large doses. Administration of β -lactams by continuous infusion is gaining increasing popularity, 6 but care must be taken regarding the stability of Structure Group Examples the drugs when exposed to room temperature for prolonged periods of time (carbapenems are unstable and cannot be used by continuous S infusion; a ‘prolonged’ infusion time of 3–4 hours has been proposed for doripenem as part of the drug labeling). In general, β -lactams show N Penam Penicillins only a moderate postantibiotic effect. O COOH O Future developments Clavam β-lactamase inhibitors N (clavulanic acid) Efforts continue to develop β -lactams active against MRSA in order O COOH to obtain compounds with increased intrinsic activity (applying the approach used with cephalosporins to penems). In parallel, efforts β Carbapenem (Thienamycin, are being made to develop more effective -lactamase inhibitors N imipenem) (especially for Gram-negative bacteria). Faropenem, an oral penem, O COOH was halted in its development in spite of excellent activity against pneumococci, largely because of fear of triggering resistance to the S whole class of penems if used indiscriminately in the community. Penem (Faropenem) Hybrid molecules combining a β -lactam part and an active antibi- N otic part from a different class (e.g. glycopeptides, fluoroquinolones) O COOH have also been described, with some potentially promising com- S pounds (because of markedly improved activity) in development. N Cephem Cephalosporins O Glycopeptides and lipoglycopeptides COOH Chemical structure O Currently available glycopeptide antibiotics (vancomycin, teicoplanin) contain two sugars and an aglycone moiety made of a relatively highly N Oxacephem (Latamoxef) conserved heptapeptide core, bearing two chloride substituents. The O aglycone fraction is responsible for the pharmacologic activity of the COOH molecule, whereas the sugars are thought to modulate its hydrophilicity and its propensity to form dimers (see below). As a result of their large N Monobactam (Aztreonam) size, glycopeptides are not only unable to cross the outer membrane of Gram-negative bacteria, explaining why they are inactive against these O SO3H organisms, but are also unable to penetrate inside bacteria, limiting them to an extracellular target. Lipoglycopeptides are semisynthetic Fig. 130.1 Diversity of β -lactam antibiotics: main ring structures names derivatives characterized by the addition of a hydrophobic moiety, and representative antibiotics. The figure highlights the fact that all drugs which confers additional properties to the drugs. share a common four-piece β -lactam ring and a carboxylate (or sulfonate) function at an appropriate, similar distance. (Clavams are weak antibiotics Mode of action but efficient β-lactamase inhibitors.) Glycopeptides inhibit the late stages of cell wall peptidoglycan synthe- sis (see Fig. 130.2