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Current Medicinal Chemistry

Author(s): Xiaodan Cai, Weihao Zheng and Zigang Li*

DOI: 10.2174/0929867324666171121102829

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High-Throughput Screening Strategies for the Development of Anti-Virulence Inhibitors Against Staphylococcus aureus

Page: [2297 - 2312] Pages: 16

  • * (Excluding Mailing and Handling)

Abstract

Background: The increasing threats of antibiotic resistance urge the need for developing new approaches to combat bacterial infections including those caused by Staphylococcus aureus (S. aureus). Unlike conventional antibiotics that aim to kill bacteria or inhibit their growth, targeting bacterial virulence may be a promising alternative approach, which imposes less selective pressure for antibiotic resistance in future generations.

Objective: Our goal is to provide a systematic review about developing high-throughput screening (HTS) strategies for the identification of inhibitors targeting virulence of S. aureus. We also describe an overview of virulence regulatory pathways for potential antivirulence targets.

Methods: We focus on five potential targets or target families, including agr quorum sensing system, SarA/MgrA protein family, sortase A, Clp protease and eukaryotic-like Ser/Thr phosphatase (Stp1). For each target, we introduce its role in virulence regulation, summarize the HTS approaches that are used to identify novel anti-virulence inhibitors, and discuss the advantages and disadvantages of these strategies.

Conclusion: The discovery of anti-virulence inhibitors via HTS underlines the promising potential of anti-virulence therapy for S. aureus. The development of HTS strategies can facilitate the identification of novel anti-virulence inhibitors for combating S. aureus infection, and may also advance our understanding on virulence regulation in S. aureus.

Keywords: High-throughput screening, anti-virulence, Staphylococcus aureus, agr, SarA/MgrA, sortase A, ClpP, Stp1.

[1]
Archer, G.L. Staphylococcus aureus: A well-armed pathogen. Clin. Infect. Dis., 1998, 26(5), 1179-1181. [http://dx.doi.org/10.1086/520289]. [PMID: 9597249].
[2]
Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States., Available at:. www.cdc.gov/drugresistance/threat-report-2013 [Accessed: April 23, 2013].
[3]
Payne, D.J.; Gwynn, M.N.; Holmes, D.J.; Pompliano, D.L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discov., 2007, 6(1), 29-40. [http://dx.doi.org/10.1038/nrd2201]. [PMID: 17159923].
[4]
Lewis, K. New approaches to antimicrobial discovery. Biochem. Pharmacol., 2017, 134, 87-98. [http://dx.doi.org/10.1016/j.bcp.2016.11.002]. [PMID: 27823963].
[5]
Proctor, R.A. Challenges for a universal Staphylococcus aureus vaccine. Clin. Infect. Dis., 2012, 54(8), 1179-1186. [http://dx.doi.org/10.1093/cid/cis033]. [PMID: 22354924].
[6]
Jansen, K.U.; Girgenti, D.Q.; Scully, I.L.; Anderson, A.S. Vaccine review: “Staphyloccocus aureus vaccines: Problems and prospects. Vaccine, 2013, 31(25), 2723-2730. [http://dx.doi.org/10.1016/j.vaccine.2013.04.002]. [PMID: 23624095].
[7]
Clatworthy, A.E.; Pierson, E.; Hung, D.T. Targeting virulence: A new paradigm for antimicrobial therapy. Nat. Chem. Biol., 2007, 3(9), 541-548. [http://dx.doi.org/10.1038/nchembio.2007.24]. [PMID: 17710100].
[8]
Rasko, D.A.; Sperandio, V. Anti-virulence strategies to combat bacteria-mediated disease. Nat. Rev. Drug Discov., 2010, 9(2), 117-128. [http://dx.doi.org/10.1038/nrd3013]. [PMID: 20081869].
[9]
Heras, B.; Scanlon, M.J.; Martin, J.L. Targeting virulence not viability in the search for future antibacterials. Br. J. Clin. Pharmacol., 2015, 79(2), 208-215. [http://dx.doi.org/10.1111/bcp.12356]. [PMID: 24552512].
[10]
Brannon, J.R.; Hadjifrangiskou, M. The arsenal of pathogens and antivirulence therapeutic strategies for disarming them. Drug Des. Devel. Ther., 2016, 10, 1795-1806. [PMID: 27313446].
[11]
Kong, C.; Neoh, H.M.; Nathan, S. Targeting Staphylococcus aureus toxins: A potential form of anti-virulence therapy. Toxins (Basel), 2016, 8(3)E72 [http://dx.doi.org/10.3390/toxins8030072]. [PMID: 26999200].
[12]
Vale, P.F.; McNally, L.; Doeschl-Wilson, A.; King, K.C.; Popat, R.; Domingo-Sananes, M.R.; Allen, J.E.; Soares, M.P.; Kümmerli, R. Beyond killing: Can we find new ways to manage infection? Evol. Med. Public Health, 2016, 2016(1), 148-157. [http://dx.doi.org/10.1093/emph/eow012]. [PMID: 27016341].
[13]
Welsh, M.A.; Blackwell, H.E. Chemical probes of quorum sensing: From compound development to biological discovery. FEMS Microbiol. Rev., 2016, 40(5), 774-794. [http://dx.doi.org/10.1093/femsre/fuw009]. [PMID: 27268906].
[14]
Braff, D.; Shis, D.; Collins, J.J. Synthetic biology platform technologies for antimicrobial applications. Adv. Drug Deliv. Rev., 2016, 105(Pt A), 35-43.. [http://dx.doi.org/10.1016/j.addr.2016.04.006]
[15]
Hwang, I.Y.; Koh, E.; Kim, H.R.; Yew, W.S.; Chang, M.W. Reprogrammable microbial cell-based therapeutics against antibiotic-resistant bacteria. Drug Resist. Updat., 2016, 27, 59-71. [http://dx.doi.org/10.1016/j.drup.2016.06.002]. [PMID: 27449598].
[16]
Markowska, K.; Grudniak, A.M.; Wolska, K.I. Silver nanoparticles as an alternative strategy against bacterial biofilms. Acta Biochim. Pol., 2013, 60(4), 523-530. [PMID: 24432308].
[17]
Chang, L.; Bertani, P.; Gallego-Perez, D.; Yang, Z.; Chen, F.; Chiang, C.; Malkoc, V.; Kuang, T.; Gao, K.; Lee, L.J.; Lu, W. 3D nanochannel electroporation for high-throughput cell transfection with high uniformity and dosage control. Nanoscale, 2016, 8(1), 243-252. [http://dx.doi.org/10.1039/C5NR03187G]. [PMID: 26309218].
[18]
Chang, L.; Gallego-Perez, D.; Chiang, C.L.; Bertani, P.; Kuang, T.; Sheng, Y.; Chen, F.; Chen, Z.; Shi, J.; Yang, H.; Huang, X.; Malkoc, V.; Lu, W.; Lee, L.J. Controllable large-scale transfection of primary mammalian cardiomyocytes on a nanochannel array platform. Small, 2016, 12(43), 5971-5980. [http://dx.doi.org/10.1002/smll.201601465]. [PMID: 27648733].
[19]
Balaban, N.; Goldkorn, T.; Nhan, R.T.; Dang, L.B.; Scott, S.; Ridgley, R.M.; Rasooly, A.; Wright, S.C.; Larrick, J.W.; Rasooly, R.; Carlson, J.R. Autoinducer of virulence as a target for vaccine and therapy against Staphylococcus aureus. Science, 1998, 280(5362), 438-440. [http://dx.doi.org/10.1126/science.280.5362.438]. [PMID: 9545222].
[20]
Novick, R.P.; Geisinger, E. Quorum sensing in staphylococci. Annu. Rev. Genet., 2008, 42, 541-564. [http://dx.doi.org/10.1146/annurev.genet.42.110807.091640]. [PMID: 18713030].
[21]
Sun, F.; Ding, Y.; Ji, Q.; Liang, Z.; Deng, X.; Wong, C.C.; Yi, C.; Zhang, L.; Xie, S.; Alvarez, S.; Hicks, L.M.; Luo, C.; Jiang, H.; Lan, L.; He, C. Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance. Proc. Natl. Acad. Sci. USA, 2012, 109(38), 15461-15466. [http://dx.doi.org/10.1073/pnas.1205952109]. [PMID: 22927394].
[22]
Zheng, W.; Cai, X.; Xie, M.; Liang, Y.; Wang, T.; Li, Z. Structure-based identification of a potent inhibitor targeting stp1-mediated virulence regulation in Staphylococcus aureus. Cell Chem. Biol., 2016, 23(8), 1002-1013. [http://dx.doi.org/10.1016/j.chembiol.2016.06.014]. [PMID: 27499528].
[23]
Sully, E.K.; Malachowa, N.; Elmore, B.O.; Alexander, S.M.; Femling, J.K.; Gray, B.M.; DeLeo, F.R.; Otto, M.; Cheung, A.L.; Edwards, B.S.; Sklar, L.A.; Horswill, A.R.; Hall, P.R.; Gresham, H.D. Selective chemical inhibition of agr quorum sensing in Staphylococcus aureus promotes host defense with minimal impact on resistance. PLoS Pathog., 2014, 10(6)e1004174 [http://dx.doi.org/10.1371/journal.ppat.1004174]. [PMID: 24945495].
[24]
Sun, F.; Zhou, L.; Zhao, B.C.; Deng, X.; Cho, H.; Yi, C.; Jian, X.; Song, C.X.; Luan, C.H.; Bae, T.; Li, Z.; He, C. Targeting MgrA-mediated virulence regulation in Staphylococcus aureus. Chem. Biol., 2011, 18(8), 1032-1041. [http://dx.doi.org/10.1016/j.chembiol.2011.05.014]. [PMID: 21867918].
[25]
Wang, B.; Muir, T.W. Regulation of Virulence in Staphylococcus aureus: Molecular mechanisms and remaining puzzles. Cell Chem. Biol., 2016, 23(2), 214-224. [http://dx.doi.org/10.1016/j.chembiol.2016.01.004]. [PMID: 26971873].
[26]
Chen, F.; Di, H.; Wang, Y.; Cao, Q.; Xu, B.; Zhang, X.; Yang, N.; Liu, G.; Yang, C.G.; Xu, Y.; Jiang, H.; Lian, F.; Zhang, N.; Li, J.; Lan, L. Small-molecule targeting of a diapophytoene desaturase inhibits S. aureus virulence. Nat. Chem. Biol., 2016, 12(3), 174-179. [http://dx.doi.org/10.1038/nchembio.2003]. [PMID: 26780405].
[27]
Gordon, C.P.; Williams, P.; Chan, W.C. Attenuating Staphylococcus aureus virulence gene regulation: A medicinal chemistry perspective. J. Med. Chem., 2013, 56(4), 1389-1404. [http://dx.doi.org/10.1021/jm3014635]. [PMID: 23294220].
[28]
Cascioferro, S.; Totsika, M.; Schillaci, D.; Sortase, A.; Sortase, A. An ideal target for anti-virulence drug development. Microb. Pathog., 2014, 77, 105-112. [http://dx.doi.org/10.1016/j.micpath.2014.10.007]. [PMID: 25457798].
[29]
Singh, R.P.; Desouky, S.E.; Nakayama, J. Quorum quenching strategy targeting gram-positive pathogenic bacteria. Adv. Exp. Med. Biol., 2016, 901, 109-130. [http://dx.doi.org/10.1007/5584_2016_1]. [PMID: 27167409].
[30]
Ye, F.; Li, J.; Yang, C.G. The development of small-molecule modulators for ClpP protease activity. Mol. Biosyst., 2016, 13(1), 23-31. [http://dx.doi.org/10.1039/C6MB00644B]. [PMID: 27831584].
[31]
Recsei, P.; Kreiswirth, B.; O’Reilly, M.; Schlievert, P.; Gruss, A.; Novick, R.P. Regulation of exoprotein gene expression in Staphylococcus aureus by agar. Mol. Gen. Genet., 1986, 202(1), 58-61. [http://dx.doi.org/10.1007/BF00330517]. [PMID: 3007938].
[32]
Novick, R.P.; Ross, H.F.; Projan, S.J.; Kornblum, J.; Kreiswirth, B.; Moghazeh, S. Synthesis of staphylococcal virulence factors is controlled by a regulatory RNA molecule. EMBO J., 1993, 12(10), 3967-3975. [http://dx.doi.org/10.1002/j.1460-2075.1993.tb06074.x]. [PMID: 7691599].
[33]
Novick, R.P.; Projan, S.J.; Kornblum, J.; Ross, H.F.; Ji, G.; Kreiswirth, B.; Vandenesch, F.; Moghazeh, S. The agr P2 operon: An autocatalytic sensory transduction system in Staphylococcus aureus. Mol. Gen. Genet., 1995, 248(4), 446-458. [http://dx.doi.org/10.1007/BF02191645]. [PMID: 7565609].
[34]
Gupta, R.K.; Luong, T.T.; Lee, C.Y. RNAIII of the Staphylococcus aureus agr system activates global regulator MgrA by stabilizing mRNA. Proc. Natl. Acad. Sci. USA, 2015, 112(45), 14036-14041. [http://dx.doi.org/10.1073/pnas.1509251112]. [PMID: 26504242].
[35]
Abdelnour, A.; Arvidson, S.; Bremell, T.; Rydén, C.; Tarkowski, A. The accessory gene regulator (agr) controls Staphylococcus aureus virulence in a murine arthritis model. Infect. Immun., 1993, 61(9), 3879-3885. [PMID: 8359909].
[36]
Mayville, P.; Ji, G.; Beavis, R.; Yang, H.; Goger, M.; Novick, R.P.; Muir, T.W. Structure-activity analysis of synthetic autoinducing thiolactone peptides from Staphylococcus aureus responsible for virulence. Proc. Natl. Acad. Sci. USA, 1999, 96(4), 1218-1223. [http://dx.doi.org/10.1073/pnas.96.4.1218]. [PMID: 9990004].
[37]
Quave, C.L.; Horswill, A.R. Flipping the switch: Tools for detecting small molecule inhibitors of staphylococcal virulence. Front. Microbiol., 2014, 5, 706. [http://dx.doi.org/10.3389/fmicb.2014.00706]. [PMID: 25566220].
[38]
Kupferwasser, L.I.; Yeaman, M.R.; Nast, C.C.; Kupferwasser, D.; Xiong, Y.Q.; Palma, M.; Cheung, A.L.; Bayer, A.S. Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus. J. Clin. Invest., 2003, 112(2), 222-233. [http://dx.doi.org/10.1172/JCI200316876]. [PMID: 12865410].
[39]
Malone, C.L.; Boles, B.R.; Lauderdale, K.J.; Thoendel, M.; Kavanaugh, J.S.; Horswill, A.R. Fluorescent reporters for Staphylococcus aureus. J. Microbiol. Methods, 2009, 77(3), 251-260. [http://dx.doi.org/10.1016/j.mimet.2009.02.011]. [PMID: 19264102].
[40]
Sully, E.K. Small Molecule Inhibitor of Staphylococcus aureus. Virulence, 2011.
[41]
Mesak, L.R.; Yim, G.; Davies, J. Improved lux reporters for use in Staphylococcus aureus. Plasmid, 2009, 61(3), 182-187. [http://dx.doi.org/10.1016/j.plasmid.2009.01.003]. [PMID: 19399993].
[42]
Figueroa, M.; Jarmusch, A.K.; Raja, H.A.; El-Elimat, T.; Kavanaugh, J.S.; Horswill, A.R.; Cooks, R.G.; Cech, N.B.; Oberlies, N.H. Polyhydroxyanthraquinones as quorum sensing inhibitors from the guttates of Penicillium restrictum and their analysis by desorption electrospray ionization mass spectrometry. J. Nat. Prod., 2014, 77(6), 1351-1358. [http://dx.doi.org/10.1021/np5000704]. [PMID: 24911880].
[43]
Daly, S.M.; Elmore, B.O.; Kavanaugh, J.S.; Triplett, K.D.; Figueroa, M.; Raja, H.A.; El-Elimat, T.; Crosby, H.A.; Femling, J.K.; Cech, N.B.; Horswill, A.R.; Oberlies, N.H.; Hall, P.R. ω-Hydroxyemodin limits Staphylococcus aureus quorum sensing-mediated pathogenesis and inflammation. Antimicrob. Agents Chemother., 2015, 59(4), 2223-2235. [http://dx.doi.org/10.1128/AAC.04564-14]. [PMID: 25645827].
[44]
Cheung, A.L.; Nishina, K.A.; Trotonda, M.P.; Tamber, S. The SarA protein family of Staphylococcus aureus. Int. J. Biochem. Cell Biol., 2008, 40(3), 355-361. [http://dx.doi.org/10.1016/j.biocel.2007.10.032]. [PMID: 18083623].
[45]
Desouky, S.E.; Nishiguchi, K.; Zendo, T.; Igarashi, Y.; Williams, P.; Sonomoto, K.; Nakayama, J. High-throughput screening of inhibitors targeting Agr/Fsr quorum sensing in Staphylococcus aureus and Enterococcus faecalis. Biosci. Biotechnol. Biochem., 2013, 77(5), 923-927. [http://dx.doi.org/10.1271/bbb.120769]. [PMID: 23649251].
[46]
Cheung, A.L.; Koomey, J.M.; Butler, C.A.; Projan, S.J.; Fischetti, V.A. Regulation of exoprotein expression in Staphylococcus aureus by a locus (sar) distinct from agr. Proc. Natl. Acad. Sci. USA, 1992, 89(14), 6462-6466. [http://dx.doi.org/10.1073/pnas.89.14.6462]. [PMID: 1321441].
[47]
Cheung, A.L.; Projan, S.J. Cloning and sequencing of sarA of Staphylococcus aureus, a gene required for the expression of agr. J. Bacteriol., 1994, 176(13), 4168-4172. [http://dx.doi.org/10.1128/jb.176.13.4168-4172.1994]. [PMID: 8021198].
[48]
Cheung, A.L.; Bayer, A.S.; Zhang, G.; Gresham, H.; Xiong, Y.Q. Regulation of virulence determinants in vitro and in vivo in Staphylococcus aureus. FEMS Immunol. Med. Microbiol., 2004, 40(1), 1-9. [http://dx.doi.org/10.1016/S0928-8244(03)00309-2]. [PMID: 14734180].
[49]
Liu, Y.; Manna, A.C.; Pan, C.H.; Kriksunov, I.A.; Thiel, D.J.; Cheung, A.L.; Zhang, G. Structural and function analyses of the global regulatory protein SarA from Staphylococcus aureus. Proc. Natl. Acad. Sci. USA, 2006, 103(7), 2392-2397. [http://dx.doi.org/10.1073/pnas.0510439103]. [PMID: 16455801].
[50]
Luong, T.T.; Newell, S.W.; Lee, C.Y. Mgr, a novel global regulator in Staphylococcus aureus. J. Bacteriol., 2003, 185(13), 3703-3710. [http://dx.doi.org/10.1128/JB.185.13.3703-3710.2003]. [PMID: 12813062].
[51]
Chen, P.R.; Bae, T.; Williams, W.A.; Duguid, E.M.; Rice, P.A.; Schneewind, O.; He, C. An oxidation-sensing mechanism is used by the global regulator MgrA in Staphylococcus aureus. Nat. Chem. Biol., 2006, 2(11), 591-595. [http://dx.doi.org/10.1038/nchembio820]. [PMID: 16980961].
[52]
Wang, Y.; Zhang, H.; Zhang, Q.; Liang, Y.; Ma, L.; Tan, H.; Lao, Y.; Xu, H.; Li, Z. Genetically encoded fluorescence screening probe for MgrA, a global regulator in Staphylococcus aureus. RSC Advances, 2015, 5(106), 87216-87220. [http://dx.doi.org/10.1039/C5RA11455A].
[53]
Mazmanian, S.K.; Liu, G.; Ton-That, H.; Schneewind, O. Staphylococcus aureus sortase, an enzyme that anchors surface proteins to the cell wall. Science, 1999, 285(5428), 760-763. [http://dx.doi.org/10.1126/science.285.5428.760]. [PMID: 10427003].
[54]
Mazmanian, S.K.; Liu, G.; Jensen, E.R.; Lenoy, E.; Schneewind, O. Staphylococcus aureus sortase mutants defective in the display of surface proteins and in the pathogenesis of animal infections. Proc. Natl. Acad. Sci. USA, 2000, 97(10), 5510-5515. [http://dx.doi.org/10.1073/pnas.080520697]. [PMID: 10805806].
[55]
Ton-That, H.; Liu, G.; Mazmanian, S.K.; Faull, K.F.; Schneewind, O. Purification and characterization of sortase, the transpeptidase that cleaves surface proteins of Staphylococcus aureus at the LPXTG motif. Proc. Natl. Acad. Sci. USA, 1999, 96(22), 12424-12429. [http://dx.doi.org/10.1073/pnas.96.22.12424]. [PMID: 10535938].
[56]
Maresso, A.W.; Schneewind, O. Sortase as a target of anti-infective therapy. Pharmacol. Rev., 2008, 60(1), 128-141. [http://dx.doi.org/10.1124/pr.107.07110]. [PMID: 18321961].
[57]
Cascioferro, S.; Raffa, D.; Maggio, B.; Raimondi, M.V.; Schillaci, D.; Daidone, G.; Sortase, A. Sortase A inhibitors: Recent advances and future perspectives. J. Med. Chem., 2015, 58(23), 9108-9123. [http://dx.doi.org/10.1021/acs.jmedchem.5b00779]. [PMID: 26280844].
[58]
Oh, K.B.; Kim, S.H.; Lee, J.; Cho, W.J.; Lee, T.; Kim, S. Discovery of diarylacrylonitriles as a novel series of small molecule sortase A inhibitors. J. Med. Chem., 2004, 47(10), 2418-2421. [http://dx.doi.org/10.1021/jm0498708]. [PMID: 15115384].
[59]
Maresso, A.W.; Wu, R.; Kern, J.W.; Zhang, R.; Janik, D.; Missiakas, D.M.; Duban, M.E.; Joachimiak, A.; Schneewind, O. Activation of inhibitors by sortase triggers irreversible modification of the active site. J. Biol. Chem., 2007, 282(32), 23129-23139. [http://dx.doi.org/10.1074/jbc.M701857200]. [PMID: 17545669].
[60]
Suree, N.; Yi, S.W.; Thieu, W.; Marohn, M.; Damoiseaux, R.; Chan, A.; Jung, M.E.; Clubb, R.T. Discovery and structure-activity relationship analysis of Staphylococcus aureus sortase A inhibitors. Bioorg. Med. Chem., 2009, 17(20), 7174-7185. [http://dx.doi.org/10.1016/j.bmc.2009.08.067]. [PMID: 19781950].
[61]
Zhulenkovs, D.; Rudevica, Z.; Jaudzems, K.; Turks, M.; Leonchiks, A. Discovery and structure-activity relationship studies of irreversible benzisothiazolinone-based inhibitors against Staphylococcus aureus sortase A transpeptidase. Bioorg. Med. Chem., 2014, 22(21), 5988-6003. [http://dx.doi.org/10.1016/j.bmc.2014.09.011]. [PMID: 25282649].
[62]
Oh, K.B.; Nam, K.W.; Ahn, H.; Shin, J.; Kim, S.; Mar, W. Therapeutic effect of (Z)-3-(2,5-dimethoxyphenyl)-2-(4-methoxyphenyl) acrylonitrile (DMMA) against Staphylococcus aureus infection in a murine model. Biochem. Biophys. Res. Commun., 2010, 396(2), 440-444. [http://dx.doi.org/10.1016/j.bbrc.2010.04.113]. [PMID: 20433810].
[63]
Kruger, R.G.; Dostal, P.; McCafferty, D.G. Development of a high-performance liquid chromatography assay and revision of kinetic parameters for the Staphylococcus aureus sortase transpeptidase SrtA. Anal. Biochem., 2004, 326(1), 42-48. [http://dx.doi.org/10.1016/j.ab.2003.10.023]. [PMID: 14769334].
[64]
Zhang, J.; Liu, H.; Zhu, K.; Gong, S.; Dramsi, S.; Wang, Y.T.; Li, J.; Chen, F.; Zhang, R.; Zhou, L.; Lan, L.; Jiang, H.; Schneewind, O.; Luo, C.; Yang, C.G. Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase. Proc. Natl. Acad. Sci. USA, 2014, 111(37), 13517-13522. [http://dx.doi.org/10.1073/pnas.1408601111]. [PMID: 25197057].
[65]
Katayama, Y.; Gottesman, S.; Pumphrey, J.; Rudikoff, S.; Clark, W.P.; Maurizi, M.R. The two-component, ATP-dependent Clp protease of Escherichia coli. Purification, cloning, and mutational analysis of the ATP-binding component. J. Biol. Chem., 1988, 263(29), 15226-15236. [PMID: 3049606].
[66]
Frees, D.; Savijoki, K.; Varmanen, P.; Ingmer, H. Clp ATPases and ClpP proteolytic complexes regulate vital biological processes in low GC, Gram-positive bacteria. Mol. Microbiol., 2007, 63(5), 1285-1295. [http://dx.doi.org/10.1111/j.1365-2958.2007.05598.x]. [PMID: 17302811].
[67]
Mei, J.M.; Nourbakhsh, F.; Ford, C.W.; Holden, D.W. Identification of Staphylococcus aureus virulence genes in a murine model of bacteraemia using signature-tagged mutagenesis. Mol. Microbiol., 1997, 26(2), 399-407. [http://dx.doi.org/10.1046/j.1365-2958.1997.5911966.x]. [PMID: 9383163].
[68]
Frees, D.; Qazi, S.N.; Hill, P.J.; Ingmer, H. Alternative roles of ClpX and ClpP in Staphylococcus aureus stress tolerance and virulence. Mol. Microbiol., 2003, 48(6), 1565-1578. [http://dx.doi.org/10.1046/j.1365-2958.2003.03524.x]. [PMID: 12791139].
[69]
Frees, D.; Gerth, U.; Ingmer, H. Clp chaperones and proteases are central in stress survival, virulence and antibiotic resistance of Staphylococcus aureus. Int. J. Med. Microbiol., 2014, 304(2), 142-149. [http://dx.doi.org/10.1016/j.ijmm.2013.11.009]. [PMID: 24457183].
[70]
Hackl, M.W.; Lakemeyer, M.; Dahmen, M.; Glaser, M.; Pahl, A.; Lorenz-Baath, K.; Menzel, T.; Sievers, S.; Böttcher, T.; Antes, I.; Waldmann, H.; Sieber, S.A. Phenyl esters are potent inhibitors of caseinolytic protease P and reveal a stereogenic switch for deoligomerization. J. Am. Chem. Soc., 2015, 137(26), 8475-8483. [http://dx.doi.org/10.1021/jacs.5b03084]. [PMID: 26083639].
[71]
Pahl, A.; Lakemeyer, M.; Vielberg, M.T.; Hackl, M.W.; Vomacka, J.; Korotkov, V.S.; Stein, M.L.; Fetzer, C.; Lorenz-Baath, K.; Richter, K.; Waldmann, H.; Groll, M.; Sieber, S.A. Reversible inhibitors arrest ClpP in a defined conformational state that can be revoked by ClpX association. Angew. Chem. Int. Ed. Engl., 2015, 54(52), 15892-15896. [http://dx.doi.org/10.1002/anie.201507266]. [PMID: 26566002].
[72]
Brautigan, D.L. Protein Ser/Thr phosphatases--the ugly ducklings of cell signalling. FEBS J., 2013, 280(2), 324-345. [http://dx.doi.org/10.1111/j.1742-4658.2012.08609.x]. [PMID: 22519956].
[73]
Muñoz-Dorado, J.; Inouye, S.; Inouye, M. A gene encoding a protein serine/threonine kinase is required for normal development of M. xanthus, a gram-negative bacterium. Cell, 1991, 67(5), 995-1006. [http://dx.doi.org/10.1016/0092-8674(91)90372-6]. [PMID: 1835671].
[74]
Wang, J.; Li, C.; Yang, H.; Mushegian, A.; Jin, S. A novel serine/threonine protein kinase homologue of Pseudomonas aeruginosa is specifically inducible within the host infection site and is required for full virulence in neutropenic mice. J. Bacteriol., 1998, 180(24), 6764-6768. [PMID: 9852028].
[75]
Beltramini, A.M.; Mukhopadhyay, C.D.; Pancholi, V. Modulation of cell wall structure and antimicrobial susceptibility by a Staphylococcus aureus eukaryote-like serine/threonine kinase and phosphatase. Infect. Immun., 2009, 77(4), 1406-1416. [http://dx.doi.org/10.1128/IAI.01499-08]. [PMID: 19188361].
[76]
Débarbouillé, M.; Dramsi, S.; Dussurget, O.; Nahori, M.A.; Vaganay, E.; Jouvion, G.; Cozzone, A.; Msadek, T.; Duclos, B. Characterization of a serine/threonine kinase involved in virulence of Staphylococcus aureus. J. Bacteriol., 2009, 191(13), 4070-4081. [http://dx.doi.org/10.1128/JB.01813-08]. [PMID: 19395491].
[77]
Cameron, D.R.; Ward, D.V.; Kostoulias, X.; Howden, B.P.; Moellering, R.C., Jr; Eliopoulos, G.M.; Peleg, A.Y. Serine/threonine phosphatase Stp1 contributes to reduced susceptibility to vancomycin and virulence in Staphylococcus aureus. J. Infect. Dis., 2012, 205(11), 1677-1687. [http://dx.doi.org/10.1093/infdis/jis252]. [PMID: 22492855].
[78]
Av-Gay, Y.; Everett, M. The eukaryotic-like Ser/Thr protein kinases of Mycobacterium tuberculosis. Trends Microbiol., 2000, 8(5), 238-244. [http://dx.doi.org/10.1016/S0966-842X(00)01734-0]. [PMID: 10785641].
[79]
Wehenkel, A.; Bellinzoni, M.; Graña, M.; Duran, R.; Villarino, A.; Fernandez, P.; Andre-Leroux, G.; England, P.; Takiff, H.; Cerveñansky, C.; Cole, S.T.; Alzari, P.M. Mycobacterial Ser/Thr protein kinases and phosphatases: Physiological roles and therapeutic potential. Biochim. Biophys. Acta, 2008, 1784(1), 193-202. [http://dx.doi.org/10.1016/j.bbapap.2007.08.006]. [PMID: 17869195].
[80]
Kristich, C.J.; Wells, C.L.; Dunny, G.M. A eukaryotic-type Ser/Thr kinase in Enterococcus faecalis mediates antimicrobial resistance and intestinal persistence. Proc. Natl. Acad. Sci. USA, 2007, 104(9), 3508-3513. [http://dx.doi.org/10.1073/pnas.0608742104]. [PMID: 17360674].
[81]
Echenique, J.; Kadioglu, A.; Romao, S.; Andrew, P.W.; Trombe, M.C. Protein serine/threonine kinase StkP positively controls virulence and competence in Streptococcus pneumoniae. Infect. Immun., 2004, 72(4), 2434-2437. [http://dx.doi.org/10.1128/IAI.72.4.2434-2437.2004]. [PMID: 15039376].
[82]
Rajagopal, L.; Clancy, A.; Rubens, C.E. A eukaryotic type serine/threonine kinase and phosphatase in Streptococcus agalactiae reversibly phosphorylate an inorganic pyrophosphatase and affect growth, cell segregation, and virulence. J. Biol. Chem., 2003, 278(16), 14429-14441. [http://dx.doi.org/10.1074/jbc.M212747200]. [PMID: 12562757].
[83]
Jin, H.; Pancholi, V. Identification and biochemical characterization of a eukaryotic-type serine/threonine kinase and its cognate phosphatase in Streptococcus pyogenes: Their biological functions and substrate identification. J. Mol. Biol., 2006, 357(5), 1351-1372. [http://dx.doi.org/10.1016/j.jmb.2006.01.020]. [PMID: 16487973].
[84]
Wright, D.P.; Ulijasz, A.T. Regulation of transcription by eukaryotic-like serine-threonine kinases and phosphatases in gram-positive bacterial pathogens. Virulence, 2014, 5(8), 863-885. [http://dx.doi.org/10.4161/21505594.2014.983404]. [PMID: 25603430].
[85]
Burnside, K.; Lembo, A.; de Los Reyes, M.; Iliuk, A.; Binhtran, N.T.; Connelly, J.E.; Lin, W.J.; Schmidt, B.Z.; Richardson, A.R.; Fang, F.C.; Tao, W.A.; Rajagopal, L. Regulation of hemolysin expression and virulence of Staphylococcus aureus by a serine/threonine kinase and phosphatase. PLoS One, 2010, 5(6)e11071 [http://dx.doi.org/10.1371/journal.pone.0011071]. [PMID: 20552019].
[86]
Ohlsen, K.; Donat, S. The impact of serine/threonine phosphorylation in Staphylococcus aureus. Int. J. Med. Microbiol., 2010, 300(2-3), 137-141. [http://dx.doi.org/10.1016/j.ijmm.2009.08.016]. [PMID: 19783479].
[87]
Zheng, W.; Liang, Y.; Zhao, H.; Zhang, J.; Li, Z. 5,5′-Methylenedisalicylic Acid (MDSA) modulates SarA/MgrA phosphorylation by targeting Ser/Thr phosphatase stp1. ChemBioChem, 2015, 16(7), 1035-1040. [http://dx.doi.org/10.1002/cbic.201500003]. [PMID: 25810089].