Synthetic Glycolipids and (p)ppGpp Analogs: Development of Inhibitors for Mycobacterial Growth, Biofilm and Stringent Response

  • Kirtimaan Syal
  • Krishnagopal Maiti
  • Kottari Naresh
  • Dipankar ChatterjiEmail author
  • N. JayaramanEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 842)


Bacterial pathogens are the major cause of mortality across the globe, as current use of antibiotics and vaccines is unable to prevent the spread of bacterial pathogens. Rapid evolution allowed bacteria to overcome the hostile environmental conditions. Survival strategies, such as, biofilm formation, stringent response, sporulation, cyst formation and horizontal transfer of resistance genes have made it even more difficult to treat the bacterial disease. Rate of bacterial evolution has subdued the pace of discovery of new antibiotics. Most of the antibiotics target the lag and log phases of bacterial growth. It is realized that for complete omission of bacterial pathogens, survival strategies have to be restricted. Under stress, bacteria give rise to stringent response which initiates various signalling cascades escalating the activation of different survival strategies, including biofilm formation. Synthetic glycolipids and (p)ppGpp analogs hold promise to potential therapeutics for impeding the survival strategies. We have noticed earlier that various analogs of stringent response modulator (p)ppGpp hold promise for therapeutic intervention during stress. In addition, several small molecules, which are overproduced during biofilm formation, may also be targeted. In this article, such attempts are discussed.


Biofilm Stringent response (p)ppGpp c-di-GMP GMP Glycolipids Mycobacteria Cell wall 



Guanosine 5′-(tri)diphosphate, 3′-diphosphate


Bis-(3′–5′)-cyclic dimeric guanosine monophosphate


C-terminal domain


Meso-2,6-diaminopimelic acid


Extracellular polymeric substance






















Plasma membrane


  1. Ackart DF, Hascall-Dove L, Caceres SM, Kirk NM, Podell BK, Melander C, Orme IM, Leid JG, Nick JA, Basaraba RJ (2014) Expression of antimicrobial drug tolerance by attached communities of Mycobacterium tuberculosis. Pathog Dis 70:359–369CrossRefGoogle Scholar
  2. Aujoulat F, Roger F, Bourdier A, Lotthe A, Lamy B, Marchandin H, Jumas-Bilak E (2012) From environment to man: genome evolution and adaptation of human opportunistic bacterial pathogens. Genes (Basel) 3:191–232CrossRefGoogle Scholar
  3. Bassetti M, Righi E (2013) Multidrug-resistant bacteria: what is the threat? Hematology Am Soc Hematol Educ Program 2013:428–432CrossRefGoogle Scholar
  4. Beceiro A, Tomas M, Bou G (2013) Antimicrobial resistance and virulence: a successful or deleterious association in the bacterial world? Clin Microbiol Rev 26:185–230CrossRefGoogle Scholar
  5. Beloin C, Roux A, Ghigo JM (2008) Escherichia coli biofilms. Curr Top Microbiol Immunol 322:249–289Google Scholar
  6. Bharati BK, Sharma IM, Kasetty S, Kumar M, Mukherjee R, Chatterji D (2012) A full-length bifunctional protein involved in c-di-GMP turnover is required for long-term survival under nutrient starvation in Mycobacterium smegmatis. Microbiology 158:1415–1427CrossRefGoogle Scholar
  7. Bharati BK, Naresh K, Chatterji D, Jayaraman N (2013) Synthetic arabinan, arabinomannan glycolipids and their effects on mycobacterial growth, sliding motility and biofilm formation. In: Rauter AP, Lindhorst TK (eds) Carbohydrate chemistry, vol 39. The Royal Society of Chemistry, Cambridge, UK, p 58–77Google Scholar
  8. Brennan PJ (2003) Structure, function, and biogenesis of the cell wall of Mycobacterium tuberculosis. Tuberculosis (Edinb) 83:91–97CrossRefGoogle Scholar
  9. Cashel M, Gallant J (1969) Two compounds implicated in the function of the RC gene of Escherichia coli. Nature 221:838–841CrossRefGoogle Scholar
  10. Centrone CA, Lowary TL (2002) Synthesis and antituberculosis activity of C-phosphonate analogues of decaprenolphosphoarabinose, a key intermediate in the biosynthesis of mycobacterial arabinogalactan and lipoarabinomannan. J Org Chem 67:8862–8870CrossRefGoogle Scholar
  11. Chatterji D, Ojha AK (2001) Revisiting the stringent response, ppGpp and starvation signaling. Curr Opin Microbiol 4:160–165CrossRefGoogle Scholar
  12. Chowdhury RP, Saraswathi R, Chatterji D (2010) Mycobacterial stress regulation: the Dps “twin sister” defense mechanism and structure–function relationship. IUBMB Life 62:67–77Google Scholar
  13. Dalebroux ZD, Swanson MS (2012) ppGpp: magic beyond RNA polymerase. Nat Rev Microbiol 10:203–212CrossRefGoogle Scholar
  14. Davis CB, Hartnell RD, Madge PD, Owen DJ, Thomson RJ, Chong AK, Coppel RL, von Itzstein M (2007) Synthesis and biological evaluation of galactofuranosyl alkyl thioglycosides as inhibitors of mycobacteria. Carbohydr Res 342:1773–1780CrossRefGoogle Scholar
  15. Etienne G, Villeneuve C, Billman-Jacobe H, Astarie-Dequeker C, Dupont MA, Daffé M (2002) The impact of the absence of glycopeptidolipids on the ultrastructure, cell surface and cell wall properties, and phagocytosis of Mycobacterium smegmatis. Microbiology 148:3089–3100Google Scholar
  16. Fiil NP, Willumsen BM, Friesen JD, von Meyenburg K (1977) Interaction of alleles of the relA, relC and spoT genes in Escherichia coli: analysis of the interconversion of GTP, ppGpp and pppGpp. Mol Gen Genet 150:87–101CrossRefGoogle Scholar
  17. Gaynor CD, McCormack FX, Voelker DR, McGowan SE, Schlesinger LS (1995) Pulmonary surfactant protein A mediates enhanced phagocytosis of Mycobacterium tuberculosis by a direct interaction with human macrophages. J Immunol 155:5343–5351Google Scholar
  18. Gropp M, Strausz Y, Gross M, Glaser G (2001) Regulation of Escherichia coli RelA requires oligomerization of the C-terminal domain. J Bacteriol 183:570–579CrossRefGoogle Scholar
  19. Hall-Stoodley L, Costerton JW, Stoodley P (2004) Bacterial biofilms: from the natural environment to infectious diseases. Nat Rev Microbiol 2:95–108CrossRefGoogle Scholar
  20. Hamasur B, Kallenius G, Svenson SB (1999) Synthesis and immunologic characterisation of Mycobacterium tuberculosis lipoarabinomannan specific oligosaccharide–protein conjugates. Vaccine 17:2853–2861CrossRefGoogle Scholar
  21. Hogg T, Mechold U, Malke H, Cashel M, Hilgenfeld R (2004) Conformational antagonism between opposing active sites in a bifunctional RelA/SpoT homolog modulates (p)ppGpp metabolism during the stringent response [corrected]. Cell 117:57–68CrossRefGoogle Scholar
  22. Hong Y, Zhou X, Fang H, Yu D, Li C, Sun B (2013) Cyclic di-GMP mediates Mycobacterium tuberculosis dormancy and pathogenecity. Tuberculosis (Edinb) 93:625–634CrossRefGoogle Scholar
  23. Jain V, Kumar M, Chatterji D (2006a) ppGpp: stringent response and survival. J Microbiol 44:1–10Google Scholar
  24. Jain V, Saleem-Batcha R, China A, Chatterji D (2006b) Molecular dissection of the mycobacterial stringent response protein Rel. Protein Sci 15:1449–1464CrossRefGoogle Scholar
  25. Jakubovics NS, Yassin SA, Rickard AH (2014) Community interactions of oral streptococci. Adv Appl Microbiol 87:43–110CrossRefGoogle Scholar
  26. Kellow NJ, Coughlan MT, Reid CM (2014) Metabolic benefits of dietary prebiotics in human subjects: a systematic review of randomised controlled trials. Br J Nutr 111:1147–1161CrossRefGoogle Scholar
  27. Kostakioti M, Hadjifrangiskou M, Hultgren SJ (2013) Bacterial biofilms: development, dispersal, and therapeutic strategies in the dawn of the postantibiotic era. Cold Spring Harb Perspect Med 3:a010306CrossRefGoogle Scholar
  28. Krasny L, Gourse RL (2004) An alternative strategy for bacterial ribosome synthesis: Bacillus subtilis rRNA transcription regulation. EMBO J 23:4473–4483CrossRefGoogle Scholar
  29. Kriel A, Bittner AN, Kim SH, Liu K, Tehranchi AK, Zou WY, Rendon S, Chen R, Tu BP, Wang JD (2012) Direct regulation of GTP homeostasis by (p)ppGpp: a critical component of viability and stress resistance. Mol Cell 48:231–241CrossRefGoogle Scholar
  30. Martinez A, Torello S, Kolter R (1999) Sliding motility in mycobacteria. J Bacteriol 181:7331–7338Google Scholar
  31. Mindolli PB, Salmani MP, Parandekar PK (2013) Improved diagnosis of pulmonary tuberculosis using bleach microscopy method. J Clin Diagn Res 7:1336–1338Google Scholar
  32. Nadell CD, Xavier JB, Levin SA, Foster KR (2008) The evolution of quorum sensing in bacterial biofilms. PLoS Biol 6:e14CrossRefGoogle Scholar
  33. Naresh K, Bharati BK, Jayaraman N, Chatterji D (2008) Synthesis and mycobacterial growth inhibition activities of bivalent and monovalent arabinofuranoside containing alkyl glycosides. Org Biomol Chem 6:2388–2393CrossRefGoogle Scholar
  34. Naresh K, Bharati BK, Avaji PG, Jayaraman N, Chatterji D (2010) Synthetic arabinomannan glycolipids and their effects on growth and motility of the Mycobacterium smegmatis. Org Biomol Chem 8:592–599CrossRefGoogle Scholar
  35. Naresh K, Bharati BK, Avaji PG, Chatterji D, Jayaraman N (2011) Synthesis, biological studies of linear and branched arabinofuranoside-containing glycolipids and their interaction with surfactant protein A. Glycobiology 21:1237–1254CrossRefGoogle Scholar
  36. Naresh K, Avaji PG, Maiti K, Bharati BK, Syal K, Chatterji D, Jayaraman N (2012) Synthesis of beta-arabinofuranoside glycolipids, studies of their binding to surfactant protein-A and effect on sliding motilities of M. smegmatis. Glycoconj J 29:107–118CrossRefGoogle Scholar
  37. O’Toole G, Kaplan HB, Kolter R (2000) Biofilm formation as microbial development. Annu Rev Microbiol 54:49–79CrossRefGoogle Scholar
  38. Ojha AK, Varma S, Chatterji D (2002) Synthesis of an unusual polar glycopeptidolipid in glucose-limited culture of Mycobacterium smegmatis. Microbiology 148:3039–3048Google Scholar
  39. Pal RR, Das B, Dasgupta S, Bhadra RK (2011) Genetic components of stringent response in Vibrio cholerae. Indian J Med Res 133:212–217Google Scholar
  40. Recht J, Kolter R (2001) Glycopeptidolipid acetylation affects sliding motility and biofilm formation in Mycobacterium smegmatis. J Bacteriol 183:5718–5724CrossRefGoogle Scholar
  41. Recht J, Martinez A, Torello S, Kolter R (2000) Genetic analysis of sliding motility in Mycobacterium smegmatis. J Bacteriol 182:4348–4351CrossRefGoogle Scholar
  42. Roberfroid M, Gibson GR, Hoyles L, McCartney AL, Rastall R, Rowland I, Wolvers D, Watzl B, Szajewska H, Stahl B, Guarner F, Respondek F, Whelan K, Coxam V, Davicco MJ, Leotoing L, Wittrant Y, Delzenne NM, Cani PD, Neyrinck AM, Meheust A (2010) Prebiotic effects: metabolic and health benefits. Br J Nutr 104(Suppl 2):S1–S63CrossRefGoogle Scholar
  43. Rose JD, Maddry JA, Comber RN, Suling WJ, Wilson LN, Reynolds RC (2002) Synthesis and biological evaluation of trehalose analogs as potential inhibitors of mycobacterial cell wall biosynthesis. Carbohydr Res 337:105–120CrossRefGoogle Scholar
  44. Roszak DB, Colwell RR (1987) Survival strategies of bacteria in the natural environment. Microbiol Rev 51:365–379Google Scholar
  45. Seidel M, Alderwick LJ, Birch HL, Sahm H, Eggeling L, Besra GS (2007) J Biol Chem 282:14729CrossRefGoogle Scholar
  46. Sharma UK, Chatterji D (2010) Transcriptional switching in Escherichia coli during stress and starvation by modulation of sigma activity. FEMS Microbiol Rev 34:646–657CrossRefGoogle Scholar
  47. Sidobre S, Nigou J, Puzo G, Riviere M (2000) Lipoglycans are putative ligands for the human pulmonary surfactant protein A attachment to mycobacteria. Critical role of the lipids for lectin-carbohydrate recognition. J Biol Chem 275:2415–2422CrossRefGoogle Scholar
  48. Sidobre S, Puzo G, Riviere M (2002) Lipid-restricted recognition of mycobacterial lipoglycans by human pulmonary surfactant protein A: a surface-plasmon-resonance study. Biochem J 365:89–97CrossRefGoogle Scholar
  49. Ursell LK, Clemente JC, Rideout JR, Gevers D, Caporaso JG, Knight R (2012) The interpersonal and intrapersonal diversity of human-associated microbiota in key body sites. J Allergy Clin Immunol 129:1204–1208CrossRefGoogle Scholar
  50. van Schaik W, Prigent J, Fouet A (2007) The stringent response of Bacillus anthracis contributes to sporulation but not to virulence. Microbiology 153:4234–4239CrossRefGoogle Scholar
  51. Vats A, Singh AK, Mukherjee R, Chopra T, Ravindran MS, Mohanty D, Chatterji D, Reyrat JM, Gokhale RS (2012) Retrobiosynthetic approach delineates the biosynthetic pathway and the structure of the acyl chain of mycobacterial glycopeptidolipids. J Biol Chem 287:30677–30687CrossRefGoogle Scholar
  52. Wakamoto Y, Dhar N, Chait R, Schneider K, Signorino-Gelo F, Leibler S, McKinney JD (2013) Dynamic persistence of antibiotic-stressed mycobacteria. Science 339:91–95CrossRefGoogle Scholar
  53. Wexselblatt E, Oppenheimer-Shaanan Y, Kaspy I, London N, Schueler-Furman O, Yavin E, Glaser G, Katzhendler J, Ben-Yehuda S (2012) Relacin, a novel antibacterial agent targeting the Stringent Response. PLoS Pathog 8:e1002925CrossRefGoogle Scholar
  54. Wexselblatt E, Kaspy I, Glaser G, Katzhendler J, Yavin E (2013) Design, synthesis and structure–activity relationship of novel Relacin analogs as inhibitors of Rel proteins. Eur J Med Chem 70:497–504CrossRefGoogle Scholar
  55. Wilson DJ (2012) Insights from genomics into bacterial pathogen populations. PLoS Pathog 8:e1002874CrossRefGoogle Scholar
  56. Xu LC, Siedlecki CA (2014) Staphylococcus epidermidis adhesion on hydrophobic and hydrophilic textured biomaterial surfaces. Biomed Mater 9:035003CrossRefGoogle Scholar
  57. Zhang J, Khoo KH, Wu SW, Chatterjee D (2007) Characterization of a distinct arabinofuranosyltransferase in Mycobacterium smegmatis. J Am Chem Soc 129:9650–9662CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Molecular Biophysics UnitIndian Institute of ScienceBangaloreIndia
  2. 2.Department of Organic ChemistryIndian Institute of ScienceBangaloreIndia

Personalised recommendations