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Determinants of the Species Selectivity of Oxazolidinone Antibiotics Targeting the Large Ribosomal Subunit

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Determinants of the Species Selectivity of Oxazolidinone Antibiotics Targeting the Large Ribosomal Subunit DOI 10.1515/hsz-2013-0188 Biol. Chem. 2013; 394(11): 1529–1541 Jagmohan S. Saini, Nadine Homeyer, Simone Fullea and Holger Gohlke* Determinants of the species selectivity of oxazolidinone antibiotics targeting the large ribosomal subunit Abstract: Oxazolidinone antibiotics bind to the highly Introduction conserved peptidyl transferase center in the ribosome. For developing selective antibiotics, a profound under- Ribosomes are complex nanomachines that perform standing of the selectivity determinants is required. We protein synthesis in all living cells. This pivotal role makes have performed for the first time technically challenging the bacterial ribosome a prominent target for antibiotics molecular dynamics simulations in combination with that exert their antimicrobial effect by interfering with molecular mechanics Poisson-Boltzmann surface area protein synthesis (David-Eden et al., 2010). Several crystal (MM-PBSA) free energy calculations of the oxazolidinones structures of ribosomal subunits bound to different classes linezolid and radezolid bound to the large ribosomal sub- of antibiotics have been published over the last decade units of the eubacterium Deinococcus radiodurans and revealing the binding site and binding mode in atomic the archaeon Haloarcula marismortui. A remarkably good detail as well as the structural basis for antibiotic specific- agreement of the computed relative binding free energy ity (Brodersen et al., 2000; Carter et al., 2000; Bottger et al., with selectivity data available from experiment for lin- 2001; Schlunzen et al., 2001; Hansen et al., 2003; Yonath, ezolid is found. On an atomic level, the analyses reveal an 2005a; Ippolito et al., 2008; Wilson et al., 2008; Belousoff intricate interplay of structural, energetic, and dynamic et al., 2011). These structural insights are complemented determinants of the species selectivity of oxazolidinone by several computational studies addressing the dynamic antibiotics: A structural decomposition of free energy and energetic determinants of antibiotics binding to the components identifies influences that originate from first ribosome (Ma et al., 2002; Trylska et al., 2005; Vaiana et al., and second shell nucleotides of the binding sites and 2006; Aleksandrov and Simonson, 2008; Ge and Roux, lead to (opposing) contributions from interaction ener- 2009, 2010; David-Eden et al., 2010; Romanowska et al., gies, solvation, and entropic factors. These findings add 2011). Overall, these studies have provided crucial insights another layer of complexity to the current knowledge on into the mode of action of several classes of antibiotics that structure-activity relationships of oxazolidinones bind- should facilitate efforts to design new antibiotics in order ing to the ribosome and suggest that selectivity analyses to combat the emerging rise in infections due to antibiotic- solely based on structural information and qualitative resistant bacteria and a related mortality rate. arguments on interactions may not reach far enough. The Oxazolidinones represent one of only two new chemi- computational analyses presented here should be of suf- cal classes of antibiotics that have been introduced in the ficient accuracy to fill this gap. clinics over the past 40 years. Linezolid, the only member of this class approved by the FDA, shows excellent activity Keywords: entropy; eubacterium; free energy; linezolid; against major Gram-positive bacteria and is very effective in MM-PBSA; molecular dynamics simulations. the treatment of infections of the respiratory tract and skin disorders (Moellering, 2003; Leach et al., 2011). The co-crys- tal structures of linezolid with the large ribosomal subunit aPresent address: BioMed X GmbH, Im Neuenheimer Feld 583, (50S) of Deinococcus radiodurans (D50S), a eubacterium, D-69120 Heidelberg, Germany. *Corresponding author: Holger Gohlke, Institute for Pharmaceutical (Wilson et al., 2008) and Haloarcula marismortui (H50S), and Medicinal Chemistry, Department of Mathematics and Natural an archaeon, (Ippolito et al., 2008) show that the antibi- Sciences, Heinrich Heine University, Universitätsstr. 1, D-40225 otic exerts its action by binding to the A-site of the peptidyl Düsseldorf, Germany, e-mail: [email protected] transferase center (PTC) and, thereby, hinders the proper Jagmohan S. Saini, Nadine Homeyer and Simone Fulle: Institute placement of the incoming aminoacyl-tRNA (Figure 1A). for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich Heine University, Archaeal ribosomes are considered more ‘eukaryotic-like’ Universitätsstr. 1, D-40225 Düsseldorf, Germany with respect to their antibiotic specificity, i.e., they possess typical eukaryotic elements at the principal antibiotic Bereitgestellt von | Heinrich Heine Universität Düsseldorf Angemeldet | 134.99.237.121 Heruntergeladen am | 14.10.13 10:18 1530 J.S. Saini et al.: Species selectivity of oxazolidinone antibiotics Figure 1 Binding site of oxazolidinone antibiotics in the 50S ribosomal subunit and investigated oxazolidinone derivatives. (A) Global view of the 50S ribosomal subunit showing the location of the binding site of oxazolidinones within the 23S RNA (red). The ribosomal protein chains and the 5S RNA are shown in gray. (B) Close-up view of the binding site with a superposition of binding site nucleotides and linezolid in the H50S (black; PDB code: 3CPW) and D50S (blue; PDB code: 3DLL) structures. Depicted are nucleotides that are part of the first shell of nucleotides around linezolid. Hydrogen bonds are marked by dotted lines: In the H50S structure, a hydrogen bond is formed between the phosphate group of G2505 and the acetamide NH group of linezolid; in the D50S structure, a hydrogen bond is formed between U2585 and the morpholino ring of linezolid. (C) Chemical structures of oxazolidinones investigated in this study: linezolid, radezolid, and rivaroxaban. target sites and require much higher than clinically rel- In order to provide a better understanding of the selec- evant antibiotic concentrations for binding (Mankin and tivity determinants of the oxazolidinone class of antibiotics, Garrett, 1991; Sanz et al., 1993; Hansen et al., 2002; Hansen we have performed for the first time molecular dynamics et al., 2003; Yonath, 2005b). This holds true also for the (MD) simulations in combination with molecular mechan- oxazolidinone class of antibiotics: for co-crystallizing line- ics Poisson-Boltzmann surface area (MM-PBSA) free energy zolid with the eubacterial D50S, a concentration of 5 μm calculations of linezolid bound to D50S and H50S. Further- was required, while a 1000-fold higher concentration was more, we investigated the oxazolidinones radezolid and required for co-crystallization with the archaeal H50S rivaroxaban (Figure 1C). Radezolid is a promising member of (Wilson et al., 2008; Wilson, 2011). Furthermore, in a func- the oxazolidinone class of antibiotics, which has completed tional assay using ribosomes isolated from Staphylococcus phase II of clinical trials [(Shaw and Barbachyn, 2011); http:// aureus, a eubacterium, a translation-inhibitory activity of www.rib-x.com, access date: 11th May 2013], requires a 100- IC50 = 0.9 μm was measured for linezolid (Skripkin et al., times lower concentration than linezolid to inhibit protein 2008), whereas in the case of H. marismortui, an IC50 of synthesis in eubacterial ribosomes (Skripkin et al., 2008), 4.96 μm was found for linezolid (E. M. Duffy, personal com- and shows an improved pattern of selectivity to bacterial munication). This also conveys a selectivity of linezolid for ribosomes (Zhou et al., 2008a). In contrast, rivaroxaban, an the eubacterial ribosome. To the best of our knowledge, no oral anticoagulant, does not bind to the ribosome, although corresponding value for D. radiodurans has been reported it is structurally related to linezolid and radezolid [ChEMBL in the literature. (Gaulton et al., 2011); access date: 11th May 2013]. Hence, The co-crystal structures of linezolid with D50S and rivaroxaban was used as a negative control in the course of H50S provided first insights into the structural basis this study. Overall, our analyses reveal an intricate interplay for the species selectivity of the oxazolidinone family of structural, energetic, and dynamic determinants of the (Figure 1B). As such, U2585 (Escherichia coli numbering) species selectivity of oxazolidinone antibiotics. forms a hydrogen bond with the morpholino ring of line- zolid in the D50S (Wilson et al., 2008) but not in the H50S structure (Ippolito et al., 2008). In contrast, the phosphate group of G2505 forms a hydrogen bond with the acetamide Results NH group of linezolid in the H50S but not in the D50S structure. Otherwise, the overall position of linezolid is Overall stability of the oxazolidinone-50S similar in both species in terms of ring orientations and complexes interactions (Figure 1B). Obviously, the origin for the dif- ference in the binding affinity of linezolid toward D50S or We studied the differences in oxazolidinone binding H50S cannot be deduced from structural data alone. to D50S and H50S by all-atom explicit solvent MD Bereitgestellt von | Heinrich Heine Universität Düsseldorf Angemeldet | 134.99.237.121 Heruntergeladen am | 14.10.13 10:18 J.S. Saini et al.: Species selectivity of oxazolidinone antibiotics 1531 simulations of the respective complexes of 50 ns length as revealed from the time series of these values (Figure each. This leads to a total of 300
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