Abstract
In bacteria, guaA encodes guanosine monophosphate synthetase that confers an ability to biosynthesize guanine nucleotides de novo. This enables bacterial colonization in different environments and, while guaA is widely distributed among Bacteroidetes and Firmicutes, its contribution to the inhabitation of the human microbiome by commensal bacteria is unclear. We studied Streptococcus as a commensal urogenital tract bacterium and opportunistic pathogen, and explored the role of guaA in bacterial survival and colonization of urine. Analysis of guaA-deficient Streptococcus revealed guanine utilization is essential for bacterial colonization of this niche. The genomic location of guaA in other commensals of the human urogenital tract revealed substantial cross-phyla diversity and organizational structures of guaA that are divergent across phyla. Essentiality of guaA for Streptococcus colonization in the urinary tract establishes that purine biosynthesis is a critical element of the ability of this bacterium to survive and colonize in the host as part of the resident human microbiome.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Jewett MW, Lawrence KA, Bestor A, Byram R, Gherardini F, Rosa PA. GuaA and GuaB are essential for Borrelia burgdorferi survival in the tick-mouse infection cycle. J Bacteriol. 2009;191:6231–41.
Eastgate JA, Thompson L, Milner J, Cooper RM, Pollitt CE, Roberts IS. Identification of a nonpathogenic Erwinia amylovora guaB mutant. Plant Pathol. 1997;46:594–9.
Duwat P, Ehrlich SD, Gruss A. Effects of metabolic flux on stress response pathways in Lactococcus lactis. Mol Microbiol. 1999;31:845–58.
Liechti G, Goldberg JB. Helicobacter pylori relies primarily on the purine salvage pathway for purine nucleotide biosynthesis. J Bacteriol. 2012;194:839–54.
Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R. Bacterial community variation in human body habitats across space and time. Science. 2009;326:1694–7.
Neugent ML, Hulyalkar NV, Nguyen VH, Zimmern PE, De Nisco NJ. Advances in understanding the human urinary microbiome and its potential role in urinary tract infection. mBio. 2020;11:pii: mBio.00218–20.
Chitty JL, Fraser JA. Purine acquisition and synthesis by human fungal pathogens. Microorganisms. 2017;5:pii: microorganisms5020033.
Maiuolo J, Oppedisano F, Gratteri S, Muscoli C, Mollace V. Regulation of uric acid metabolism and excretion. Int J Cardiol. 2016;213:8–14.
Hull RA, Hull SI. Nutritional requirements for growth of uropathogenic Escherichia coli in human urine. Infect Immun. 1997;65:1960–1.
Russo TA, Jodush ST, Brown JJ, Johnson JR. Identification of two previously unrecognized genes (guaA and argC) important for uropathogenesis. Mol Microbiol. 1996;22:217–29.
Subashchandrabose S, Hazen TH, Brumbaugh AR, Himpsl SD, Smith SN, Ernst RD, et al. Host-specific induction of Escherichia coli fitness genes during human urinary tract infection. Proc Natl Acad Sci USA. 2014;111:18327–32.
Kofoed EM, Yan D, Katakam AK, Reichelt M, Lin B, Kim J, et al. De Novo guanine biosynthesis but not the riboswitch-regulated purine salvage pathway is required for Staphylococcus aureus infection in vivo. J Bacteriol. 2016;198:2001–15.
Mehra RK, Drabble WT. Dual control of the gua operon of Escherichia coli K12 by adenine and guanine nucleotides. J Gen Microbiol. 1981;123:27–37.
Dobrindt U, Wullt B, Svanborg C. Asymtomatic bacteriuria as a model to study the coevolution of hosts and bacteria. Pathogens. 2016;5:pii: E21.
Ipe DS, Horton E, Ulett GC. The basics of bacteriuria: strategies of microbes for persistence in urine. Front Cell Infect Microbiol. 2016;6:14.
Jones AL, Knoll KM, Rubens CE. Identification of Streptococcus agalactiae virulence genes in the neonatal rat sepsis model using signature-tagged mutagenesis. Mol Microbiol. 2000;37:1444–55.
Sullivan MJ, Ulett GC. Evaluation of hematogenous spread and ascending infection in the pathogenesis of acute pyelonephritis due to group B streptococcus in mice. Micro Pathog. 2020;138:103796.
Freudenstein D, Reinshagen K, Petzold A, Debus A, Schroten H, Tenenbaum T. Ultra late onset group B streptococcal sepsis with acute renal failure in a child with urethral obstruction: a case report. J Med Case Rep. 2012;6:68.
Alizzi M, Rathnayake R, Sivabalan P, Emeto TI, Norton R. Group B streptococcal bacteraemia—changing trends in a tropical region of Australia. Intern Med J. 2020. https://doi.org/10.1111/imj.15164.
McFarland WC, Stocker BA. Effect of different purine auxotrophic mutations on mouse-virulence of a Vi-positive strain of Salmonella dublin and of two strains of Salmonella typhimurium. Micro Pathog. 1987;3:129–41.
Song L, Pan Y, Chen S, Zhang X. Structural characteristics of genomic islands associated with GMP synthases as integration hotspot among sequenced microbial genomes. Comput Biol Chem. 2012;36:62–70.
Brochet M, Rusniok C, Couve E, Dramsi S, Poyart C, Trieu-Cuot P, et al. Shaping a bacterial genome by large chromosomal replacements, the evolutionary history of Streptococcus agalactiae. Proc Natl Acad Sci USA. 2008;105:15961–6.
Hilt EE, McKinley K, Pearce MM, Rosenfeld AB, Zilliox MJ, Mueller ER, et al. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol. 2014;52:871–6.
Sargun A, Gerner RR, Raffatellu M, Nolan EM. Harnessing iron acquisition machinery to target Enterobacteriaceae. J Infect Dis. 2020:pii: 6039829. https://doi.org/10.1093/infdis/jiaa440.
Mulhbacher J, Brouillette E, Allard M, Fortier LC, Malouin F, Lafontaine DA. Novel riboswitch ligand analogs as selective inhibitors of guanine-related metabolic pathways. PLoS Pathog. 2010;6:e1000865.
Leclercq SY, Sullivan MJ, Ipe DS, Smith JP, Cripps AW, Ulett GC. Pathogenesis of Streptococcus urinary tract infection depends on bacterial strain and beta-hemolysin/cytolysin that mediates cytotoxicity, cytokine synthesis, inflammation and virulence. Sci Rep. 2016;6:29000.
Ipe DS, Ben Zakour NL, Sullivan MJ, Beatson SA, Ulett KB, Benjamin WHJ, et al. Discovery and characterization of human urine utilization by asymptomatic-bacteriuria-causing Streptococcus agalactiae. Infect Immun. 2015;84:307–19.
Ulett KB, Benjamin WH Jr., Zhuo F, Xiao M, Kong F, Gilbert GL, et al. Diversity of group B streptococcus serotypes causing urinary tract infection in adults. J Clin Microbiol. 2009;47:2055–60.
Carey AJ, Tan CK, Ipe DS, Sullivan MJ, Cripps AW, Schembri MA, et al. Urinary tract infection of mice to model human disease: practicalities, implications and limitations. Crit Rev Microbiol. 2016;42:780–99.
Brannon JR, Dunigan TL, Beebout CJ, Ross T, Wiebe MA, Reynolds WS, et al. Invasion of vaginal epithelial cells by uropathogenic Escherichia coli. Nat Commun. 2020;11:2803.
Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol. 2015;13:269–84.
Acknowledgements
This work was supported by funding from a Griffith University New Researcher Grant (MSC GUNRG 219152; to DSI), the National Health and Medical Research Council (Project Grant APP1146820; to GCU), the Griffith Health Institute and a Future Fellowship from the Australian Research Council (FT110101048; to GCU). The authors thank Harry Sakelaris and James A. Fraser for helpful discussions.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Ipe, D.S., Sullivan, M.J., Goh, K.G.K. et al. Conserved bacterial de novo guanine biosynthesis pathway enables microbial survival and colonization in the environmental niche of the urinary tract. ISME J 15, 2158–2162 (2021). https://doi.org/10.1038/s41396-021-00934-w
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41396-021-00934-w
This article is cited by
-
Analysis of stress response in multiple bacterial pathogens using a network biology approach
Scientific Reports (2025)
-
Dual RNA sequencing of group B Streptococcus-infected human monocytes reveals new insights into host–pathogen interactions and bacterial evasion of phagocytosis
Scientific Reports (2023)
