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Targeting Cyclic Dinucleotide Signaling with Small Molecules

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Microbial Cyclic Di-Nucleotide Signaling

Abstract

Cyclic dinucleotides (CDNs) are now established as master regulators of bacterial physiology (cyclic di-GMP, cyclic di-AMP, 3′3′-cGAMP) and immune function (bacterial cyclic dinucleotides and host’s 2′3′-cGAMP). Metabolic enzymes that modulate the concentrations of CDNs and/or effector proteins or nucleic acids that bind to these second messengers are potential therapeutic targets for the development of antibiofilm, antivirulence, and immunomodulatory agents. Here, we discuss some of the recent advances in the development of small molecule regulators of cyclic di-GMP, cyclic di-AMP, and cGAMP signaling.

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References

  1. Kalia D, Merey G, Nakayama S, Zheng Y, Zhou J, Luo Y, Guo M, Roembke BT, Sintim HO (2013) Nucleotide, c-di-GMP, c-di-AMP, cGMP, cAMP, (p)ppGpp signaling in bacteria and implications in pathogenesis. Chem Soc Rev 42(1):305–341. https://doi.org/10.1039/c2cs35206k

    Article  CAS  PubMed  Google Scholar 

  2. Opoku-Temeng C, Zhou J, Zheng Y, Su J, Sintim HO (2016) Cyclic dinucleotide (c-di-GMP, c-di-AMP, and cGAMP) signalings have come of age to be inhibited by small molecules. Chem Commun 52(60):9327–9342. https://doi.org/10.1039/c6cc03439j

    Article  CAS  Google Scholar 

  3. Ross P, Weinhouse H, Aloni Y, Michaeli D, Weinbergerohana P, Mayer R, Braun S, Devroom E, Vandermarel GA, Vanboom JH, Benziman M (1987) Regulation of cellulose synthesis in Acetobacter xylinum by cyclic diguanylic acid. Nature 325(6101):279–281. https://doi.org/10.1038/325279a0

    Article  CAS  PubMed  Google Scholar 

  4. Hengge R (2009) Principles of c-di-GMP signalling in bacteria. Nat Rev Microbiol 7(4):263–273. https://doi.org/10.1038/nrmicro2109

    Article  CAS  PubMed  Google Scholar 

  5. Römling U, Galperin MY, Gomelsky M (2013) Cyclic di-GMP: the first 25 years of a universal bacterial second messenger. Microbiol Mol Biol Rev 77(1):1–52. https://doi.org/10.1128/MMBR.00043-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Barker JR, Koestler BJ, Carpenter VK, Burdette DL, Waters CM, Vance RE, Valdivia RH (2013) STING-dependent recognition of cyclic di-AMP mediates type I interferon responses during Chlamydia trachomatis infection. mBio 4(3):e00018–e00013. https://doi.org/10.1128/mBio.00018-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Corrigan RM, Gründling A (2013) Cyclic di-AMP: another second messenger enters the fray. Nat Rev Microbiol 11(8):513–524. https://doi.org/10.1038/nrmicro3069

    Article  CAS  PubMed  Google Scholar 

  8. Commichau FM, Dickmanns A, Gundlach J, Ficner R, Stülke J (2015) A jack of all trades: the multiple roles of the unique essential second messenger cyclic di-AMP. Mol Microbiol 97(2):189–204. https://doi.org/10.1111/mmi.13026

    Article  CAS  PubMed  Google Scholar 

  9. Davies BW, Bogard RW, Young TS, Mekalanos JJ (2012) Coordinated regulation of accessory genetic elements produces cyclic di-nucleotides for V. cholerae virulence. Cell 149(2):358–370. https://doi.org/10.1016/j.cell.2012.01.053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Roehl I, Hopfner K-P, Ludwig J, Hornung V (2013) cGAS produces a 2-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498(7454):380–384. https://doi.org/10.1038/nature12306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang X, Shi H, Wu J, Zhang X, Sun L, Chen C, Chen ZJ (2013) Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol Cell 51(2):226–235. https://doi.org/10.1016/j.molcel.2013.05.022

    Article  CAS  PubMed  Google Scholar 

  12. Sun L, Wu J, Du F, Chen X, Chen ZJ (2013) Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339(6121):786–791. https://doi.org/10.1126/science.1232458

    Article  CAS  PubMed  Google Scholar 

  13. Römling U, Gomelsky M, Galperin MY (2005) C-di-GMP: the dawning of a novel bacterial signalling system. Mol Microbiol 57(3):629–639. https://doi.org/10.1111/j.1365-2958.2005.04697.x

    Article  CAS  PubMed  Google Scholar 

  14. Schirmer T, Jenal U (2009) Structural and mechanistic determinants of c-di-GMP signalling. Nat Rev Microbiol 7(10):724–735. https://doi.org/10.1038/nrmicro2203

    Article  CAS  PubMed  Google Scholar 

  15. Hecht GB, Newton A (1995) Identification of a novel response regulator required for the swarmer-to-stalked-cell transition in Caulobacter crescentus. J Bacteriol 177(21):6223–6229. PMID: 7592388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jenal U, Malone J (2006) Mechanisms of cyclic-di-GMP signaling in bacteria. Annu Rev Genet 40:385–407. https://doi.org/10.1146/annurev.genet.40.110405.090423

    Article  CAS  PubMed  Google Scholar 

  17. Witte G, Hartung S, Buettner K, Hopfner K-P (2008) Structural biochemistry of a bacterial checkpoint protein reveals diadenylate cyclase activity regulated by DNA recombination intermediates. Mol Cell 30(2):167–178. https://doi.org/10.1016/j.molcel.2008.02.020

    Article  CAS  PubMed  Google Scholar 

  18. Rosenberg J, Dickmanns A, Neumann P, Gunka K, Arens J, Kaever V, Stülke J, Ficner R, Commichau FM (2015) Structural and biochemical analysis of the essential diadenylate cyclase CdaA from Listeria monocytogenes. J Biol Chem 290(10):6596–6606. https://doi.org/10.1074/jbc.M114.630418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mehne FM, Schröder-Tittmann K, Eijlander RT, Herzberg C, Hewitt L, Kaever V, Lewis RJ, Kuipers OP, Tittmann K, Stülke J (2014) Control of the diadenylate cyclase CdaS in Bacillus subtilis: an autoinhibitory domain limits cyclic di-AMP production. J Biol Chem 289(30):21098–21107. https://doi.org/10.1074/jbc.M114.562066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Blötz C, Treffon K, Kaever V, Schwede F, Hammer E, Stülke J (2017) Identification of the components involved in cyclic di-AMP signaling in Mycoplasma pneumoniae. Front Microbiol 8:1328. https://doi.org/10.3389/fmicb.2017.01328

    Article  PubMed  PubMed Central  Google Scholar 

  21. Rao F, See RY, Zhang D, Toh DC, Ji Q, Liang Z-X (2010) YybT is a signaling protein that contains a cyclic dinucleotide phosphodiesterase domain and a GGDEF domain with ATPase activity. J Biol Chem 285(1):473–482. https://doi.org/10.1074/jbc.M109.040238

    Article  CAS  PubMed  Google Scholar 

  22. Huynh TN, Luo SK, Pensinger D, Sauer JD, Tong L, Woodward JJ (2015) An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence. Proc Natl Acad Sci U S A 112(7):E747–E756. https://doi.org/10.1073/pnas.1416485112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gao J, Tao J, Liang W, Zhao M, Du X, Cui S, Duan H, Kan B, Su X, Jiang Z (2015) Identification and characterization of phosphodiesterases that specifically degrade 3′ 3′-cyclic GMP-AMP. Cell Res 25(5):539–550. https://doi.org/10.1038/cr.2015.40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kellenberger CA, Wilson SC, Hickey SF, Gonzalez TL, Su Y, Hallberg ZF, Brewer TF, Iavarone AT, Carlson HK, Hsieh YF, Hammond MC (2015) GEMM-I riboswitches from Geobacter sense the bacterial second messenger cyclic AMP-GMP. Proc Natl Acad Sci U S A 112(17):5383–5388. https://doi.org/10.1073/pnas.1419328112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hallberg ZF, Wang XC, Wright TA, Nan B, Ad O, Yeo J, Hammond MC (2016) Hybrid promiscuous (Hypr) GGDEF enzymes produce cyclic AMP-GMP (3′, 3′-cGAMP). Proc Natl Acad Sci U S A 113(7):1790–1795. https://doi.org/10.1073/pnas.1515287113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li L, Yin Q, Kuss P, Maliga Z, Millan JL, Wu H, Mitchison TJ (2015) Hydrolysis of 2′3′-cGAMP by ENPP1 and design of nonhydrolyzable analogs. Nat Chem Biol 11(3):235–235. https://doi.org/10.1038/nchembio0315-235d

    Article  PubMed  Google Scholar 

  27. Dey RJ, Dey B, Zheng Y, Cheung LS, Zhou J, Sayre D, Kumar P, Guo H, Lamichhane G, Sintim HO, Bishai WR (2017) Inhibition of innate immune cytosolic surveillance by an M. tuberculosis phosphodiesterase. Nat Chem Biol 13(2):210–217. https://doi.org/10.1038/nchembio.2254

    Article  CAS  PubMed  Google Scholar 

  28. Sambanthamoorthy K, Sloup RE, Parashar V, Smith JM, Kim EE, Semmelhack MF, Neiditch MB, Waters CM (2012) Identification of small molecules that antagonize diguanylate cyclase enzymes to inhibit biofilm formation. Antimicrob Agents Chemother 56(10):5202–5211. https://doi.org/10.1128/aac.01396-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kim SK, Park HY, Lee JH (2015) Anthranilate deteriorates the structure of Pseudomonas aeruginosa biofilms and antagonizes the biofilm-enhancing indole effect. Appl Environ Microbiol 81(7):2328–2338. https://doi.org/10.1128/AEM.03551-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zheng Y, Tsuji G, Opoku-Temeng C, Sintim HO (2016) Inhibition of P. aeruginosa c-di-GMP phosphodiesterase RocR and swarming motility by a benzoisothiazolinone derivative. Chem Sci 7(9):6238–6244. https://doi.org/10.1039/c6sc02103d

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kim B, Park JS, Choi HY, Yoon SS, Kim WG (2018) Terrein is an inhibitor of quorum sensing and c-di-GMP in Pseudomonas aeruginosa: a connection between quorum sensing and c-di-GMP. Sci Rep 8:8617. https://doi.org/10.1038/s41598-018-26974-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sambanthamoorthy K, Luo C, Pattabiraman N, Feng X, Koestler B, Waters CM, Palys TJ (2014) Identification of small molecules inhibiting diguanylate cyclases to control bacterial biofilm development. Biofouling 30(1):17–28. https://doi.org/10.1080/08927014.2013.832224

    Article  CAS  PubMed  Google Scholar 

  33. Lieberman OJ, Orr MW, Wang Y, Lee VT (2014) High-throughput screening using the differential radial capillary action of ligand assay identifies ebselen as an inhibitor of diguanylate cyclases. ACS Chem Biol 9(1):183–192. https://doi.org/10.1021/cb400485k

    Article  CAS  PubMed  Google Scholar 

  34. Christen M, Kamischke C, Kulasekara HD, Olivas KC, Kulasekara BR, Christen B, Kline T, Miller SI (2018) Identification of small molecule modulators of diguanylate cyclase by FRET-based high-throughput-screening. Chembiochem 20(3):394–407. https://doi.org/10.1002/cbic.201800593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kulasakara H, Lee V, Brencic A, Liberati N, Urbach J, Miyata S, Lee DG, Neely AN, Hyodo M, Hayakawa Y, Ausubel FM, Lory S (2006) Analysis of Pseudomonas aeruginosa diguanylate cyclases and phosphodiesterases reveals a role for bis-(3′-5′)-cyclic-GMP in virulence. Proc Natl Acad Sci U S A 103(8):2839–2844

    Article  PubMed  Google Scholar 

  36. Ryan RP, Fouhy Y, Lucey JF, Jiang BL, He YQ, Feng JX, Tang JL, Dow JM (2007) Cyclic di-GMP signalling in the virulence and environmental adaptation of Xanthomonas campestris. Mol Microbiol 63(2):429–442. https://doi.org/10.1111/j.1365-2958.2006.05531.x

    Article  CAS  PubMed  Google Scholar 

  37. Zhou J, Sayre DA, Zheng Y, Szmacinski H, Sintim HO (2014) Unexpected complex formation between coralyne and cyclic diadenosine monophosphate providing a simple fluorescent turn-on assay to detect this bacterial second messenger. Anal Chem 86(5):2412–2420. https://doi.org/10.1021/ac403203x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Opoku-Temeng C, Dayal N, Miller J, Sintim HO (2017) Hydroxybenzylidene-indolinones, c-di-AMP synthase inhibitors, have antibacterial and anti-biofilm activities and also re-sensitize resistant bacteria to methicillin and vancomycin. RSC Adv 7(14):8288–8294. https://doi.org/10.1039/c6ra28443d

    Article  CAS  Google Scholar 

  39. Zheng Y, Zhou J, Sayre DA, Sintim HO (2014) Identification of bromophenol thiohydantoin as an inhibitor of DisA, a c-di-AMP synthase, from a 1000 compound library, using the coralyne assay. Chem Commun 50(76):11234–11237. https://doi.org/10.1039/c4cc02916j

    Article  CAS  Google Scholar 

  40. Lackey K, Cory M, Davis R, Frye SV, Harris PA, Hunter RN, Jung DK, McDonald OB, McNutt RW, Peel MR, Rutkowske RD, Veal JM, Wood ER (2000) The discovery of potent cRaf1 kinase inhibitors. Bioorg Med Chem Lett 10(3):223–226

    Article  CAS  PubMed  Google Scholar 

  41. Chin PC, Liu L, Morrison BE, Siddiq A, Ratan RR, Bottiglieri T, D’Mello SR (2004) The c-Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK-ERK and Akt-independent mechanism. J Neurochem 90(3):595–608. https://doi.org/10.1111/j.1471-4159.2004.02530.x

    Article  CAS  PubMed  Google Scholar 

  42. An J, Durcan L, Karr RM, Briggs TA, Rice GI, Teal TH, Woodward JJ, Elkon KB (2017) Expression of cyclic GMP-AMP synthase in patients with systemic lupus erythematosus. Arthritis Rheumatol 69(4):800–807. https://doi.org/10.1002/art.40002

    Article  CAS  PubMed  Google Scholar 

  43. Hall J, Brault A, Vincent F, Weng S, Wang H, Dumlao D, Aulabaugh A, Aivazian D, Castro D, Chen M, Culp J, Dower K, Gardner J, Hawrylik S, Golenbock D, Hepworth D, Horn M, Jones L, Jones P, Latz E, Li J, Lin LL, Lin W, Lin D, Lovering F, Niljanskul N, Nistler R, Pierce B, Plotnikova O, Schmitt D, Shanker S, Smith J, Snyder W, Subashi T, Trujillo J, Tyminski E, Wang G, Wong J, Lefker B, Dakin L, Leach K (2017) Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay. PLoS One 12(9):e0184843. https://doi.org/10.1371/journal.pone.0184843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Vincent J, Adura C, Gao P, Luz A, Lama L, Asano Y, Okamoto R, Imaeda T, Aida J, Rothamel K, Gogakos T, Steinberg J, Reasoner S, Aso K, Tuschl T, Patel DJ, Glickman JF, Ascano M (2017) Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice. Nat Commun 8(1):750. https://doi.org/10.1038/s41467-017-00833-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. An J, Minie M, Sasaki T, Woodward JJ, Elkon KB (2017) Antimalarial drugs as immune modulators: new mechanisms for old drugs. Annu Rev Med 68:317–330. https://doi.org/10.1146/annurev-med-043015-123453

    Article  CAS  PubMed  Google Scholar 

  46. Wang M, Sooreshjani MA, Mikek C, Opoku-Temeng C, Sintim HO (2018) Suramin potently inhibits cGAMP synthase, cGAS, in THP1 cells to modulate IFN-β levels. Fut Med Chem 10(11):1301–1317. https://doi.org/10.4155/fmc-2017-0322

    Article  CAS  Google Scholar 

  47. Simm R, Morr M, Kader A, Nimtz M, Römling U (2004) GGDEF and EAL domains inversely regulate cyclic di-GMP levels and transition from sessility to motility. Mol Microbiol 53(4):1123–1134. https://doi.org/10.1111/j.1365-2958.2004.04206.x

    Article  CAS  PubMed  Google Scholar 

  48. Valentini M, Filloux A (2016) Biofilms and cyclic di-GMP (c-di-GMP) signaling: lessons from Pseudomonas aeruginosa and other bacteria. J Biol Chem 291(24):12547–12555. https://doi.org/10.1074/jbc.R115.711507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kader A, Simm R, Gerstel U, Morr M, Römling U (2006) Hierarchical involvement of various GGDEF domain proteins in rdar morphotype development of Salmonella enterica serovar Typhimurium. Mol Microbiol 60(3):602–616. https://doi.org/10.1111/j.1365-2958.2006.05123.x

    Article  CAS  PubMed  Google Scholar 

  50. He M, Ouyang Z, Troxell B, Xu H, Moh A, Piesman J, Norgard MV, Gomelsky M, Yang XF (2011) Cyclic di-GMP is essential for the survival of the Lyme disease spirochete in ticks. PLoS Pathog 7(6):e1002133. https://doi.org/10.1371/journal.ppat.1002133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sultan SZ, Pitzer JE, Miller MR, Motaleb MA (2010) Analysis of a Borrelia burgdorferi phosphodiesterase demonstrates a role for cyclic-di-guanosine monophosphate in motility and virulence. Mol Microbiol 77(1):128–142. https://doi.org/10.1111/j.1365-2958.2010.07191.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sultan SZ, Pitzer JE, Boquoi T, Hobbs G, Miller MR, Motaleb MA (2011) Analysis of the HD-GYP domain cyclic dimeric GMP phosphodiesterase reveals a role in motility and the enzootic life cycle of Borrelia burgdorferi. Infect Immun 79(8):3273–3283. https://doi.org/10.1128/IAI.05153-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Srivastava D, Harris RC, Waters CM (2011) Integration of cyclic di-GMP and quorum sensing in the control of vpsT and aphA in Vibrio cholerae. J Bacteriol 193(22):6331–6341. https://doi.org/10.1128/JB.05167-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Krasteva PV, Fong JCN, Shikuma NJ, Beyhan S, Navarro M, Yildiz FH, Sondermann H (2010) Vibrio cholerae VpsT regulates matrix production and motility by directly sensing cyclic di-GMP. Science 327(5967):866–868. https://doi.org/10.1126/science.1181185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Chambers JR, Liao J, Schurr MJ, Sauer K (2014) BrlR from Pseudomonas aeruginosa is a c-di-GMP-responsive transcription factor. Mol Microbiol 92(3):471–487. https://doi.org/10.1111/mmi.12562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chatterjee D, Cooley RB, Boyd CD, Mehl RA, O’Toole GA, Sondermann H (2014) Mechanistic insight into the conserved allosteric regulation of periplasmic proteolysis by the signaling molecule cyclic-di-GMP. elife 3:e03650. https://doi.org/10.7554/eLife.03650

    Article  PubMed  PubMed Central  Google Scholar 

  57. Hengge R, Gründling A, Jenal U, Ryan R, Yildiz F (2016) Bacterial signal transduction by cyclic di-GMP and other nucleotide second messengers. J Bacteriol 198(1):15–26. https://doi.org/10.1128/JB.00331-15

    Article  CAS  PubMed  Google Scholar 

  58. Lee VT, Matewish JM, Kessler JL, Hyodo M, Hayakawa Y, Lory S (2007) A cyclic-di-GMP receptor required for bacterial exopolysaccharide production. Mol Microbiol 65(6):1474–1484. https://doi.org/10.1111/j.1365-2958.2007.05879.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lory S, Merighi M, Hyodo M (2009) Multiple activities of c-di-GMP in Pseudomonas aeruginosa. Nucleic Acids Symp Ser (Oxf) 53:51–52. https://doi.org/10.1093/nass/nrp026

    Article  CAS  Google Scholar 

  60. Lee ER, Baker JL, Weinberg Z, Sudarsan N, Breaker RR (2010) An allosteric self-splicing ribozyme triggered by a bacterial second messenger. Science 329(5993):845–848. https://doi.org/10.1126/science.1190713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sudarsan N, Lee ER, Weinberg Z, Moy RH, Kim JN, Link KH, Breaker RR (2008) Riboswitches in eubacteria sense the second messenger cyclic di-GMP. Science 321(5887):411–413. https://doi.org/10.1126/science.1159519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Luo Y, Chen B, Zhou J, Sintim HO, Dayie TK (2014) E88, a new cyclic-di-GMP class I riboswitch aptamer from Clostridium tetani, has a similar fold to the prototypical class I riboswitch, Vc2, but differentially binds to c-di-GMP analogs. Mol BioSyst 10(3):384–390. https://doi.org/10.1039/c3mb70467j

    Article  CAS  PubMed  Google Scholar 

  63. Luo Y, Zhou J, Wang J, Dayie TK, Sintim HO (2013) Selective binding of 2'-F-c-di-GMP to Ct-E88 and Cb-E43, new class I riboswitches from Clostridium tetani and Clostridium botulinum respectively. Mol BioSyst 9(6):1535–1539. https://doi.org/10.1039/c3mb25560c

    Article  CAS  PubMed  Google Scholar 

  64. Launer-Felty KD, Strobel SA (2018) Enzymatic synthesis of cyclic dinucleotide analogs by a promiscuous cyclic-AMP-GMP synthetase and analysis of cyclic dinucleotide responsive riboswitches. Nucleic Acids Res 46(6):2765–2776. https://doi.org/10.1093/nar/gky137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Shanahan CA, Gaffney BL, Jones RA, Strobel SA (2011) Differential analogue binding by two classes of c-di-GMP riboswitches. J Am Chem Soc 133(39):15578–15592. https://doi.org/10.1021/ja204650q

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zeden MS, Schuster CF, Bowman L, Zhong Q, Williams HD, Gründling A (2018) Cyclic di-adenosine monophosphate (c-di-AMP) is required for osmotic regulation in Staphylococcus aureus but dispensable for viability in anaerobic conditions. J Biol Chem 293(9):3180–3200. https://doi.org/10.1074/jbc.M117.818716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Corrigan RM, Bowman L, Willis AR, Kaever V, Gründling A (2015) Cross-talk between two nucleotide-signaling pathways in Staphylococcus aureus. J Biol Chem 290(9):5826–5839. https://doi.org/10.1074/jbc.M114.598300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wright GD (2016) Antibiotic adjuvants: rescuing antibiotics from resistance. Trends Microbiol 24(11):862–871. https://doi.org/10.1016/j.tim.2016.07.008

    Article  CAS  PubMed  Google Scholar 

  69. Opoku-Temeng C, Onyedibe KI, Aryal UK, Sintim HO (2019) Proteomic analysis of bacterial response to a 4-hydroxybenzylidene indolinone compound, which re-sensitizes bacteria to traditional antibiotics. J Proteome 202:103368. https://doi.org/10.1016/j.jprot.2019.04.018

    Article  CAS  Google Scholar 

  70. Sooreshjani MA, Gursoy UK, Aryal UK, Sintim HO (2018) Proteomic analysis of RAW macrophages treated with cGAMP or c-di-GMP reveals differentially activated cellular pathways. RSC Adv 8:36840. https://doi.org/10.1039/c8ra04603d

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank the NSF for funding our cyclic dinucleotide research.

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Authors and Affiliations

  1. Chemistry Department, Purdue University, West Lafayette, IN, USA

    Herman O. Sintim & Clement Opoku-Temeng

  2. Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN, USA

    Herman O. Sintim

  3. Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, IN, USA

    Herman O. Sintim

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  1. Herman O. Sintim
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  2. Clement Opoku-Temeng
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Correspondence to Herman O. Sintim .

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Editors and Affiliations

  1. Institute of Biochemistry and Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan

    Shan-Ho Chou

  2. Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile

    Nicolas Guiliani

  3. Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA

    Vincent T. Lee

  4. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden

    Ute Römling

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Sintim, H.O., Opoku-Temeng, C. (2020). Targeting Cyclic Dinucleotide Signaling with Small Molecules. In: Chou, SH., Guiliani, N., Lee, V., Römling, U. (eds) Microbial Cyclic Di-Nucleotide Signaling. Springer, Cham. https://doi.org/10.1007/978-3-030-33308-9_33

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