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How Powerful Is It in the Fight Against Antibiotic-Resistant Bacteria?

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How Powerful Is It in the Fight Against Antibiotic-Resistant Bacteria? 240 Medicina (Kaunas) 2010;46(4):240-8 Tigecycline – how powerful is it in the fight against antibiotic-resistant bacteria? Vaida Šeputienė1, Justas Povilonis1, Julija Armalytė1, 2, Kęstutis Sužiedėlis1, 2, Alvydas Pavilonis3, Edita Sužiedėlienė1 1Department of Biochemistry and Biophysics, Faculty of Natural Sciences, Vilnius University, 2Institute of Oncology, Vilnius University, 3Department of Microbiology, Kaunas University of Medicine, Lithuania Key words: tigecycline; mechanism of action; in vitro and in vivo activity; resistance. Summary. Tigecycline is a semisynthetic analogue of earlier tetracyclines and represents the first member of a novel class of antimicrobials – glycylcyclines – recently approved for clinical use. It is active against a broad range of gram-negative and gram-positive bacterial species including clinically important multidrug-resistant nosocomial and community-acquired bacterial pathogens. The exact molecular basis of tigecycline action is not clear at present, although similarly to the tetra- cyclines, it has been shown to inhibit the translation elongation step by binding to the ribosome 30S subunit and preventing aminoacylated tRNAs to accommodate in the ribosomal A site. Importantly, tigecycline overcomes the action of ribosomal protection proteins and is not a substrate for tetracy- cline efflux pumps of most bacteria – well-known and prevalent cellular mechanisms of microbial tetracycline resistance. The present review summarizes current knowledge on the molecular mecha- nism of the tigecycline action, antibacterial activity against various bacteria, clinical application, development of resistance to glycylcyclines. Introduction intra-abdominal infections (cIAIs), and communi- Use of antimicrobial drugs over the last 60 years ty-acquired bacterial pneumonia (CABP) (1–2) and in medicine and veterinary has triggered a devel- introduced during the past two decades into clinical opment of very effi cient genetic and biochemi- practice (1). cal mechanisms within bacteria enabling them to Clinical and pharmacological studies of tigecy- live in the antibiotic-containing environments. In cline are summarized recently in several compre- recent years, the emergence and spread of multi- hensive reviews including data on the large in vitro drug-resistant (MDR) pathogenic microorganisms, and clinical trials performed in number of countries which possess exceptional risk to human health, worldwide (3–5). In the present work, we focused have become a problem of special signifi cance. The our attention on molecular basis of tigecycline ac- list of antibiotics available for effi cient treatment tion and on the issue of microbial resistance to gly- of community-acquired and nosocomial infections cylcyclines. caused by methicillin-resistant Staphylococcus au- reus (MRSA), vancomycin-resistant Enterococcus, Glycylcycline structure and molecular extended-spectrum β-lactamase (ESBL)-producing basis of action Escherichia coli, Klebsiella pneumoniae, Pseudomonas From the chemical point of view, glycylcyclines aeruginosa, carbapenemase-producing Acinetobacter are related to tetracyclines, albeit constitute a new baumannii became dramatically short. The avail- class of antibacterials (Fig. 1). Tigecycline (formerly ability of the effective antibacterials, which are ac- GAR-936, Trademark: Tygacil®; Wyeth Pharma- tive against a broad spectrum of antibiotic resistant ceuticals, Inc., Philadelphia, PA, USA), the fi rst gram-positive, gram-negative bacteria and anaero- member of the class, is a structural derivative of bic species, becomes of critical importance in the semisynthetic drug minocycline, differing from it cases of serious bacterial infections, when empiri- by the long side chain at the 9 position of carbon cal therapy often must be applied to avoid patient atom (9-tert-butyl-glycylamido moiety) of the D morbidity and mortality, and reduce the costs of ring of tetracyclic nucleus (Fig. 1). Search for more healthcare. microbiologically active structural analogs of tetra- Tigecycline is the fi rst antimicrobial of glycylcy- cycline in 1990s led to discovery of some derivatives cline class, recently approved for use in the clinical of minocycline such as N, N-dimethylglycylamido practice for the treatment of adult complicated skin (DMG) substituent at 9 position (DMG-MINO), and skin-structure infections (cSSSIs), complicated which differently from other developed analogs was Correspondence to E. Sužiedėlienė, Department of Biochem- Adresas susirašinėti: E. Sužiedėlienė, VU Gamtos mokslų fa- istry and Biophysics, Faculty of Natural Sciences, Vilnius Uni- kulteto Biochemijos ir biofi zikos katedra, M. K. Čiurlionio 21, versity, M. K. Čiurlionio 21, 03101 Vilnius, Lithuania 03101 Vilnius. El. paštas: [email protected] E-mail: [email protected] Medicina (Kaunas) 2010; 46(4) Tigecycline – how powerful is it in the fi ght against antibiotic-resistant bacteria? 241 Tetracycline Minocycline N, N-dimethylglycyclamido minocycline (DMG-MINO) Tigecycline Fig. 1. Chemical structures of tetracycline derivatives and tigecycline active in vitro not only against a wide range of tet- is thought to be achieved, similarly to tetracyclines, racycline-susceptible bacteria but against those pos- through interfering with accommodation of ami- sessing known determinants of resistance to early noacyl-tRNA in the ribosomal A site, which pre- tetracyclines (6). Further development of more ef- cedes the peptidyl-transfer reaction (Fig. 3) (8–10). fi cient compounds led to discovery of GAR-963 in Notably, tigecycline binds 5 times stronger to the 1993, presently known as tigecycline (7) (Fig. 2). N- same ribosomal high-affi nity site as compared to alkyl glycylamido side chain at the carbon 9 position tetracycline, albeit in different orientation (8–10). equips tigecycline by several features, responsible Structural data of the tigecycline/ribosome com- for its biological activity: 1) increases lipid solubil- plex are still lacking, although three dimensional ity of the drug; 2) creates a steric hindrance, which structures of T. thermophilus ribosome 30S subunit prevents tigecycline from the effl ux out the cell by with bound tetracycline, determined by x-ray crys- most membrane-bound effl ux proteins; 3) increases tallography, have shown that the high-affi nity bind- affi nity to the binding site of its cellular target – ri- ing site 1 (Tet-1) is located between the head and bosome. the shoulder of the 30S subunit proximal to 16S Tigecycline enters bacterial cell either through rRNA helix 34 and A site (11). The oxygen atoms passive diffusion or active transport routes (Fig. 3). of the 16S rRNA phosphate backbone interact with In the cytosol, similarly to tetracyclines and their the hydrophilic part of tetracycline through many structural analogs, it reversibly binds to ribosome hydrogen-bonding interactions and are additionally 30S subunit and blocks bacterial growth by inhibi- coordinated by Mg2+, bound to tetracycline mol- tion of protein biosynthesis (8–9). The effect is bac- ecule. From structural data, tetracycline binding is teriostatic rather than bactericidal in most bacteria. proposed to create a steric hindrance, which pre- The inhibition of tigecycline-mediated translation vents aminoacyl-tRNA from positioning (rotation) Medicina (Kaunas) 2010; 46(4) 242 Vaida Šeputienė, Justas Povilonis, Julija Armalytė, et al. 1993 2005 2006 2007 2008 2009 Fig. 2. Timetable of tigecycline (Tygacil) discovery, approval for clinical use, and reports on resistance Fig. 3. Molecular mechanism of tigecycline action Ribosome A (aminoacyl), P (peptidyl) and E (exit) sites, ribosome 30S and 50S subunits, messenger RNA (mRNA) aminoacyl-tRNA/EF-Tu complexes are shown. in A site for peptidyl-transfer reaction (11). Similar is, indeed, a predominant tetracycline binding site mode of action has been proposed for tigecycline and thus steric interference is a major mechanism of (Fig. 3). Notably, tetracycline binding appears do tetracycline action (13). In a similar study, neither not interfere with earlier events of elongation cy- tetracycline nor tigecycline binding to EF-Tu has cle – the binding of aminoacyl-tRNA to the ribos- been shown to have a signifi cant role in translation ome in a form of ternary complex with EF-Tu/GTP inhibition (14). and the codon/anticodon (decoding) recognition- As it has been mentioned above, tigecycline is dependent ribosome-mediated GTP hydrolysis. active against tetracycline-resistant bacterial strains Therefore, bound tetracycline prevents accommo- (6). Tetracycline resistance in various bacteria is dation of aminoacyl-tRNA in the A site just after very common and is mediated through two most decoding and release of EF-Tu/GDP. The second prevailing protein-based mechanisms: export of tet- tetracycline-binding site, Tet-5, is located in 30S racyclines from the cell by the Tet effl ux proteins subunit body, close to the 16S rRNA helix 44 and is (TetA-E, TetK) and protection of the ribosome proposed to participate in the mechanism of inhibi- from tetracycline binding by ribosomal protection tion (11). Additionally, tetracycline has been crys- proteins (TetO, TetM) (8). Large diversity of tet tallized in complex (1:1) with a modifi ed form of genes coding for both groups of proteins are known E. coli EF-Tu-Mg-GDP suggesting another possible to function in tetracycline-resistant gram-negative mode of action through its binding to EF-Tu (12). and gram-positive bacteria either alone or in com- However, recent molecular
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