Abstract
In the cell, the protein synthetic machinery is a highly complex apparatus that offers many potential sites for functional interference and therefore represents a major target for antibiotics. The recent plethora of crystal structures of ribosomal subunits in complex with various antibiotics has provided unparalleled insight into their mode of interaction and inhibition. However, differences in the conformation, orientation and position of some of these drugs bound to ribosomal subunits of Deinococcus radiodurans (D50S) compared to Haloarcula marismortui (H50S) have raised questions regarding the species specificity of binding. Revisiting the structural data for the bacterial D50S-antibiotic complexes reveals that the mode of binding of the macrolides, ketolides, streptogramins and lincosamides is generally similar to that observed in the archaeal H50S structures. However, small discrepancies are observed, predominantly resulting from species-specific differences in the ribosomal proteins and rRNA constituting the drug-binding sites. Understanding how these small alterations at the binding site influence interaction with the drug will be essential for rational design of more potent inhibitors.
References
Ban, N., Nissen, P., Hansen, J., Moore, P.B., and Steitz, T.A. (2000). The complete atomic structure of the large ribosomal subunit at 2.4 Å resolution. Science289, 905–920.Search in Google Scholar
Baram, D., Pyetan, E., Sittner, A., Auerbach-Nevo, T., Bashan, A., and Yonath, A. (2005). Structure of trigger factor binding domain in biologically homologous complex with eubacterial ribosome reveals its chaperone action. Proc. Natl. Acad. Sci. USA102, 12017–22.10.1073/pnas.0505581102Search in Google Scholar
Berisio, R., Harms, J., Schluenzen, F., Zarivach, R., Hansen, H., Fucini, P., and Yonath, A. (2003). Structural insight into the antibiotic action of telithromycin on resistant mutants. J. Bacteriol.185, 4276–4279.10.1128/JB.185.14.4276-4279.2003Search in Google Scholar
Canu, A. and Leclercq, R. (2001). Overcoming bacterial resistance by dual target inhibition: the case of streptogramins. Curr. Drug Targets Infect. Disord.1, 215–225.10.2174/1568005014606152Search in Google Scholar
Canu, A., Malbruny, B., Coquemont, M., Davies, T.A., Appelbaum, P.C., and Leclercq, R. (2002). Diversity of ribosomal mutations conferring resistance to macrolides, clindamycin, streptogramin, and telithromycin in Streptococcus pneumoniae. Antimicrob. Agents Chemother.46, 125–131.10.1128/AAC.46.1.125-131.2002Search in Google Scholar
Carter, A.P., Clemons, W.M., Brodersen, D.E., Morgan-Warren, R.J., Wimberly, B.T., and Ramakrishnan, V. (2000). Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. Nature407, 340–348.10.1038/35030019Search in Google Scholar
Carter, A.P., Clemons, W.M. Jr., Brodersen, D.E., Morgan-Warren, R.J., Hartsch, T., Wimberly, B.T., and Ramakrishnan, V. (2001). Crystal structure of an initiation factor bound to the 30S ribosomal subunit. Science291, 498–501.10.1126/science.1057766Search in Google Scholar
Chinali, G., Moureau, P., and Cocito, C. (1984). The action of virginiamycin M on the acceptor, donor, and catalytic sites of peptidyltransferase. J. Biol. Chem.259, 9563–9568.10.1016/S0021-9258(17)42737-2Search in Google Scholar
Chittum, H.S. and Champney, W.S. (1994). Ribosomal protein gene sequence changes in erythromycin-resistant mutants of Escherichia coli. J. Bacteriol.176, 6192–6198.10.1128/jb.176.20.6192-6198.1994Search in Google Scholar PubMed PubMed Central
Clark, C., Bozdogan, B., Peric, M., Dewasse, B., Jacobs, M., and Appelbaum, P. (2002). In vitro selection of resistance in Haemophilus influenzae by amoxicillin-clavulanate, cefpodoxime, cefprozil, azithromycin, and clarithromycin. Antimicrob. Agents Chemother.46, 2956–2962.10.1128/AAC.46.9.2956-2962.2002Search in Google Scholar PubMed PubMed Central
Cocito, C., Di Giambattista, M., Nyssen, E., and Vannuffel, P. (1997). Inhibition of protein synthesis by streptogramins and related antibiotics. J. Antimicrob. Chemother.39, 7–13.10.1093/jac/39.suppl_1.7Search in Google Scholar PubMed
Depardieu, F. and Courvalin, P. (2001). Mutation in 23S rRNA responsible for resistance to 16-membered macrolides and streptogramins in Streptococcus pneumoniae. Antimicrob. Agents Chemother.45, 319–323.10.1128/AAC.45.1.319-323.2001Search in Google Scholar
Diaconu, M., Kothe, U., Schlünzen, F., Fischer, N., Harms, J., Tonevitski, A., Stark, H., Rodnina, M., and Wahl, M. (2005). Structural basis for the function of the ribosomal L7/12 stalk in factor binding and GTPase activation. Cell121, 991–1004.10.1016/j.cell.2005.04.015Search in Google Scholar
Dinos, G., Michelinaki, M., and Kalpaxis, D. (2001). Insights into the mechanism of azithromycin interaction with an Escherichia coli functional ribosomal complex. Mol. Pharmacol.59, 1441–1445.10.1124/mol.59.6.1441Search in Google Scholar
Douthwaite, S. (1992). Interaction of the antibiotics clindamycin and lincomycin with Escherichia coli 23S ribosomal RNA. Nucleic Acids Res.20, 4717–4720.10.1093/nar/20.18.4717Search in Google Scholar
Ferbitz, L., Maier, T., Patzelt, H., Bukau, B., Deuerling, E., and Ban, N. (2004). Trigger factor in complex with the ribosome forms a molecular cradle for nascent proteins. Nature431, 590–596.10.1038/nature02899Search in Google Scholar
Franceschi, F., Kanyo, Z., Sherer, E., and Sutcliffe, J. (2004). Macrolide resistance from the ribosome perspective. Curr. Drug Targets Infect. Disord.4, 177–191.10.2174/1568005043340740Search in Google Scholar
Gale, E.F., Cundliffe, E., Reynolds, P.E., Richmond, M.H., and Waring, M.J. (1981). Antibiotic inhibitors of ribosome function. In: The Molecular Basis of Antibiotic Action (Bristol, UK: John Wiley and Sons), pp. 278–379.Search in Google Scholar
Garza-Ramos, G., Xiong, L., Zhong, P., and Mankin, A. (2001). Binding site of macrolide antibiotics on the ribosome: new resistance mutation identifies a specific interaction of ketolides with rRNA. J. Bacteriol.183, 6898–907.10.1128/JB.183.23.6898-6907.2001Search in Google Scholar
Gregory, S.T. and Dahlberg, A.E. (1999). Erythromycin resistance mutations in ribosomal proteins L22 and L4 perturb the higher order structure of 23S ribosomal RNA. J. Mol. Biol.289, 827–834.10.1006/jmbi.1999.2839Search in Google Scholar
Hansen, J.L., Ippolito, J.A., Ban, N., Nissen, P., Moore, P.B., and Steitz, T.A. (2002). The structures of four macrolide antibiotics bound to the large ribosomal subunit. Mol. Cell10, 117–128.10.1016/S1097-2765(02)00570-1Search in Google Scholar
Hansen, J.L., Moore, P.B., and Steitz, T.A. (2003). Structures of five antibiotics bound at the peptidyl transferase center of the large ribosomal subunit. J. Mol. Biol.330, 1061–1075.10.1016/S0022-2836(03)00668-5Search in Google Scholar
Harms, J., Schlünzen, F., Zarivach, R., Bashan, A., Gat, S., Agmon, I., Bartels, H., Franceschi, F., and Yonath, A. (2001). High resolution structure of the large ribosomal subunit from a mesophilic eubacterium. Cell107, 679–688.10.1016/S0092-8674(01)00546-3Search in Google Scholar
Harms, J., Schlünzen, F., Fucini, P., Bartels, H., and Yonath, A. (2004). Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the streptogramins dalfopristin and quinupristin. BMC Biol.2, 4.10.1186/1741-7007-2-4Search in Google Scholar
Jenni, S. and Ban, N. (2003). The chemistry of protein synthesis and voyage through the ribosomal tunnel. Curr. Opin. Struct. Biol.13, 212–219.10.1016/S0959-440X(03)00034-4Search in Google Scholar
Liu, M. and Douthwaite, S. (2002). Activity of the ketolide telithromycin is refractory to Erm monomethylation of bacterial rRNA. Antimicrob. Agents Chemother.46, 1629–1633.10.1128/AAC.46.6.1629-1633.2002Search in Google Scholar
Mankin, A.S. (2001). Ribosomal antibiotics. Mol. Biol.35, 509–520.10.1023/A:1010510623805Search in Google Scholar
Nyssen, E., Di Giambattista, M., and Cocito, C. (1989). Analysis of the reversible binding of virginiamycin M to ribosome and particle functions after removal of the antibiotic. Biochim. Biophys. Acta1009, 39–46.10.1016/0167-4781(89)90076-6Search in Google Scholar
Ogle, J.M., Brodersen, D.E., Clemons W.M. Jr., Tarry, M.J., Carter, A.P., and Ramakrishnan, V. (2001). Recognition of cognate transfer RNA by the 30S ribosomal subunit. Science292, 897–902.10.1126/science.1060612Search in Google Scholar
Okamoto, H., Miyazaki, S., Tateda, K., Ishii, Y., and Yamaguchi, K. (2001). In vivo efficacy of telithromycin (HMR3647) against Streptococcus pneumoniae and Haemophilus influenzae. Antimicrob. Agents Chemother.45, 3250–3252.10.1128/AAC.45.11.3250-3252.2001Search in Google Scholar
Parfait, R. and Cocito, C. (1980). Lasting damage to bacterial ribosomes by reversibly bound virginiamycin M. Proc. Natl. Acad. Sci. USA77, 5492–5496.10.1073/pnas.77.9.5492Search in Google Scholar
Parfait, R., Di Giambattista, M., and Cocito, C. (1981). Competition between erythromycin and virginiamycin for in vitro binding to the large ribosomal subunit. Biochim. Biophys. Acta654, 236–241.10.1016/0005-2787(81)90177-5Search in Google Scholar
Pfister, P., Jenni, S., Poehlsgaard, J., Thomas, A., Douthwaite, S., Ban, N., and Bottger, E. (2004). The structural basis of macrolide-ribosome binding assessed using mutagenesis of 23S rRNA positions 2058 and 2059. J. Mol. Biol.342, 1569–1581.10.1016/j.jmb.2004.07.095Search in Google Scholar
Pioletti, M., Schlünzen, F., Harms, J., Zarivach, R., Gluhmann, M., Avila, H., Bashan, A., Bartels, H., Auerbach, T., Jacobi, C., et al. (2001). Crystal structures of complexes of the small ribosomal subunit with tetracycline, edeine and IF3. EMBO J.20, 1829–1839.10.1093/emboj/20.8.1829Search in Google Scholar
Poehlsgaard, J. and Douthwaite, S. (2003). Macrolide antibiotic interaction and resistance on the bacterial ribosome. Curr. Opin. Invest. Drugs4, 140–148.Search in Google Scholar
Porse, B.T. and Garrett, R.A. (1999). Sites of interaction of streptogramin A and B antibiotics in the peptidyl transferase loop of 23 S rRNA and the synergism of their inhibitory mechanisms. J. Mol. Biol.286, 375–387.10.1006/jmbi.1998.2509Search in Google Scholar
Rodriguez-Fonseca, C., Amils, R., and Garrett, R.A. (1995). Fine structure of the peptidyl transferase centre on 23 S-like rRNAs deduced from chemical probing of antibiotic-ribosome complexes. J. Mol. Biol.247, 224–235.10.1006/jmbi.1994.0135Search in Google Scholar
Schlünzen, F., Tocilj, A., Zarivach, R., Harms, J., Gluehmann, M., Janell, D., Bashan, A., Bartels, H., Agmon, I., Franceschi, F., and Yonath, A. (2000). Structure of functionally activated small ribosomal subunit at 3.3 Å resolution. Cell102, 615–623.10.1016/S0092-8674(00)00084-2Search in Google Scholar
Schlünzen, F., Zarivach, R., Harms, J., Bashan, A., Tocilj, A., Albrecht, R., Yonath, A., and Franceschi, F. (2001). Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature413, 814–821.10.1038/35101544Search in Google Scholar
Schlünzen, F., Harms, J.M., Franceschi, F., Hansen, H.A., Bartels, H., Zarivach, R., and Yonath, A. (2003). Structural basis for the antibiotic activity of ketolides and azalides. Structure (Camb.)11, 329–338.10.1016/S0969-2126(03)00022-4Search in Google Scholar
Schlünzen, F., Wilson, D., Tian, P., Harms, J., McInnes, S., HAS, H., Albrecht, R., Buerger, J., Wilbanks, S., and Fucini, P. (2005). The binding mode of the trigger factor on the ribosome: implications for protein folding and SRP interaction. Structure (Camb.)13, 1–15.10.1016/j.str.2005.08.007Search in Google Scholar
Spizek, J., Novotna, J., and Rezanka, T. (2004). Lincosamides: chemical structure, biosynthesis, mechanism of action, resistance, and applications. Adv. Appl. Microbiol.56, 121–154.10.1016/S0065-2164(04)56004-5Search in Google Scholar
Sumbatyan, N., Korshunova, G., and Bogdanov, A. (2003). Peptide derivatives of antibiotics tylosin and desmycosin, protein synthesis inhibitors. Biochemistry (Moscow)68, 1156–1158.10.1023/A:1026318914546Search in Google Scholar
Tenson, T. and Ehrenberg, M. (2002). Regulatory nascent peptides in the ribosomal tunnel. Cell108, 591–594.10.1016/S0092-8674(02)00669-4Search in Google Scholar
Tu, D., Blaha, G., Moore, P., and Steitz, T. (2005a). Gene replacement in Haloarcula marismortui: construction of a strain with two of its three chromosomal rRNA operons deleted. Extremophiles (Epub ahead of print; DOI 10.1007/s00792-005-0459-y).10.1007/s00792-005-0459-ySearch in Google Scholar
Tu, D., Blaha, G., Moore, P., and Steitz, T. (2005b). Structures of MLSBK antibiotics bound to mutated large ribosomal sub-units provide a structural explanation for resistance. Cell121, 257–270.10.1016/j.cell.2005.02.005Search in Google Scholar
Vannuffel, P. and Cocito, C. (1996). Mechanism of action of streptogramins and macrolides. Drugs51, 20–30.10.2165/00003495-199600511-00006Search in Google Scholar
Vannuffel, P., Di Giambattista, M., and Cocito, C. (1992). The role of rRNA bases in the interaction of peptidyltransferase inhibitors with bacterial ribosomes. J. Biol. Chem.267, 16114–16120.10.1016/S0021-9258(18)41974-6Search in Google Scholar
Vannuffel, P., Di Giambattista, M., and Cocito, C. (1994). Chemical probing of a virginiamycin M-promoted conformational change of the peptidyl-transferase domain. Nucleic Acids Res.22, 4449–4453.10.1093/nar/22.21.4449Search in Google Scholar PubMed PubMed Central
Verdier, L., Bertho, G., Gharbi-Benarous, J., and Girault, J. (2000). Lincomycin and clindamycin conformations. A fragment shared by macrolides, ketolides and lincosamides determined from TRNOE ribosome-bound conformations. Bioorg. Med. Chem.8, 1225–1243.Search in Google Scholar
Wilson, D.N. (2004). Antibiotics and the inhibition of ribosome function. In: Protein Synthesis and Ribosome Structure, K.H. Nierhaus and D.N. Wilson, eds. (Weinheim, Germany: Wiley-VCH), pp. 449–527.10.1002/3527603433.ch12Search in Google Scholar
Wilson, D.N., Schlünzen, F., Harms, J.M., Yoshida, T., Ohkubo, T., Albrecht, R., Buerger, J., Kobayashi, Y., and Fucini, P. (2005). X-Ray crystallography study on ribosome recycling: the mechanism of binding and action of RRF on the 50S ribosomal subunit. EMBO J.24, 251–260.10.1038/sj.emboj.7600525Search in Google Scholar PubMed PubMed Central
Wimberly, B.T., Brodersen, D.E., Clemons, W.M., Morgan-Warren, R.J., Carter, A.P., Vonrhein, C., Hartsch, T., and Ramakrishnan, V. (2000). Structure of the 30S ribosomal subunit. Nature407, 327–339.10.1038/35030006Search in Google Scholar PubMed
Wittmann, H.G., Stoffler, G., Apirion, D., Rosen, L., Tanaka, K., Tamaki, M., Takata, R., Dekio, S., and Otaka, E. (1973). Biochemical and genetic studies on two different types of erythromycin resistant mutants of Escherichia coli with altered ribosomal proteins. Mol. Gen. Genet.127, 175–189.10.1007/BF00333665Search in Google Scholar PubMed
Xiong, L., Shah, S., Mauvais, P., and Mankin, A.S. (1999). A ketolide resistance mutation in domain II of 23S rRNA reveals the proximity of hairpin 35 to the peptidyl transferase centre. Mol. Microbiol.31, 633–639.10.1046/j.1365-2958.1999.01203.xSearch in Google Scholar
Youngman, E.M., Brunelle, J.L., Kochaniak, A.B., and Green, R. (2004). The active site of the ribosome is composed of two layers of conserved nucleotides with distinct roles in peptide bond formation and peptide release. Cell117, 589–599.10.1016/S0092-8674(04)00411-8Search in Google Scholar
©2005 by Walter de Gruyter Berlin New York