Skip to main content

Advertisement

SpringerLink
Log in

Quantitative proteomic reveals gallium maltolate induces an iron-limited stress response and reduced quorum-sensing in Pseudomonas aeruginosa

  • Original Paper
  • Published:
JBIC Journal of Biological Inorganic Chemistry Aims and scope Submit manuscript

Abstract

Gallium-based drugs have been repurposed as antibacterial therapeutic candidates and have shown significant potential as an alternative treatment option against drug resistant pathogens. The activity of gallium (Ga3+) is a result of its chemical similarity to ferric iron (Fe3+) and substitution into iron-dependent pathways. Ga3+ is redox inactive in typical physiological environments and therefore perturbs iron metabolism vital for bacterial growth. Gallium maltolate (GaM) is a well-known water-soluble formulation of gallium, consisting of a central gallium cation coordinated to three maltolate ligands, [Ga(Maltol-1H)3]. This study implemented a label-free quantitative proteomic approach to observe the effect of GaM on the bacterial pathogen, Pseudomonas aeruginosa. The replacement of iron for gallium mimics an iron-limitation response, as shown by increased abundance of proteins associated with iron acquisition and storage. A decreased abundance of proteins associated with quorum-sensing and swarming motility was also identified. These processes are a fundamental component of bacterial virulence and dissemination and hence suggest a potential role for GaM in the treatment of P. aeruginosa infection.

Graphic abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

AMR:

Antimicrobial resistance

GaM:

Gallium maltolate

PBS:

Phosphate buffered saline

QS:

Quorum sensing

PQS:

Pseudomonas Quinolone signal

SSDA:

Statistically significant and differentially abundant

References

  1. Exner M, Bhattacharya S, Christiansen B, Gebel J, Goroncy-Bermes P, Hartemann P, Heeg P, Ilschner C, Kramer A, Larson E, Merkens W, Mielke M, Oltmanns P, Ross B, Rotter M, Schmithausen RM, Sonntag HG, Trautmann M (2017) Antibiotic resistance: what is so special about multidrug-resistant Gram-negative bacteria? GMS Hygiene Infect Control. https://doi.org/10.3205/dgkh000290

    Article  Google Scholar 

  2. Ghai I, Ghai S (2018) Understanding antibiotic resistance via outer membrane permeability. Infect Drug Resist 11:523–530. https://doi.org/10.2147/IDR.S156995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Breijyeh Z, Jubeh B, Karaman R (2020) Resistance of gram-negative bacteria to current antibacterial agents and approaches to resolve it. Molecules (Basel, Switzerland) 25(6):1340. https://doi.org/10.3390/molecules25061340

    Article  CAS  Google Scholar 

  4. El Zowalaty ME, Al Thani AA, Webster TJ, El Zowalaty AE, Schweizer HP, Nasrallah GK, Marei HE, Ashour HM (2015) Pseudomonas aeruginosa: arsenal of resistance mechanisms, decades of changing resistance profiles, and future antimicrobial therapies. Future Microbiol 10(10):1683–1706. https://doi.org/10.2217/fmb.15.48

    Article  CAS  PubMed  Google Scholar 

  5. Wang T, Hou Y, Wang R (2019) A case report of community-acquired Pseudomonas aeruginosa pneumonia complicated with MODS in a previously healthy patient and related literature review. BMC Infect Dis 19(1):130. https://doi.org/10.1186/s12879-019-3765-1

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bassetti M, Vena A, Croxatto A, Righi E, Guery B (2018) How to manage Pseudomonas aeruginosa infections. Drugs Context 7:212527. https://doi.org/10.7573/dic.212527

    Article  PubMed  PubMed Central  Google Scholar 

  7. Faure E, Kwong K, Nguyen D (2018) Pseudomonas aeruginosa in Chronic lung infections: How to adapt within the host? Front Immunol 9:2416. https://doi.org/10.3389/fimmu.2018.02416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sordé R, Pahissa A, Rello J (2011) Management of refractory Pseudomonas aeruginosa infection in cystic fibrosis. Infect Drug Resist 4:31–41. https://doi.org/10.2147/IDR.S16263

    Article  PubMed  PubMed Central  Google Scholar 

  9. Moradali MF, Ghods S, Rehm BH (2017) Pseudomonas aeruginosa lifestyle: a paradigm for adaptation, survival, and persistence. Front Cell Infect Microbiol 7:39. https://doi.org/10.3389/fcimb.2017.00039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Frimmersdorf E, Horatzek S, Pelnikevich A, Wiehlmann L, Schomburg D (2010) How Pseudomonas aeruginosa adapts to various environments: a metabolomic approach. Environ Microbiol 12(6):1734–1747. https://doi.org/10.1111/j.1462-2920.2010.02253.x

    Article  CAS  PubMed  Google Scholar 

  11. Melander RJ, Zurawski DV, Melander C (2018) Narrow-spectrum antibacterial agents. Med Chem Commun 9(1):12–21. https://doi.org/10.1039/C7MD00528H

    Article  CAS  Google Scholar 

  12. Pachori P, Gothalwal R, Gandhi P (2019) Emergence of antibiotic resistance Pseudomonas aeruginosa in intensive care unit; a critical review. Genes Dis 6(2):109–119. https://doi.org/10.1016/j.gendis.2019.04.001

    Article  PubMed  PubMed Central  Google Scholar 

  13. Beceiro A, Tomás M, Bou G (2013) Antimicrobial resistance and virulence: a successful or deleterious association in the bacterial world? Clin Microbiol Rev 26(2):185–230. https://doi.org/10.1128/CMR.00059-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Goss CH, Kaneko Y, Khuu L, Anderson GD, Ravishankar S, Aitken ML, Lechtzin N, Zhou G, Czyz DM, McLean K, Olakanmi O, Shuman HA, Teresi M, Wilhelm E, Caldwell E, Salipante SJ, Hornick DB, Siehnel RJ, Becker L, Britigan BE et al (2018) Gallium disrupts bacterial iron metabolism and has therapeutic effects in mice and humans with lung infections. Sci Trans Med 10(460):eaat7520. https://doi.org/10.1126/scitranslmed.aat7520

    Article  CAS  Google Scholar 

  15. Chitambar CR (2017) The therapeutic potential of iron-targeting gallium compounds in human disease: from basic research to clinical application. Pharmacol Res 115:56–64. https://doi.org/10.1016/j.phrs.2016.11.009

    Article  CAS  PubMed  Google Scholar 

  16. Kaneko Y, Thoendel M, Olakanmi O, Britigan BE, Singh PK (2007) The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity. J Clin Investig 117(4):877–888. https://doi.org/10.1172/JCI30783

    Article  CAS  PubMed  Google Scholar 

  17. Cherayil BJ (2011) The role of iron in the immune response to bacterial infection. Immunol Res 50(1):1–9. https://doi.org/10.1007/s12026-010-8199-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ganz T, Nemeth E (2006) Regulation of iron acquisition and iron distribution in mammals. Biochem Biophys Acta 1763(7):690–699. https://doi.org/10.1016/j.bbamcr.2006.03.014

    Article  CAS  PubMed  Google Scholar 

  19. Puig S, Ramos-Alonso L, Romero AM, Martínez-Pastor MT (2017) The elemental role of iron in DNA synthesis and repair. Metallomics 9(11):1483–1500. https://doi.org/10.1039/c7mt00116a

    Article  PubMed  Google Scholar 

  20. Caza M, Kronstad JW (2013) Shared and distinct mechanisms of iron acquisition by bacterial and fungal pathogens of humans. Front Cell Infect Microbiol 3:80. https://doi.org/10.3389/fcimb.2013.00080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cornelis P, Dingemans J (2013) Pseudomonas aeruginosa adapts its iron uptake strategies in function of the type of infections. Front Cell Infect Microbiol 3:75. https://doi.org/10.3389/fcimb.2013.00075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lau CK, Krewulak KD, Vogel HJ (2016) Bacterial ferrous iron transport: the Feo system. FEMS Microbiol Rev 40(2):273–298. https://doi.org/10.1093/femsre/fuv049

    Article  CAS  PubMed  Google Scholar 

  23. Dumas Z, Ross-Gillespie A, Kümmerli R (2013) Switching between apparently redundant iron-uptake mechanisms benefits bacteria in changeable environments. Proc Biol Sci 280(1764):20131055. https://doi.org/10.1098/rspb.2013.1055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chitambar CR, Zivkovic-Gilgenbach Z (1990) Role of the acidic receptosome in the uptake and retention of 67Ga by human leukemic HL60 cells. Can Res 50(5):1484–1487

    CAS  Google Scholar 

  25. Chikh Z, Ha-Duong NT, Miquel G, El Hage Chahine JM (2007) Gallium uptake by transferrin and interaction with receptor 1. J Biol Inorg Chem 12(1):90–100. https://doi.org/10.1007/s00775-006-0169-7

    Article  CAS  PubMed  Google Scholar 

  26. Chitambar CR (2016) Gallium and its competing roles with iron in biological systems. Biochem Biophys Acta 1863(8):2044–2053. https://doi.org/10.1016/j.bbamcr.2016.04.027

    Article  CAS  PubMed  Google Scholar 

  27. Harris WR, Pecoraro VL (1983) Thermodynamic binding constants for gallium transferrin. Biochemistry 22(2):292–299. https://doi.org/10.1021/bi00271a010

    Article  CAS  PubMed  Google Scholar 

  28. van Amsterdam JA, Kluin-Nelemans JC, van Eck-Smit BL, Pauwels EK (1996) Role of 67Ga scintigraphy in localization of lymphoma. Ann Hematol 72(4):202–207. https://doi.org/10.1007/s002770050161

    Article  PubMed  Google Scholar 

  29. Chitambar CR (2012) Gallium-containing anticancer compounds. Future Med Chem 4(10):1257–1272. https://doi.org/10.4155/fmc.12.69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hayes RL (1978) The medical use of gallium radionuclides: a brief history with some comments. Semin Nucl Med 8(3):183–191. https://doi.org/10.1016/s0001-2998(78)80027-0

    Article  CAS  PubMed  Google Scholar 

  31. Timerbaev AR (2009) Advances in developing tris(8-quinolinolato)gallium(iii) as an anticancer drug: critical appraisal and prospects. Metallomics 1(3):193–198. https://doi.org/10.1039/b902861g

    Article  CAS  PubMed  Google Scholar 

  32. Hara T (1974) On the binding of gallium to transferrin. Int J Nuclear Med Biol 1(3):152–154. https://doi.org/10.1016/0047-0740(74)90021-7

    Article  CAS  Google Scholar 

  33. Sephton RG, Harris AW (1975) Gallium-67 citrate uptake by cultured tumor cells, stimulated by serum transferrin. J Natl Cancer Inst 54(5):1263–1266. https://doi.org/10.1093/jnci/54.5.1263

    Article  CAS  PubMed  Google Scholar 

  34. Chitambar CR, Seligman PA (1986) Effects of different transferrin forms on transferrin receptor expression, iron uptake, and cellular proliferation of human leukemic HL60 cells. Mechanisms responsible for the specific cytotoxicity of transferrin-gallium. J Clin Investig 78(6):1538–1546. https://doi.org/10.1172/JCI112746

    Article  CAS  PubMed  Google Scholar 

  35. Chitambar CR, Wereley JP, Matsuyama S (2006) Gallium-induced cell death in lymphoma: role of transferrin receptor cycling, involvement of Bax and the mitochondria, and effects of proteasome inhibition. Mol Cancer Ther 5(11):2834–2843

    Article  CAS  Google Scholar 

  36. Kubista B, Schoefl T, Mayr L, van Schoonhoven S, Heffeter P, Windhager R, Keppler BK, Berger W (2017) Distinct activity of the bone-targeted gallium compound KP46 against osteosarcoma cells—synergism with autophagy inhibition. J Exp Clin Cancer Res 36(1):52. https://doi.org/10.1186/s13046-017-0527-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hart MM, Smith CF, Yancey ST, Adamson RH (1971) Toxicity and antitumor activity of gallium nitrate and periodically related metal salts. J Natl Cancer Inst 47(5):1121–1127

    CAS  PubMed  Google Scholar 

  38. Giacani L, Bernstein LR, Haynes AM, Godornes BC, Ciccarese G, Drago F, Parodi A, Valdevit S, Anselmi L, Tomasini CF, Baca AM (2019) Topical treatment with gallium maltolate reduces Treponema pallidum subsp. pertenue burden in primary experimental lesions in a rabbit model of yaws. PLoS Neglect Trop Dis 13(1):e0007076. https://doi.org/10.1371/journal.pntd.0007076

    Article  CAS  Google Scholar 

  39. Finnegan M, Lutz T, Nelson W, Smith A, Orvig C (1987) Neutral water-soluble post-transition-metal chelate complexes of medical interest: aluminum and gallium tris(3-hydroxy-4-pyronates). Inorg Chem 26(13):2171–2176. https://doi.org/10.1021/ic00260a033

    Article  CAS  Google Scholar 

  40. Bernstein LR, Tanner T, Godfrey C, Noll B (2000) Chemistry and pharmacokinetics of gallium maltolate, a compound with high oral gallium bioavailability. Met-Based Drugs 7(1):33–47. https://doi.org/10.1155/MBD.2000.33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. DeLeon K, Balldin F, Watters C, Hamood A, Griswold J, Sreedharan S, Rumbaugh KP (2009) Gallium maltolate treatment eradicates Pseudomonas aeruginosa infection in thermally injured mice. Antimicrob Agents Chemother 53(4):1331–1337. https://doi.org/10.1128/AAC.01330-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Myette MS, Elford HL, Chitambar CR (1998) Interaction of gallium nitrate with other inhibitors of ribonucleotide reductase: effects on the proliferation of human leukemic cells. Cancer Lett 129(2):199–204. https://doi.org/10.1016/s0304-3835(98)00104-9

    Article  CAS  PubMed  Google Scholar 

  43. Olakanmi O, Kesavalu B, Pasula R, Abdalla MY, Schlesinger LS, Britigan BE (2013) Gallium nitrate is efficacious in murine models of tuberculosis and inhibits key bacterial Fe-dependent enzymes. Antimicrob Agents Chemother 57(12):6074–6080. https://doi.org/10.1128/AAC.01543-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bernstein LR, van der Hoeven JJ, Boer RO (2011) Hepatocellular carcinoma detection by gallium scan and subsequent treatment by gallium maltolate: rationale and case study. Anticancer Agents Med Chem 11(6):585–590. https://doi.org/10.2174/187152011796011046

    Article  CAS  PubMed  Google Scholar 

  45. Jakupec MA, Keppler BK (2004) Gallium in cancer treatment. Curr Top Med Chem 4(15):1575–1583. https://doi.org/10.2174/1568026043387449

    Article  CAS  PubMed  Google Scholar 

  46. Merli D, Profumo A, Bloise N, Risi G, Momentè S, Cucca L, Visai L (2018) Indium/Gallium Maltolate effects on human breast carcinoma cells: in vitro investigation on cytotoxicity and synergism with mitoxantrone. ACS Omega 3(4):4631–4640. https://doi.org/10.1021/acsomega.7b02026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chitambar CR, Matthaeus WG, Antholine WE, Graff K, O’Brien WJ (1988) Inhibition of leukemic HL60 cell growth by transferrin-gallium: effects on ribonucleotide reductase and demonstration of drug synergy with hydroxyurea. Blood 72(6):1930–1936

    Article  CAS  Google Scholar 

  48. Narasimhan J, Antholine WE, Chitambar CR (1992) Effect of gallium on the tyrosyl radical of the iron-dependent M2 subunit of ribonucleotide reductase. Biochem Pharmacol 44(12):2403–2408. https://doi.org/10.1016/0006-2952(92)90686-d

    Article  CAS  PubMed  Google Scholar 

  49. Mowa MB, Warner DF, Kaplan G, Kana BD, Mizrahi V (2009) Function and regulation of class I ribonucleotide reductase-encoding genes in mycobacteria. J Bacteriol 191(3):985–995. https://doi.org/10.1128/JB.01409-08

    Article  CAS  PubMed  Google Scholar 

  50. Pfeifhofer-Obermair C, Tymoszuk P, Petzer V, Weiss G, Nairz M (2018) Iron in the tumor microenvironment-connecting the dots. Front Oncol 8:549. https://doi.org/10.3389/fonc.2018.00549

    Article  PubMed  PubMed Central  Google Scholar 

  51. Wang Y, Yu L, Ding J, Chen Y (2018) Iron metabolism in cancer. Int J Mol Sci 20(1):95. https://doi.org/10.3390/ijms20010095

    Article  CAS  PubMed Central  Google Scholar 

  52. Chitambar CR (2010) Medical applications and toxicities of gallium compounds. Int J Environ Res Public Health 7(5):2337–2361. https://doi.org/10.3390/ijerph7052337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chitambar CR (2004a) Apoptotic mechanisms of gallium nitrate: basic and clinical investigations. Oncology (Williston Park, N.Y.) 18(13 Suppl 10):39–44

    Google Scholar 

  54. Başar I, Ayhan A, Bircan K, Ergen A, Taşar C (1991) Transferrin receptor activity as a marker in transitional cell carcinoma of the bladder. Br J Urol 67(2):165–168. https://doi.org/10.1111/j.1464-410x.1991.tb15101.x

    Article  PubMed  Google Scholar 

  55. Habeshaw JA, Lister TA, Stansfeld AG, Greaves MF (1983) Correlation of transferrin receptor expression with histological class and outcome in non-Hodgkin lymphoma. Lancet (London, England) 1(8323):498–501. https://doi.org/10.1016/s0140-6736(83)92191-8

    Article  CAS  Google Scholar 

  56. Chitambar CR (2004b) Gallium nitrate for the treatment of non-Hodgkin’s lymphoma. Expert Opin Investig Drugs 13(5):531–541. https://doi.org/10.1517/13543784.13.5.531

    Article  CAS  PubMed  Google Scholar 

  57. Malfetano JH, Blessing JA, Homesley HD, Hanjani P (1991) A phase II trial of gallium nitrate (NSC #15200) in advanced or recurrent squamous cell carcinoma of the cervix. A gynecologic oncology group study. Investig New Drugs 9(1):109–111. https://doi.org/10.1007/BF00194560

    Article  CAS  Google Scholar 

  58. Hijazi S, Visaggio D, Pirolo M, Frangipani E, Bernstein L, Visca P (2018) Antimicrobial activity of gallium compounds on ESKAPE pathogens. Front Cell Infect Microbiol 8:316. https://doi.org/10.3389/fcimb.2018.00316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rzhepishevska O, Ekstrand-Hammarström B, Popp M, Björn E, Bucht A, Sjöstedt A, Antti H, Ramstedt M (2011) The antibacterial activity of Ga3+ is influenced by ligand complexation as well as the bacterial carbon source. Antimicrob Agents Chemother 55(12):5568–5580. https://doi.org/10.1128/AAC.00386-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang Y, Han B, Xie Y, Wang H, Wang R, Xia W, Li H, Sun H (2019) Combination of gallium(iii) with acetate for combating antibiotic resistant Pseudomonas aeruginosa. Chem Sci 10(24):6099–6106. https://doi.org/10.1039/c9sc01480b

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Arnold CE, Bordin A, Lawhon SD, Libal MC, Bernstein LR, Cohen ND (2012) Antimicrobial activity of gallium maltolate against Staphylococcus aureus and methicillin-resistant S. aureus and Staphylococcus pseudintermedius: an in vitro study. Vet Microbiol 155(2–4):389–394. https://doi.org/10.1016/j.vetmic.2011.09.009

    Article  CAS  PubMed  Google Scholar 

  62. Fecteau ME, Aceto HW, Bernstein LR, Sweeney RW (2014) Comparison of the antimicrobial activities of gallium nitrate and gallium maltolate against Mycobacterium avium subsp. paratuberculosis in vitro. Vet J (London, England: 1997) 202(1):195–197

    Article  CAS  Google Scholar 

  63. Sheehan G, Kavanagh K (2018) Analysis of the early cellular and humoral responses of Galleria mellonella larvae to infection by Candida albicans. Virulence 9(1):163–172. https://doi.org/10.1080/21505594.2017.1370174

    Article  CAS  PubMed  Google Scholar 

  64. The Uniprot Consortium (2019) A worldwide hub of protein knowledge. Nucleic Acids Res 47(D1):D506–D515. https://doi.org/10.1093/nar/gky1049

    Article  CAS  Google Scholar 

  65. Perez-Riverol Y, Csordas A, Bai J, Bernal-Llinares M, Hewapathirana S, Kundu D et al (2018) The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res 47(D1):D442–D450. https://doi.org/10.1093/nar/gky1106

    Article  CAS  PubMed Central  Google Scholar 

  66. Deslyper G, Colgan TJ, Cooper AJ, Holland CV, Carolan JC (2016) A proteomic investigation of hepatic resistance to ascaris in a murine model. PLoS Neglect Trop Dis 10(8):e0004837. https://doi.org/10.1371/journal.pntd.0004837

    Article  CAS  Google Scholar 

  67. Skaar EP (2010) The battle for iron between bacterial pathogens and their vertebrate hosts. PLoS Pathog 6(8):e1000949. https://doi.org/10.1371/journal.ppat.1000949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cohen ND, Slovis NM, Giguère S, Baker S, Chaffin MK, Bernstein LR (2015) Gallium maltolate as an alternative to macrolides for treatment of presumed Rhodococcus equi pneumonia in foals. J Vet Intern Med 29(3):932–939. https://doi.org/10.1111/jvim.12595

    Article  PubMed  PubMed Central  Google Scholar 

  69. Browne N, Kavanagh K (2013) Developing the potential of using Galleria mellonella larvae as models for studying brain infection by Listeria monocytogenes. Virulence 4(4):271–272. https://doi.org/10.4161/viru.24174

    Article  PubMed  PubMed Central  Google Scholar 

  70. Kavanagh K, Sheehan G (2018) The use of Galleria mellonella Larvae to identify novel antimicrobial agents against fungal species of medical interest. J Fungi (Basel, Switzerland) 4(3):113. https://doi.org/10.3390/jof4030113

    Article  CAS  Google Scholar 

  71. Taszłow P, Vertyporokh L, Wojda I (2017) Humoral immune response of Galleria mellonella after repeated infection with Bacillus thuringiensis. J Invertebr Pathol 149:87–96. https://doi.org/10.1016/j.jip.2017.08.008

    Article  CAS  PubMed  Google Scholar 

  72. Sheehan G, Clarke G, Kavanagh K (2018) Characterisation of the cellular and proteomic response of Galleria mellonella larvae to the development of invasive aspergillosis. BMC Microbiol 18(1):63. https://doi.org/10.1186/s12866-018-1208-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gandra RM, McCarron P, Viganor L, Fernandes MF, Kavanagh K, McCann M, Branquinha MH, Santos A, Howe O, Devereux M (2020) In vivo Activity of copper(II), manganese(II), and silver(I) 1,10-phenanthroline chelates against Candida haemulonii using the Galleria mellonella model. Front Microbiol 11:470. https://doi.org/10.3389/fmicb.2020.00470

    Article  PubMed  PubMed Central  Google Scholar 

  74. Fuchs BB, Li Y, Li D, Johnston T, Hendricks G, Li G, Rajamuthiah R, Mylonakis E (2016) Micafungin elicits an immunomodulatory effect in galleria mellonella and mice. Mycopathologia 181(1–2):17–25. https://doi.org/10.1007/s11046-015-9940-z

    Article  CAS  PubMed  Google Scholar 

  75. Kiley TB, Stanley-Wall NR (2010) Post-translational control of Bacillus subtilis biofilm formation mediated by tyrosine phosphorylation. Mol Microbiol 78(4):947–963. https://doi.org/10.1111/j.1365-2958.2010.07382.x

    Article  CAS  PubMed  Google Scholar 

  76. Klein G, Dartigalongue C, Raina S (2003) Phosphorylation-mediated regulation of heat shock response in Escherichia coli. Mol Microbiol 48(1):269–285. https://doi.org/10.1046/j.1365-2958.2003.03449.x

    Article  CAS  PubMed  Google Scholar 

  77. Standish AJ, Morona R (2014) The role of bacterial protein tyrosine phosphatases in the regulation of the biosynthesis of secreted polysaccharides. Antioxid Redox Signal 20(14):2274–2289. https://doi.org/10.1089/ars.2013.5726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Musumeci L, Bongiorni C, Tautz L, Edwards RA, Osterman A, Perego M, Mustelin T, Bottini N (2005) Low-molecular-weight protein tyrosine phosphatases of Bacillus subtilis. J Bacteriol 187(14):4945–4956. https://doi.org/10.1128/JB.187.14.4945-4956.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Yao Q, Zhang L, Wan X, Chen J, Hu L, Ding X, Li L, Karar J, Peng H, Chen S, Huang N, Rauscher FJ 3rd, Shao F (2014) Structure and specificity of the bacterial cysteine methyltransferase effector NleE suggests a novel substrate in human DNA repair pathway. PLoS Pathog 10(11):e1004522. https://doi.org/10.1371/journal.ppat.1004522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Schlagman SL, Hattman S, Marinus MG (1986) Direct role of the Escherichia coli Dam DNA methyltransferase in methylation-directed mismatch repair. J Bacteriol 165(3):896–900. https://doi.org/10.1128/jb.165.3.896-900.1986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Cohen NR, Ross CA, Jain S, Shapiro RS, Gutierrez A, Belenky P, Li H, Collins JJ (2016) A role for the bacterial GATC methylome in antibiotic stress survival. Nat Genet 48(5):581–586. https://doi.org/10.1038/ng.3530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ghosh D, Veeraraghavan B, Elangovan R, Vivekanandan P (2020) Antibiotic resistance and epigenetics: more to it than meets the eye. Antimicrob Agents Chemother 64(2):e02225-e2319. https://doi.org/10.1128/AAC.02225-19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Truglio JJ, Croteau DL, Van Houten B, Kisker C (2006) Prokaryotic nucleotide excision repair: the UvrABC system. Chem Rev 106(2):233–252. https://doi.org/10.1021/cr040471u

    Article  CAS  PubMed  Google Scholar 

  84. Burby PE, Simmons LA (2019) A bacterial DNA repair pathway specific to a natural antibiotic. Mol Microbiol 111(2):338–353. https://doi.org/10.1111/mmi.14158

    Article  CAS  PubMed  Google Scholar 

  85. Crowley DJ, Hanawalt PC (1998) Induction of the SOS response increases the efficiency of global nucleotide excision repair of cyclobutane pyrimidine dimers, but not 6–4 photoproducts, in UV-irradiated Escherichia coli. J Bacteriol 180(13):3345–3352. https://doi.org/10.1128/JB.180.13.3345-3352.1998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. O’Neill M, Bhakta M, Fleming K, Wilks A (2012) Induced fit on heme binding to the Pseudomonas aeruginosa cytoplasmic protein (PhuS) drives interaction with heme oxygenase (HemO). Proc Natl Acad Sci 109(15):5639–5644. https://doi.org/10.1073/pnas.1121549109

    Article  PubMed  Google Scholar 

  87. Nguyen AT, O’Neill MJ, Watts AM, Robson CL, Lamont IL, Wilks A, Oglesby-Sherrouse AG (2014) Adaptation of iron homeostasis pathways by a Pseudomonas aeruginosa pyoverdine mutant in the cystic fibrosis lung. J Bacteriol 196(12):2265–2276

    Article  Google Scholar 

  88. Reyda MR, Fugate CJ, Jarrett JT (2009) A complex between biotin synthase and the iron-sulfur cluster assembly chaperone HscA that enhances in vivo cluster assembly. Biochemistry 48(45):10782–10792. https://doi.org/10.1021/bi901393t

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Romsang A, Duang-Nkern J, Leesukon P, Saninjuk K, Vattanaviboon P, Mongkolsuk S (2014) The iron-sulphur cluster biosynthesis regulator IscR contributes to iron homeostasis and resistance to oxidants in Pseudomonas aeruginosa. PLoS ONE 9(1):e86763. https://doi.org/10.1371/journal.pone.0086763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Miller HK, Auerbuch V (2015) Bacterial iron-sulfur cluster sensors in mammalian pathogens. Metallomics 7(6):943–956. https://doi.org/10.1039/c5mt00012b

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Nelson CE, Huang W, Brewer LK, Nguyen AT, Kane MA, Wilks A, Oglesby-Sherrouse AG (2019) Proteomic analysis of the Pseudomonas aeruginosa iron starvation response reveals PrrF small regulatory RNA-dependent iron regulation of twitching motility, amino acid metabolism, and zinc homeostasis proteins. J Bacteriol 201(12):e00754-e818. https://doi.org/10.1128/JB.00754-18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Choi SR, Britigan BE, Narayanasamy P (2019) Dual Inhibition of Klebsiella pneumoniae and Pseudomonas aeruginosa iron metabolism using gallium porphyrin and gallium nitrate. ACS Infect Dis 5(9):1559–1569. https://doi.org/10.1021/acsinfecdis.9b00100

    Article  CAS  PubMed  Google Scholar 

  93. Wegele R, Tasler R, Zeng Y, Rivera M, Frankenberg-Dinkel N (2004) The heme oxygenase(s)-phytochrome system of Pseudomonas aeruginosa. J Biol Chem 279(44):45791–45802. https://doi.org/10.1074/jbc.M408303200

    Article  CAS  PubMed  Google Scholar 

  94. Rutherford ST, Bassler BL (2012) Bacterial quorum sensing: its role in virulence and possibilities for its control. Cold Spring Harbor Perspect Med 2(11):a012427. https://doi.org/10.1101/cshperspect.a012427

    Article  CAS  Google Scholar 

  95. Glessner A, Smith RS, Iglewski BH, Robinson JB (1999) Roles of Pseudomonas aeruginosa las and rhl quorum-sensing systems in control of twitching motility. J Bacteriol 181(5):1623–1629. https://doi.org/10.1128/JB.181.5.1623-1629.1999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Turkina MV, Vikström E (2019) Bacteria-host crosstalk: sensing of the quorum in the context of Pseudomonas aeruginosa infections. J Innate Immunity 11(3):263–279. https://doi.org/10.1159/000494069

    Article  CAS  Google Scholar 

  97. Drees SL, Li C, Prasetya F, Saleem M, Dreveny I, Williams P, Hennecke U, Emsley J, Fetzner S (2016) PqsBC, a condensing enzyme in the biosynthesis of the Pseudomonas aeruginosa quinolone signal: crystal structure, inhibition, and reaction mechanism. J Biol Chem 291(13):6610–6624. https://doi.org/10.1074/jbc.M115.708453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Liu YC, Hussain F, Negm O, Pavia A, Halliday N, Dubern JF, Singh S, Muntaka S, Wheldon L, Luckett J, Tighe P, Bosquillon C, Williams P, Cámara M, Martínez-Pomares L (2018) Contribution of the alkylquinolone quorum-sensing system to the interaction of Pseudomonas aeruginosa with bronchial epithelial cells. Front Microbiol 9:3018. https://doi.org/10.3389/fmicb.2018.03018

    Article  PubMed  PubMed Central  Google Scholar 

  99. Diggle SP, Winzer K, Chhabra SR, Worrall KE, Cámara M, Williams P (2003) The Pseudomonas aeruginosa quinolone signal molecule overcomes the cell density-dependency of the quorum sensing hierarchy, regulates rhl-dependent genes at the onset of stationary phase and can be produced in the absence of LasR. Mol Microbiol 50(1):29–43. https://doi.org/10.1046/j.1365-2958.2003.03672.x

    Article  CAS  PubMed  Google Scholar 

  100. Heeb S, Fletcher MP, Chhabra SR, Diggle SP, Williams P, Cámara M (2011) Quinolones: from antibiotics to autoinducers. FEMS Microbiol Rev 35(2):247–274. https://doi.org/10.1111/j.1574-6976.2010.00247.x

    Article  CAS  PubMed  Google Scholar 

  101. Whiteley M, Lee KM, Greenberg EP (1999) Identification of genes controlled by quorum sensing in Pseudomonas aeruginosa. Proc Natl Acad Sci USA 96(24):13904–13909. https://doi.org/10.1073/pnas.96.24.13904

    Article  CAS  PubMed  Google Scholar 

  102. Stintzi A, Evans K, Meyer JM, Poole K (1998) Quorum-sensing and siderophore biosynthesis in Pseudomonas aeruginosa: lasR/lasI mutants exhibit reduced pyoverdine biosynthesis. FEMS Microbiol Lett 166(2):341–345. https://doi.org/10.1111/j.1574-6968.1998.tb13910.x

    Article  CAS  PubMed  Google Scholar 

  103. Coin D, Louis D, Bernillon J, Guinand M, Wallach J (1997) LasA, alkaline protease and elastase in clinical strains of Pseudomonas aeruginosa: quantification by immunochemical methods. FEMS Immunol Med Microbiol 18(3):175–184. https://doi.org/10.1111/j.1574-695X.1997.tb01043.x

    Article  CAS  PubMed  Google Scholar 

  104. Wen Y, Kim IH, Son JS, Lee BH, Kim KS (2012) Iron and quorum sensing coordinately regulate the expression of vulnibactin biosynthesis in Vibrio vulnificus. J Biol Chem 287(32):26727–26739. https://doi.org/10.1074/jbc.M112.374165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Zolfaghar I, Evans DJ, Fleiszig SM (2003) Twitching motility contributes to the role of pili in corneal infection caused by Pseudomonas aeruginosa. Infect Immun 71(9):5389–5393. https://doi.org/10.1128/iai.71.9.5389-5393.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Murray TS, Ledizet M, Kazmierczak BI (2010) Swarming motility, secretion of type 3 effectors and biofilm formation phenotypes exhibited within a large cohort of Pseudomonas aeruginosa clinical isolates. J Med Microbiol 59(Pt 5):511–520

    Article  CAS  Google Scholar 

  107. Chuang SK, Vrla GD, Fröhlich KS, Gitai Z (2019) Surface association sensitizes Pseudomonas aeruginosa to quorum sensing. Nat Commun 10(1):4118. https://doi.org/10.1038/s41467-019-12153-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lakshmanan D, Harikrishnan A, Jyoti K, Idul Ali M, Jeevaratnam K (2020) A compound isolated from Alpinia officinarum Hance. inhibits swarming motility of Pseudomonas aeruginosa and down regulates virulence genes. J Appl Microbiol 128(5):1355–1365

    Article  CAS  Google Scholar 

  109. Frisk A, Jyot J, Arora SK, Ramphal R (2002) Identification and functional characterization of flgM, a gene encoding the anti-sigma 28 factor in Pseudomonas aeruginosa. J Bacteriol 184(6):1514–1521. https://doi.org/10.1128/jb.184.6.1514-1521.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Burrage AM, Vanderpool E, Kearns DB (2018) Assembly order of flagellar rod subunits in Bacillus subtilis. J Bacteriol 200(23):e00425-e518. https://doi.org/10.1128/JB.00425-18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhu S, Schniederberend M, Zhitnitsky D, Jain R, Galán JE, Kazmierczak BI, Liu J (2019) In situ structures of polar and lateral flagella revealed by cryo-electron tomography. J Bacteriol 201(13):e00117-e119. https://doi.org/10.1128/JB.00117-19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Patriquin GM, Banin E, Gilmour C, Tuchman R, Greenberg EP, Poole K (2008) Influence of quorum sensing and iron on twitching motility and biofilm formation in Pseudomonas aeruginosa. J Bacteriol 190(2):662–671. https://doi.org/10.1128/JB.01473-07

    Article  CAS  PubMed  Google Scholar 

  113. Lim CK, Hassan KA, Tetu SG, Loper JE, Paulsen IT (2012) The effect of iron limitation on the transcriptome and proteome of Pseudomonas fluorescens Pf-5. PLoS ONE 7(6):e39139. https://doi.org/10.1371/journal.pone.0039139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sader HS, Huband MD, Castanheira M, Flamm RK (2017) Pseudomonas aeruginosa antimicrobial susceptibility results from four years (2012 to 2015) of the international network for optimal resistance monitoring program in the United States. Antimicrob Agents Chemother 61(3):e02252-e2316. https://doi.org/10.1128/AAC.02252-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Ekkelenkamp MB, Cantón R, Díez-Aguilar M, Tunney MM, Gilpin DF, Bernardini F, Dale GE, Elborn JS, Bayjanov JR, Fluit A (2020) Susceptibility of Pseudomonas aeruginosa recovered from cystic fibrosis patients to murepavadin and 13 comparator antibiotics. Antimicrob Agents Chemother 64(2):e01541-e1619. https://doi.org/10.1128/AAC.01541-19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Mustafa MH, Chalhoub H, Denis O, Deplano A, Vergison A, Rodriguez-Villalobos H, Tunney MM, Elborn JS, Kahl BC, Traore H, Vanderbist F, Tulkens PM, Van Bambeke F (2016) Antimicrobial susceptibility of Pseudomonas aeruginosa isolated from cystic fibrosis patients in Northern Europe. Antimicrob Agents Chemother 60(11):6735–6741. https://doi.org/10.1128/AAC.01046-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Pathmanathan SG, Samat NA, Mohamed R (2009) Antimicrobial susceptibility of clinical isolates of Pseudomonas aeruginosa from a Malaysian Hospital. Malaysian J Med Sci 16(2):27–32

    Google Scholar 

  118. Oglesby AG, Farrow JM 3rd, Lee JH, Tomaras AP, Greenberg EP, Pesci EC, Vasil ML (2008) The influence of iron on Pseudomonas aeruginosa physiology: a regulatory link between iron and quorum sensing. J Biol Chem 283(23):15558–15567

    Article  CAS  Google Scholar 

  119. Kaur AP, Lansky IB, Wilks A (2009) The role of the cytoplasmic heme-binding protein (PhuS) of Pseudomonas aeruginosa in intracellular heme trafficking and iron homeostasis. J Biol Chem 284(1):56–66. https://doi.org/10.1074/jbc.M806068200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Bollinger N, Hassett DJ, Iglewski BH, Costerton JW, McDermott TR (2001) Gene expression in Pseudomonas aeruginosa: evidence of iron override effects on quorum sensing and biofilm-specific gene regulation. J Bacteriol 183(6):1990–1996

    Article  CAS  Google Scholar 

  121. Juhas M, Wiehlmann L, Huber B, Jordan D, Lauber J, Salunkhe P, Limpert AS, von Götz F, Steinmetz I, Eberl L, Tümmler B (2004) Global regulation of quorum sensing and virulence by VqsR in Pseudomonas aeruginosa. Microbiology (Reading, England) 150(Pt 4):831–841

    Article  CAS  Google Scholar 

  122. Jiang Q, Chen J, Yang C, Yin Y, Yao K (2019) Quorum sensing: a prospective therapeutic target for bacterial diseases. Biomed Res Int 2019:2015978. https://doi.org/10.1155/2019/2015978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Asif M, Acharya M (2012) Quorum sensing: a nobel target for antibacterial agents. Avicenna J Med 2(4):97–99. https://doi.org/10.4103/2231-0770.110743

    Article  PubMed  PubMed Central  Google Scholar 

  124. Suga H, Smith KM (2003) Molecular mechanisms of bacterial quorum sensing as a new drug target. Curr Opin Chem Biol 7(5):586–591. https://doi.org/10.1016/j.cbpa.2003.08.001

    Article  CAS  PubMed  Google Scholar 

  125. Imperi F, Massai F, Ramachandran Pillai C, Longo F, Zennaro E, Rampioni G, Visca P, Leoni L (2013) New life for an old drug: the anthelmintic drug niclosamide inhibits Pseudomonas aeruginosa quorum sensing. Antimicrob Agents Chemother 57(2):996–1005. https://doi.org/10.1128/AAC.01952-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The production of this publication was supported by funding from a research grant from Science Foundation Ireland (SFI) and is co-funded under the European Regional Development Fund under grant number 12/RC/2275_P2. Q-exactive mass spectrometer was funded under the SFI Research Infrastructure Call 2012; Grant Number: 12/RI/2346 (3).

Author information

Authors and Affiliations

  1. Department of Biology, SSPC Pharma Research Centre, Maynooth University, Maynooth, Co Kildare, Ireland

    Magdalena Piatek & Kevin Kavanagh

  2. Department of Chemistry, SSPC Pharma Research Centre, RCSI, 123 St. Stephens Green, Dublin 2, Ireland

    Darren M. Griffith

Authors
  1. Magdalena Piatek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Darren M. Griffith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kevin Kavanagh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Funding: KK. Experimental design: MP, DG, KK. Experimental procedures: MP, KK. Manuscript draft: MP, KK, DG. Editing and approval of manuscript: MP, KK, DG.

Corresponding author

Correspondence to Kevin Kavanagh.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical approval

Ethical permission was not required for this work.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Piatek, M., Griffith, D.M. & Kavanagh, K. Quantitative proteomic reveals gallium maltolate induces an iron-limited stress response and reduced quorum-sensing in Pseudomonas aeruginosa. J Biol Inorg Chem 25, 1153–1165 (2020). https://doi.org/10.1007/s00775-020-01831-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-020-01831-x

Keyword

Search

Navigation