Alarmones as bacterial persistence factor

Article Sidebar

pdf
Published: Dec 15, 2023
DOI: https://doi.org/10.17072/1994-9952-2023-4-356-366
Keywords:
bacterial persistence antimicrobial resistance alarmones (p)ppGpp dormancy RSH alarmone synthetase inhibitors

Main Article Content

Roman Yu. Sidorov
Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center, the Ural branch of Russian Academy of Sciences
Alexander G. Tkachenko
Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center, the Ural branch of Russian Academy of Sciences

Abstract

The treatment of bacterial infections with antibiotics is greatly challenged by the adaptive mechanisms employed by bacteria. Chronic and recurrent infections are often linked to bacterial persistence, biofilm formation, and antibiotic tolerance. These processes result in reduced metabolic activity, rendering bacteria insensitive to conventional antibiotics that primarily target actively growing cells. The stringent response, regulated by (p)ppGpp alarmone molecules, serves as a stress adaptation mechanism. It is conserved across numerous bacterial species and plays an important role in long-term survival under nutrient-depleted conditions. (p)ppGpp alarmones also play a significant role in bacterial persistence and the formation of biofilms. The pursuit of novel antibacterial agents that specifically target (p)ppGpp synthesis, thereby inhibiting the stringent response, presents a promising strategy in the battle against bacterial infections. In this context, alarmone synthetase inhibitors emerge as promising candidates for clinical application, as they have demonstrated their effectiveness in suppressing bacterial survival mechanisms, inhibiting biofilm formation, and reducing antibiotic tolerance and bacterial persistence.

Article Details

How to Cite
Sidorov, R. Y., & Tkachenko, A. G. (2023). Alarmones as bacterial persistence factor. Bulletin of Perm University. Biology, (4), 356–366. https://doi.org/10.17072/1994-9952-2023-4-356-366
Issue
No. 4 (2023): Bulletin of Perm University. BIOLOGY
Section
Микробиология

License agreement

 

Author Biographies

Roman Yu. Sidorov, Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center, the Ural branch of Russian Academy of Sciences

Engineer of the laboratory of microbial adaptation, junior researcher at the Laboratory of organic synthesis

Alexander G. Tkachenko, Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center, the Ural branch of Russian Academy of Sciences

Doctor of medicine, professor, head of the Laboratory of microbial adaptation, professor of the Department of Microbiology and Immunology

References

Amato S.M., Orman M.A., Brynildsen M.P. Metabolic control of persister formation in Escherichia coli. Mol Cell. V. 50, No. 4 (2013): pp. 475-87. DOI: 10.1016/j.molcel.2013.04.002.

Amato S.M., Brynildsen M.P. Persister heterogeneity arising from a single metabolic stress. Curr Biol. V. 25, No. 16 (2015): pp. 2090-8. DOI: 10.1016/j.cub.2015.06.034.

Anderson B.W., Liu K., Wolak C., Dubiel K., She F. et al. Evolution of (p)ppGpp-HPRT regulation through diversification of an allosteric oligomeric interaction. Elife. 8:e47534 (2019). DOI: 10.7554/eLife.47534.

Balaban N.Q., Merrin J., Chait R., Kowalik L., Leibler S. Bacterial persistence as a phenotypic switch. Sci-ence. V. 305, No. 5690 (2004): pp. 1622-5. DOI: 10.1126/science.1099390.

Beljantseva J., Kudrin P., Jimmy S., Ehn M., Pohl R. et al. Molecular mutagenesis of ppGpp: turning a RelA activator into an inhibitor. Nature Scientific Reports. V. 7, 41839 (2017). DOI: 10.1038/srep41839.

Bhaskar A., De Piano C., Gelman E., McKinney J.D., Dhar N. Elucidating the role of (p)ppGpp in myco-bacterial persistence against antibiotics. IUBMB Life. V. 70, No. 9 (2018): pp. 836-844. DOI: 10.1002/iub.1888.

Brauner A., Fridman O., Gefen O., Balaban N.Q. Distinguishing between resistance, tolerance and persis-tence to antibiotic treatment. Nature Reviews Microbiology. V. 14 (2016): pp. 320–330. DOI: 10.1038/nrmicro.2016.34.

Burgos H.L., O'Connor K., Sanchez-Vazquez P., Gourse R.L. Roles of transcriptional and translational control mechanisms in regulation of ribosomal protein synthesis in Escherichia coli. J Bacteriol. V. 199, No. 21 (2017): e00407-17. DOI: 10.1128/JB.00407-17.

Cashel M., Gallant J. Two compounds implicated in the function of the RC gene of Escherichia coli. Na-ture. V. 221, No. 5183 (1969): pp. 838-41. DOI: 10.1038/221838a0.

Chowdhury N., Kwan B.W., Wood T.K. Persistence increases in the absence of the alarmone guanosine tetraphosphate by reducing cell growth. Scientific Reports. V. 6 (2016): 20519. DOI: 10.1038/srep20519.

Cohen N.R., Lobritz M.A., Collins J.J. Microbial persistence and the road to drug resistance. Cell Host Microbe. V. 13, No. 6 (2013): pp. 632-42. DOI: 10.1016/j.chom.2013.05.009.

Corrigan R.M., Bellows L.E., Wood A., Gründling A. ppGpp negatively impacts ribosome assembly af-fecting growth and antimicrobial tolerance in Gram-positive bacteria. Proc Natl Acad Sci USA. V. 113, No. 12 (2016): E1710-9. DOI: 10.1073/pnas.1522179113.

Dahl J., Kraus C.N., Boshoff H.I., Doan B., Foley K., Avarbock D. et al. The role of RelMtb-mediated ad-aptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice. Proc. Natl. Acad. Sci. USA. V. 100 (2003): pp. 10026–10031. DOI: 10.1073/pnas.1631248100a.

Danchik C., Wang S., Karakousis P.C. Targeting the Mycobacterium tuberculosis stringent response as a strategy for shortening tuberculosis treatment. Front Microbiol. V. 12 (2021): 744167. DOI: 10.3389/fmicb.2021.744167.

Davis K.M., Isberg R.R. Defining heterogeneity within bacterial populations via single cell approaches. Bioessays. V. 38, No. 8 (2016): pp. 782-90. DOI: 10.1002/bies.201500121.

Diez S., Ryu J., Caban K., Gonzalez R.L. Jr., Dworkin J. The alarmones (p)ppGpp directly regulate trans-lation initiation during entry into quiescence. Proc Natl Acad Sci USA. V. 117, No. 27 (2020): pp. 15565-15572. DOI: 10.1073/pnas.1920013117.

Dutta N.K., Klinkenberg L.G., Vazquez M.-J. et al. Inhibiting the stringent response blocks Mycobacte-rium tuberculosis entry into quiescence and reduces persistence. Sci Adv. V. 5, No. 3 (2019): eaav2104. DOI: 10.1126/sciadv.aav2104.

Ehrt S., Schnappinger D., Rhee K.Y. Metabolic principles of persistence and pathogenicity in Mycobacte-rium tuberculosis. Nat Rev Microbiol. V. 16, No. 8 (2018): pp. 496–507. DOI: 10.1038/s41579-018-0013-4.

Fernández-Coll L., Maciag-Dorszynska M., Tailor K., Vadia S., Levin P.A. et al. The absence of (p)ppGpp renders initiation of Escherichia coli chromosomal DNA synthesis independent of growth rates. mBio. V. 11, No. 2 (2020): e03223-19. DOI: 10.1128/mBio.03223-19.

Giramma C.N., DeFoer M.B., Wang J.D. The alarmone (p)ppGpp regulates primer extension by bacterial primase. J Mol Biol. V. 433, No. 19 (2021): 167189. DOI: 10.1016/j.jmb.2021.167189.

Gong W., Wu X. Differential diagnosis of latent tuberculosis infection and active tuberculosis: a key to a successful tuberculosis control strategy. Front Microbiol. V. 12 (2021): 745592. DOI: 10.3389/fmicb.2021.745592.

Grimbergen A.J., Siebring J., Solopova A., Kuipers O.P. Microbial bet-hedging: the power of being differ-ent. Curr Opin Microbiol. V. 25 (2015): pp. 67-72. DOI: 10.1016/j.mib.2015.04.008.

Gupta K.R., Kasetty S., Chatterji D. Novel functions of (p)ppGpp and cyclic di-GMP in mycobacterial physiology revealed by phenotype microarray analysis of wild-type and isogenic strains of Mycobacterium smegmatis. Appl Environ Microbiol. V. 81, No. 7 (2015): pp. 2571–8. DOI: 10.1128/AEM.03999-14.

Gupta K.R., Arora G., Mattoo A., Sajid A. Stringent response in mycobacteria: from biology to therapeu-tic potential. Pathogens. V. 10, No. 11 (2021): 1417. DOI: 10.3390/pathogens10111417.

Harms A., Maisonneuve E., Gerdes K. Mechanisms of bacterial persistence during stress and antibiotic exposure. Science. V. 354, No. 6318 (2016): aaf4268. DOI: 10.1126/science.aaf4268.

Henry T.C., Brynildsen M.P. Development of Persister-FACSeq: a method to massively parallelize quan-tification of persister physiology and its heterogeneity. Sci Rep. V. 6 (2016): 25100. DOI: 10.1038/srep25100.

Hobbs J.K., Boraston, A.B. (p)ppGpp and the stringent response: an emerging threat to antibiotic thera-py. ACS Infect Dis. V. 5, No. 9 (2019): pp.1505-1517. DOI: 10.1021/acsinfecdis.9b00204.

Hong S.H., Wang X., O'Connor H.F., Benedik M.J., Wood T.K. Bacterial persistence increases as envi-ronmental fitness decreases. Microb Biotechnol. V. 5, No. 4 (2012): pp. 509-522. DOI: 10.1111/j.1751-7915.2011.00327.x.

Huaman M.A., Sterling T.R. Treatment of Latent Tuberculosis Infection-An Update. Clin Chest Med. V. 40, No. 4 (2019): pp. 839-848. DOI: 10.1016/j.ccm.2019.07.008.

Irving S.E., Choudhury N.R., Corrigan R.M. The stringent response and physiological roles of (pp)pGpp in bacteria. Nat Rev Microbiol. V. 19, No. 4 (2021): pp. 256-271. DOI: 10.1038/s41579-020-00470-y.

Izutsu K., Wada A., Wada C. Expression of ribosome modulation factor (RMF) in Escherichia coli re-quires ppGpp. Genes Cells. V. 6, No. 8 (2001): pp. 665-76. DOI: 10.1046/j.1365-2443.2001.00457.x.

Kaldalu N., Hauryliuk V., Tenson T. Persisters – as elusive as ever. Appl Microbiol Biotechnol. V. 100, No. 15 (2016): pp. 6545-6553. DOI: 10.1007/s00253-016-7648-8.

Keren I., Kaldalu N., Spoering A., Wang Y., Lewis K. Persister cells and tolerance to antimicrobials. FEMS Microbiology Letters. V. 230 (2004): pp. 13-18.

Kester J.C., Fortune S.M. Persisters and beyond: mechanisms of phenotypic drug resistance and drug tol-erance in bacteria. Crit Rev Biochem Mol Biol. V. 49, No. 2 (2014): pp. 91-101. DOI: 10.3109/10409238.2013.869543.

Kim H.Y., Go J., Lee K.M., Oh Y.T., Yoon S.S. Guanosine tetra- and pentaphosphate increase antibiotic tolerance by reducing reactive oxygen species production in Vibrio cholerae. J Biol Chem. V. 293, No. 15 (2018): pp. 5679-5694. DOI: 10.1074/jbc.RA117.000383.

Klapper I., Dockery J. Mathematical Description of Microbial Biofilms. SIAM Review. V. 52, No. 2 (2010): pp. 221-265. DOI: 10.1137/080739720.

Klinkenberg L.G., Lee J., Bishai W.R., Karakousis P.C. The stringent response is required for full virulence of Mycobacterium tuberculosis in Guinea pigs. J. Infect. Dis. V. 202 (2010): pp. 1397-1404. DOI: 10.1086/656524.

Kohanski M.A., Dwyer D.J., Hayete B., Lawrence C.A., Collins J.J. A common mechanism of cellular death induced by bactericidal antibiotics. Cell. V. 130, No. 5 (2007): pp. 797-810. DOI: 10.1016/j.cell.2007.06.049.

Korch S.B., Henderson T.A., Hill T.M. Characterization of the hipA7 allele of Escherichia coli and evi-dence that high persistence is governed by (p)ppGpp synthesis. Mol Microbiol. V. 50, No. 4 (2003): pp. 1199-213. DOI: 10.1046/j.1365-2958.2003.03779.x.

Kushwaha G.S., Oyeyemi B.F., Bhavesh N.S. Stringent response protein as a potential target to intervene persistent bacterial infection. Biochimie. V. 165 (2019): pp. 67-75. DOI: 10.1016/j.biochi.2019.07.006.

Kushwaha G.S., Patra A., Bhavesh N.S. Structural analysis of (p)ppGpp reveals its versatile binding pat-tern for diverse types of target proteins. Front Microbiol. V. 11 (2020): 575041. DOI: 10.3389/fmicb.2020.575041.

Kwan B.W., Valenta J.A., Benedik M.J., Wood T.K. Arrested protein synthesis increases persister-like cell formation. Antimicrob Agents Chemother. V. 57, No. 3 (2013): pp. 1468-1473. DOI: 10.1128/AAC.02135-12.

Lewis K. Persister cells. The Annual Review of Microbiology. V. 64 (2010): pp. 357-72. DOI: 10.1146/annurev.micro.112408.134306.

Li Y., Sun F., Zhang W. Bedaquiline and delamanid in the treatment of multidrug-resistant tuberculosis: Promising but challenging. Drug Dev Res. V. 80, No. 1 (2019): pp. 98-105. DOI: 10.1002/ddr.21498.

Liu H., Xiao Y., Nie H., Huang Q., Chen W. Influence of (p)ppGpp on biofilm regulation in Pseudomonas putida KT2440. Microbiol Res. V. 204 (2017): pp. 1-8. DOI: 10.1016/j.micres.2017.07.003.

Maisonneuve E., Gerdes K. Molecular mechanisms underlying bacterial persisters. Cell. 157, No. 3 (2014): pp. 539-48. DOI: 10.1016/j.cell.2014.02.050.

Mandal S., Njikan S., Kumar A., Early J.V., Parish T. The relevance of persisters in tuberculosis drug dis-covery. Microbiology. V. 165, No. 5 (2019): pp. 492-499. DOI: 10.1099/mic.0.000760.

Maciag M., Kochanowska M., Lyzeń R., Wegrzyn G., Szalewska-Pałasz A. ppGpp inhibits the activity of Escherichia coli DnaG primase. Plasmid. V. 63, No. 1 (2019): pp. 61-7. DOI: 10.1016/j.plasmid.2009.11.002.

Mechold U., Potrykus K., Murphy H., Murakami K.S., Cashel M. Differential regulation by ppGpp versus pppGpp in Escherichia coli. Nucleic Acids Res. V. 41, No. 12 (2013): pp. 6175-89. DOI: 10.1093/nar/gkt302.

Merrikh H., Ferrazzoli A.E., Lovett S.T. Growth phase and (p)ppGpp control of IraD, a regulator of RpoS stability, in Escherichia coli. J Bacteriol. V. 191, No. 24 (2009): pp. 7436-46. DOI: 10.1128/JB.00412-09.

Mok W.W., Orman M.A., Brynildsen M.P. Impacts of global transcriptional regulators on persister me-tabolism. Antimicrob Agents Chemother. V. 59, No. 5 (2015): pp. 2713-9. DOI: 10.1128/AAC.04908-14.

Murakami K.S. Structural biology of bacterial RNA polymerase. Biomolecules. V. 5, No. 2 (2015): pp. 848-64. DOI: 10.3390/biom5020848.

Nguyen D. et al. Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria. Science. V. 334 (2011): pp. 982-986. DOI: 10.1126/science.1211037.

Orman M.A., Brynildsen M.P. Dormancy is not necessary or sufficient for bacterial persistence. Antimi-crob Agents Chemother. V. 57, No. 7 (2013): pp. 3230-3239. DOI: 10.1128/AAC.00243-13.

Pacios, O., Blasco, L., Bleriot, I. et al. (p)ppGpp and its role in bacterial persistence: new challenges. Anti-microb Agents Chemother. V. 64, No. 10 (2020): e01283-20. DOI: 10.1128/AAC.01283-20.

Potrykus K., Murphy H., Philippe N., Cashel M. ppGpp is the major source of growth rate control in E. coli. Environmental Microbiology. V. 13, No. 3 (2011): pp. 563-575. DOI: 10.1111/j.1462-2920.2010.02357.x.

Prax M., Bertram R. Metabolic aspects of bacterial persisters. Front Cell Infect Microbiol. V. 4 (2014): 148. DOI: 10.3389/fcimb.2014.00148.

Primm T.P., Andersen S.J., Mizrahi V., Avarbock D., Rubin H., Barry C.E. The stringent response of My-cobacterium tuberculosis is required for long-term survival. J Bacteriol. V. 182, No. 17 (2000): pp. 4889-4898. DOI: 10.1128/jb.182.17.4889-4898.2000.

Pu Y., Li Y., Jin X., Tian T., Qi M., et al. ATP-dependent dynamic protein aggregation regulates bacterial dormancy depth critical for antibiotic tolerance. Molecular Cell. V. 73 (2019): pp. 143-156. DOI: 10.1016/j.molcel.2018.10.022.

Rodionov D.G., Ishiguro E.E. Direct correlation between overproduction of guanosine 3',5'-bispyrophosphate (ppGpp) and penicillin tolerance in Escherichia coli. J Bacteriol. V. 177, No. 15 (1995): pp. 4224-9. DOI: 10.1128/jb.177.15.4224-4229.1995.

Salcedo-Sora J. E., Kell D.B. A quantitative survey of bacterial persistence in the presence of antibiotics: towards antipersister antimicrobial discovery. Antibiotics. V. 9, No. 8 (2020): 508. DOI: 10.3390/antibiotics9080508.

Sebastian J. et al. De novo emergence of genetically resistant mutants of Mycobacterium tuberculosis from the persistence phase cells formed against antituberculosis drugs in vitro. Antimicrob Agents Chemother. V. 61, No. 2 (2017): e01343-16. DOI: 10.1128/AAC.01343-16.

Shan Y., Gandt A.B., Lewis K. et al. ATP-dependent persister formation in Escherichia coli. mBio. V. 8, No. 1 (2017): e02267-16. DOI: 10.1128/mBio.02267-16.

Sinha S.K., Neethu R.S., Devarakonda Y., Rathi A., Regatti P.R. et al. Tale of Twin Bifunctional Second Messenger (p)ppGpp Synthetases and Their Function in Mycobacteria. ACS Omega. V. 8, No. 36 (2023): pp. 32258-32270. DOI: 10.1021/acsomega.3c03557.

Starosta A.L., Lassak J., Jung K., Wilson D.N. The bacterial translation stress response. FEMS Microbiol Rev. V. 38, No. 6 (2014): pp. 1172-201. DOI: 10.1111/1574-6976.12083.

Stokes J.M., Lopatkin A.J., Lobritz M.A., Collins J.J. Bacterial metabolism and antibiotic efficacy. Cell Metab. V. 30, No. 2 (2019): pp. 251-259. DOI: 10.1016/j.cmet.2019.06.009.

Syal K., Flentie K., Bhardwaj N., Maiti K., Jayaraman N. et al. Synthetic (p)ppGpp analogue is an inhibi-tor of stringent response in mycobacteria. Antimicrob Agents Chemother. V. 61, No. 6 (2017): e00443-17. DOI: 10.1128/AAC.00443-17.

Syal K., Rs N., Reddy M.V.N.J. The extended (p)ppGpp family: new dimensions in stress response. Curr Res Microb Sci. V. 2 (2021): 100052. DOI: 10.1016/j.crmicr.2021.100052.

Tkachenko A.G., Kashevarova N.M., Sidorov R.Yu., Nesterova L.Yu., Akhova A.V. et al. A synthetic diterpene analogue inhibits mycobacterial persistence and biofilm formation by targeting (p)ppGpp synthetases. Cell Chemical Biology. V. 28, No. 10 (2021): pp. 1420-1432.e9. DOI: 10.1016/j.chembiol.2021.01.018.

Viducic D., Ono T., Murakami K. et al. Functional analysis of spoT, relA and dksA genes on quinolone tolerance in Pseudomonas aeruginosa under nongrowing condition. Microbiol Immunol. V. 50, No. 4 (2006): pp. 349-57. DOI: 10.1111/j.1348-0421.2006.tb03793.x.

Vogwill T., Comfort A.C., Furió V., MacLean R.C. Persistence and resistance as complementary bacterial adaptations to antibiotics. J Evol Biol. V. 29, No. 6 (2016): pp. 1223-1233. DOI: 10.1111/jeb.12864.

Wagner R. Regulation of ribosomal RNA synthesis in E. coli: effects of the global regulator guanosine tetraphosphate (ppGpp). J Mol Microbiol Biotechnol. V. 4, No. 3 (2002): pp. 331-40.

Warner D.F., Mizrahi V. Tuberculosis chemotherapy: the influence of bacillary stress and damage re-sponse pathways on drug efficacy. Clin Microbiol Rev. V. 19(3) (2006): 558-70. DOI: 10.1128/CMR.00060-05.

Weiss L.A., Stallings C.L. Essential roles for Mycobacterium tuberculosis Rel beyond the production of (p)ppGpp. J. of Bacteriol. V. 195, No. 24 (2013): pp. 5629-38. DOI: 10.1128/JB.00759-13.

Wexselblatt E., Oppenheimer-Shaanan Y., Kaspy I. et al. Relacin, a novel antibacterial agent targeting the stringent response. PLoS Pathog. V. 8, No. 9 (2012): e1002925. DOI: 10.1371/journal.ppat.1002925.

Winther K.S., Roghanian M., Gerdes K. Activation of the stringent response by loading of RelA-tRNA complexes at the ribosomal A-site. Mol Cell. V. 70, No. 1 (2018): pp. 95-105.e4. DOI: 10.1016/j.molcel.2018.02.033.

Wood T.K., Knabel S.J., Kwan B.W. Bacterial persister cell formation and dormancy. Applied and Envi-ronmental Microbiology. V. 79, No. 23 (2013): 7116-21. DOI: 10.1128/AEM.02636-13.

Wu J., Long Q., Xie J. (p)ppGpp and drug resistance. J Cell Physiol. 224. No. 2 (2010): pp. 300-4. DOI: 10.1002/jcp.22158.

Wu Y., Vulić M., Keren I., Lewis K. Role of oxidative stress in persister tolerance. Antimicrob Agents Chemother. V. 56, No. 9 (2012): pp. 4922-6. DOI: 10.1128/AAC.00921-12.

Yan J., Bassler B.L. Surviving as a community: antibiotic tolerance and persistence in bacterial biofilms. Cell Host Microbe. V. 26, No. 1 (2019): pp. 15-21. DOI: 10.1016/j.chom.2019.06.002.

Zhang Y. Persisters, persistent infections and the Yin–Yang model. Emerging Microbes and Infections. V. 3, No. 1 (2014): e3. DOI: 10.1038/emi.2014.3.

Zhao Y., Cai Y., Chen Z., Li H., et al. SpoT-mediated NapA upregulation promotes oxidative stress-induced Helicobacter pylori biofilm formation and confers multidrug resistance. Antimicrob Agents Chemother. V. 65, No. 5 (2021): e00152-21. DOI: 10.1128/AAC.00152-21.

Zheng E.J., Stokes J.M., Collins J.J. Eradicating bacterial persisters with combinations of strongly and weakly metabolism-dependent antibiotics. Cell Chem Biol. V. 27, No. 12 (2020): pp. 1544-1552.e3. DOI: 10.1016/j.chembiol.2020.08.015.

Zamakhaev M.V., Goncharenko A.V., Shumkov M.S. [Toxin-antitoxin systems and bacterial persistence (Review)]. Appl. Biochem. Microbiol. V. 55, No. 6 (2019): pp. 571-581. (In Russ.). DOI: 10.1134/S055510991906014X.