UNVEILING STRATEGIES FOR SHORTENING TUBERCULOSIS TREATMENT: TARGETING MYCOBACTERIUM TUBERCULOSIS STRINGENT RESPONSE AND REVIEWING POLYPHOSPHATE KINASE 2 (PPK2) ENZYMES
DOI:
https://doi.org/10.22159/ajpcr.2025v18i11.55585Keywords:
Mycobacterium tuberculosis, Polyphosphate kinase 2,, Stringent response,, Poly P and GalleinAbstract
Tuberculosis (TB) is one of the oldest infectious diseases known to humankind, with traces of its presence found in remains that are around 17,000 years old. TB is mostly caused by the tiny aerobic non-motile bacillus Mycobacterium TB (MTB). The unique shape and chemical content of the mycobacterial cell wall make an efficient TB therapy method challenging. A strict bacterial survival strategy for establishing drug tolerance in the stringent response (SR), MTB is a sophisticated remodeling of metabolism that slows down growth and energy requirements during famine. Recent studies emphasize the need to focus on the SR in MTB as a means of reducing the treatment duration. The MTB genome codes two polyphosphate kinases (PPK-1 and PPK-2), for maintenance of intracellular Inorganic Polyphosphate (Poly P) levels. The identification of a virulence factor of TB growth as well as persistence in host tissues may be helped in MTB using PPK2, which is required to modulate intracellular levels of regulating molecules and to sustain sensitivity to the first-line anti-drug isoniazid. Synthesized and under control by PPK2 enzymes, inorganic polyP is essential in this process since it controls stress reactions. This research, therefore, investigates the significance of PPK2 in the MTB, the chemicals suppressing a bacterial SR in MTB, and the list of PPK2 inhibitors for shortening TB.
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References
1. Williams PM, Pratt RH, Walker WL, Price SF, Stewart RJ, Feng PJ. Tuberculosis-United States, 2023. MMWR Morb Mortal Wkly Rep. 2024;73:265-70.
2. Miggiano R, Rizzi M, Ferraris DM. Mycobacterium tuberculosis pathogenesis, Infection prevention and treatment. Pathogens. 2020 May 18;9(5):385. doi: 10.3390/pathogens9050385, PMID 32443469
3. Martini M, Besozzi G, Barberis I. The never-ending story of the fight against tuberculosis: From Koch’s Bacillus to global control programs. J Prev Med Hyg. 2018 Sep 28;59(3):E241-7. doi: 10.15167/2421-4248/ jpmh2018.59.3.1051, PMID 30397682
4. Frick M, Gaudino A, Harrington M, Horn T, Jefferys R, Johnson J, et al. Pipeline Report Drugs, Diagnostics, Vaccines, Preventive Technologies, Cure Research, and Immune-Based and Gene Therapies in Development. Treatment Action Group; 2017. Available from: https://www.treatmentactiongroup.org/wp-content/uploads/2017/07/ Pipeline-Report_2017_FINAL.pdf
5. Müller WE, Schröder HC, Wang X. Inorganic polyphosphates as storage for and generator of metabolic energy in the extracellular matrix. Chem Rev. 2019 Nov 18;119(24):12337-74. doi: 10.1021/acs. chemrev.9b00460, PMID 31738523
6. Tiwari P, Gosain TP, Singh M, Sankhe GD, Arora G, Kidwai S, et al. Inorganic polyphosphate accumulation suppresses the dormancy response and virulence in Mycobacterium tuberculosis. J Biol Chem. 2019 Jul 1;294(28):10819-32. doi: 10.1074/jbc.RA119.008370, PMID 31113860
7. Albi T, Serrano A. Inorganic polyphosphate in the microbial world. Emerging roles for a multifaceted biopolymer. World J Microbiol Biotechnol. 2016 Feb;32(2):27. doi: 10.1007/s11274-015-1983-2, PMID 26748804
8. Kumar A, Gangaiah D, Torrelles JB, Rajashekara G. Polyphosphate and associated enzymes as global regulators of stress response and virulence in Campylobacter jejuni. World J Gastroenterol. 2016 Sep 7;22(33):7402- 14. doi: 10.3748/wjg.v22.i33.7402, PMID 27672264
9. Wang L, Yan J, Wise MJ, Liu Q, Asenso J, Huang Y, et al. Distribution patterns of polyphosphate metabolism pathway and its relationships with bacterial durability and virulence. Front Microbiol. 2018 Apr 24;9:782. doi: 10.3389/fmicb.2018.00782, PMID 29755430
10. Moonan PK, Nair SA, Agarwal R, Chadha VK, Dewan PK, Gupta UD, et al. Tuberculosis preventive treatment: The next chapter of tuberculosis elimination in India. BMJ Glob Health. 2018 Oct 1;3(5):e001135. doi: 10.1136/bmjgh-2018-001135, PMID 30364389
11. Neville N, Roberge N, Jia Z. Polyphosphate kinase 2 (PPK2) enzymes: Structure, function, and roles in bacterial physiology and virulence. Int J Mol Sci. 2022 Jan 8;23(2):670. doi: 10.3390/ijms23020670, PMID 35054854
12. Singh M, Tiwari P, Arora G, Agarwal S, Kidwai S, Singh R. Establishing virulence associated polyphosphate kinase 2 as a drug target for Mycobacterium tuberculosis. Sci Rep. 2016 Jun 9;6(1):26900. doi: 10.1038/srep26900, PMID 27279366
13. Danchik C, Wang S, Karakousis PC. Targeting the Mycobacterium tuberculosis stringent response as a strategy for shortening tuberculosis treatment. Front Microbiol. 2021 Oct 7;12:744167. doi: 10.3389/ fmicb.2021.744167, PMID 34690990
14. Chuang YM, Belchis DA, Karakousis PC. The polyphosphate kinase gene ppk2 is required for Mycobacterium tuberculosis inorganic polyphosphate regulation and virulence. mBio. 2013 Jul 1;4(3):e00039- 13. doi: 10.1128/mBio.00039-13, PMID 23695835
15. Baijal K. Defining the Role of Polyphosphate in the Bacterial Stress Response (Doctoral Dissertation, Université d’Ottawa/University of Ottawa).
16. Jagannathan V, Kaur P, Datta S. Polyphosphate kinase from M. tuberculosis: An interconnect between the genetic and biochemical role. PLoS One. 2010 Dec 15;5(12):e14336. doi: 10.1371/journal. pone.0014336, PMID 21179463
17. Rijal R, Gomer RH. Gallein potentiates isoniazid’s ability to suppress Mycobacterium tuberculosis growth. Front Microbiol. 2024 Apr 15;15:1369763. doi: 10.3389/fmicb.2024.1369763, PMID 38690363
18. Gancedo JM. Biological roles of cAMP: Variations on a theme in the different kingdoms of life. Biol Rev Camb Philos Soc. 2013 Aug;88(3):645-68. doi: 10.1111/brv.12020, PMID 23356492
19. Rijal R, Gomer RH. Gallein potentiates isoniazid’s ability to suppress Mycobacterium tuberculosis growth. Frontiers in Microbiology 2024; 15: 1369763. doi: 10.3389/fmicb.2024.1369763, PMID 38690363.
20. Baijal K, Downey M. Targeting polyphosphate kinases in the fight against Pseudomonas aeruginosa. mBio. 2021 Aug 31;12(4):e0147721. doi: 10.1128/mBio.01477-21, PMID 34340551
21. Gupta KR, Arora G, Mattoo A, Sajid A. Stringent response in mycobacteria: from biology to therapeutic potential. Pathogens 2021;10:1417. Doi: 10.3390/pathogens10111417, PMID 34832573.
22. Pawełczyk J, Brzostek A, Minias A, Płociński P, Rumijowska-Galewicz A, Strapagiel D, et al. Cholesterol-dependent transcriptome remodeling reveals new insight into the contribution of cholesterol to Mycobacterium tuberculosis pathogenesis. Sci Rep. 2021 Jun 11;11(1):12396. doi: 10.1038/s41598-021-91812-0, PMID 34117327
23. Rao SD, Datta P, Gennaro ML, Igoshin OA. Chaperone-mediated stress sensing in Mycobacterium tuberculosis enables fast activation and sustained response. mSystems. 2021 Feb 23;6(1):e00979-20. doi: 10.1128/mSystems.00979-20, PMID 33594002
24. Hunt-Serracín AC, Kazi MI, Boll JM, Boutte CC. In Mycobacterium abscessus, the stringent factor rel regulates metabolism but is not the only (p) ppGpp synthase. J Bacteriol. 2022 Feb 15;204(2):e0043421. doi: 10.1128/JB.00434-21, PMID 34898264
25. Dutta NK, Klinkenberg LG, Vazquez MJ, Segura-Carro D, Colmenarejo G, Ramon F, et al. Inhibiting the stringent response blocks Mycobacterium tuberculosis entry into quiescence and reduces persistence. Sci Adv. 2019 Mar 20;5(3):eaav2104. doi: 10.1126/sciadv. aav2104, PMID 30906866
26. Manganelli R, Cioetto-Mazzabò L, Segafreddo G, Boldrin F, Sorze D, Conflitti M, et al. SigE: A master regulator of Mycobacterium tuberculosis. Front Microbiol. 2023 Mar 7;14:1075143. doi: 10.3389/fmicb.2023.1075143, PMID 36960291
27. Baruzzo G, Serafini A, Finotello F, Sanavia T, Cioetto-Mazzabò L, Boldrin F, et al. Role of the extracytoplasmic function sigma factor SigE in the stringent response of Mycobacterium tuberculosis. Microbiol Spectr. 2023 Apr 13;11(2):e0294422. doi: 10.1128/spectrum.02944-22, PMID 36946740
28. Karanika S, Gordy JT, Neupane P, Karantanos T, Ruelas Castillo J, Quijada D, et al. An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis. Front Immunol. 2022 Sep 16;13:972266. doi: 10.3389/fimmu.2022.972266, PMID 36189260
29. Ellison AL. Exploring the Role of the Stringent Response in Mycobacterium tuberculosis Dormancy. Dissertations: Johns Hopkins University; 2018.
30. Pokhrel A. Evaluating the Role of the Stringent Response Mechanism in Clostridioides difficile Survival and Pathogenesis (Doctoral Dissertation, Old Dominion University); 2021.
31. Gao H, Li M, Wang Q, Liu T, Zhang X, Yang T, et al. A high-throughput dual system to screen polyphosphate kinase mutants for efficient ATP regeneration in L-theanine biocatalysis. Biotechnol Biofuels Bioprod. 2023 Aug 3;16(1):122. doi: 10.1186/s13068-023-02361-9, PMID 37537682
32. Peng L, Zeng L, Jin H, Yang L, Xiao Y, Lan Z, et al. Discovery and antibacterial study of potential PPK1 inhibitors against uropathogenic E. coli. J Enzyme Inhib Med Chem. 2020 Jan 1;35(1):1224-32. doi: 10.1080/14756366.2020.1766453, PMID 32420773
33. Chuang YM, Dutta NK, Hung CF, Wu TC, Rubin H, Karakousis PC. Stringent response factors PPX1 and PPK2 play an important role in Mycobacterium tuberculosis metabolism, biofilm formation, and sensitivity to isoniazid in vivo. Antimicrob Agents Chemother. 2016 Nov;60(11):6460-70. doi: 10.1128/AAC.01139-16, PMID 27527086
34. Cao H, Nie K, Li C, Xu H, Wang F, Tan T, et al. Rational design of substrate binding pockets in polyphosphate kinase for use in cost-effective ATP-dependent cascade reactions. Appl Microbiol Biotechnol. 2017 Jul;101(13):5325-32. doi: 10.1007/s00253-017- 8268-7, PMID 28417169
35. Nocek BP, Khusnutdinova AN, Ruszkowski M, Flick R, Burda M, Batyrova K, et al. Structural insights into substrate selectivity and activity of bacterial polyphosphate kinases. ACS Catal. 2018 Oct 12;8(11):10746-60. doi: 10.1021/acscatal.8b03151
36. Mordhorst S, Singh J, Mohr MK, Hinkelmann R, Keppler M, Jessen HJ, Andexer JN. Several polyphosphate kinase 2 enzymes catalyse the production of adenosine 5′‐polyphosphates. ChemBioChem 2019 15;20:1019-22. Doi: 10.1002/cbic.201800704, PMID 30549179.
37. Du Y, Wang X, Han Z, Hua Y, Yan K, Zhang B, et al. Polyphosphate kinase 1 is a pathogenesis determinant in enterohemorrhagic Escherichia coli O157: H7. Front Microbiol. 2021 Oct 27;12:762171. doi: 10.3389/fmicb.2021.762171, PMID 34777317
38. Tumlirsch T, Sznajder A, Jendrossek D. Formation of polyphosphate by polyphosphate kinases and its relationship to poly (3-hydroxybutyrate) accumulation in Ralstonia eutropha strain H16. Appl Environ Microbiol. 2015 Dec 15;81(24):8277-93. doi: 10.1128/AEM.02279-15, PMID 26407880
39. Chandrashekhar K, Kassem II, Nislow C, Gangaiah D, Candelero- Rueda RA, Rajashekara G. Transcriptome analysis of Campylobacter jejuni polyphosphate kinase (ppk1 and ppk2) mutants. Virulence. 2015 Nov 17;6(8):814-8. doi: 10.1080/21505594.2015.1104449, PMID 26537695
40. Kumar D, Mandal S, Bailey JV, Flood BE, Jones RS. Fluoride and gallein inhibit polyphosphate accumulation by oral pathogen Rothia dentocariosa. Lett Appl Microbiol. 2023 Feb;76(2):ovad017. doi: 10.1093/lambio/ovad017, PMID 36715153
41. Gopalakrishnan AV, Kanagaraja A, Sakthivelu M, Devadasan V, Gopinath SC, Raman P. Role of fatty acids in modulating quorum sensing in Pseudomonas aeruginosa and Chromobacterium violaceum: An integrated experimental and computational analysis. International Microbiology 2025;28:979-92. Doi: 10.1007/s10123-024-00590-y, PMID 39292411
42. Srisanga K, Suthapot P, Permsirivisarn P, Govitrapong P, Tungpradabkul S, Wongtrakoongate P. Polyphosphate kinase 1 of Burkholderia pseudomallei controls quorum sensing, RpoS and host cell invasion. J Proteomics. 2019 Mar 1;194:14-24. doi: 10.1016/j. jprot.2018.12.024, PMID 30597312
43. Latorre-Estivalis JM, Almeida FC, Pontes G, Dopazo H, Barrozo RB, Lorenzo MG. Evolution of the insect PPK gene family. Genome Biol Evol. 2021 Sep 1;13(9):evab185. doi: 10.1093/gbe/evab185, PMID 34390578
44. Samanovic MI, Darwin KH. Game of ’Somes: Protein destruction for Mycobacterium tuberculosis pathogenesis. Trends Microbiol. 2016 Jan 1;24(1):26-34. doi: 10.1016/j.tim.2015.10.001, PMID 26526503
45. Acharya B, Acharya A, Gautam S, Ghimire SP, Mishra G, Parajuli N, Sapkota B. Advances in diagnosis of Tuberculosis: an update into molecular diagnosis of Mycobacterium tuberculosis. Molecular biology reports 2020;47(5):4065-75. Doi: 10.1007/s11033-020-05413-7, PMID 32248381.
46. Sharma D, Bisht D. Role of bacterioferritin & ferritin in M. tuberculosis pathogenesis and drug resistance: A future perspective by interactomic approach. Front Cell Infect Microbiol. 2017 Jun 8;7:240. doi: 10.3389/ fcimb.2017.00240, PMID 28642844
47. Bowlin MQ, Gray MJ. Inorganic polyphosphate in host and microbe biology. Trends Microbiol. 2021 Nov 1;29(11):1013-23. doi: 10.1016/j. tim.2021.02.002, PMID 33632603
48. Sgaragli G, Frosini M. Human tuberculosis I. Epidemiology, diagnosis and pathogenetic mechanisms. Curr Med Chem. 2016 Aug 1;23(25):2836-73. doi: 10.2174/0929867323666160607222 854, PMID 27281297
49. Hildenbrand JC, Teleki A, Jendrossek D. A universal polyphosphate kinase: PPK2c of Ralstonia eutropha accepts purine and pyrimidine nucleotides including uridine diphosphate. Appl Microbiol Biotechnol. 2020 Aug;104(15):6659-67. doi: 10.1007/s00253-020-10706-9 PMID 32500270
50. He C, Li B, Gong Z, Huang S, Liu X, Wang J, et al. Polyphosphate kinase 1 is involved in formation, the morphology and ultramicrostructure of biofilm of Mycobacterium smegmatis and its survivability in macrophage. Heliyon. 2023 Mar 1;9(3):e14513. doi: 10.1016/j. heliyon.2023.e14513, PMID 36967885
51. Rijal R, Cadena LA, Smith MR, Carr JF, Gomer RH. Polyphosphate is an extracellular signal that can facilitate bacterial survival in eukaryotic cells. Proc Natl Acad Sci U S A. 2020 Dec 15;117(50):31923-34. doi: 10.1073/pnas.2012009117, PMID 33268492
52. Parnell AE, Mordhorst S, Kemper F, Giurrandino M, Prince JP, Schwarzer NJ, et al. Substrate recognition and mechanism revealed by ligand-bound polyphosphate kinase 2 structures. Proc Natl Acad Sci U S A. 2018 Mar 27;115(13):3350-5. doi: 10.1073/pnas.1710741115, PMID 29531036
53. Huang L, Nazarova EV, Tan S, Liu Y, Russell DG. Growth of Mycobacterium tuberculosis in vivo segregates with host macrophage metabolism and ontogeny. J Exp Med. 2018 Apr 2;215(4):1135-52. doi: 10.1084/jem.20172020, PMID 29500179
54. Zhang X, Cui X, Li Z. Characterization of two polyphosphate kinase 2 enzymes used for ATP synthesis. Appl Biochem Biotechnol. 2020 Jun;191(2):881-92. doi: 10.1007/s12010-019-03224-6, PMID 31907778
55. Winkle M, El-Daly SM, Fabbri M, Calin GA. Noncoding RNA therapeutics-challenges and potential solutions. Nat Rev Drug Discov. 2021 Aug;20(8):629-51. doi: 10.1038/s41573-021-00219-z, PMID 34145432
56. Baijal K, Abramchuk I, Herrera CM, Mah TF, Trent MS, Lavallée- Adam M, et al. Polyphosphate kinase regulates LPS structure and polymyxin resistance during starvation in E. coli. PLoS Biol. 2024 Mar 13;22(3):e3002558. doi: 10.1371/journal.pbio.3002558, PMID 38478588
57. Baijal K, Abramchuk I, Herrera CM, Stephen Trent MS, Lavallée- Adam M, Downey M. Proteomics analysis reveals a role for E. coli polyphosphate kinase in membrane structure and polymyxin resistance during starvation. bioRxiv. 2023 Jul 6. doi: 10.1101/2023.07.06.546892, PMID 37461725
58. Neville NA. Polyphosphate: A New Target to Fight Bacterial Infections and Regulate Eukaryotic Protein Activity (Doctoral Dissertation. Canada: Queen’s University; 2023.
59. Platella C, Riccardi C, Montesarchio D, Roviello GN, Musumeci D. G-quadruplex-based aptamers against protein targets in therapy and diagnostics. Biochim Biophys Acta Gen Subj. 2017 May 1;1861(5 Pt B):1429-47. doi: 10.1016/j.bbagen.2016.11.027, PMID 27865995
60. Neville N, Roberge N, Ji X, Stephen P, Lu JL, Jia Z. A dual-specificity inhibitor targets polyphosphate kinase 1 and 2 enzymes to attenuate virulence of Pseudomonas aeruginosa. mBio. 2021 Jul 7;12(3):e0059221. doi: 10.1128/mBio.00592-21, PMID 34126765
61. Baig IA, Moon JY, Lee SC, Ryoo SW, Yoon MY. Development of ssDNA aptamers as potent inhibitors of Mycobacterium tuberculosis acetohydroxyacid synthase. Biochim Biophys Acta. 2015 Oct 1;1854(10 Pt A):1338-50. doi: 10.1016/j.bbapap.2015.05.003, PMID 25988243
62. Ilchenko O, Nikolaevskaya E, Zinchenko O, Ivanytsia V, Prat- Aymerich C, Ramstedt M, et al. Combination of gallium citrate and
levofloxacin induces a distinct metabolome profile and enhances growth inhibition of multidrug-resistant Mycobacterium tuberculosis compared to linezolid. Front Microbiol. 2024 Nov 29;15:1474071. doi: 10.3389/fmicb.2024.1474071, PMID 39697659
63. Jian Y, Hulpia F, Risseeuw MD, Forbes HE, Munier-Lehmann H, Caljon G, et al. Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents. Eur J Med Chem. 2020 Sep 1;201:112450. doi: 10.1016/j.ejmech.2020.112450, PMID 32623208
64. Burda-Grabowska M, Macegoniuk K, Flick R, Nocek BP, Joachimiak A, Yakunin AF, et al. Bisphosphonic acids and related compounds as inhibitors of nucleotide- and polyphosphate-processing enzymes: A PPK1 and PPK2 case study. Chem Biol Drug Des. 2019 Jun;93(6):1197-206. doi: 10.1111/cbdd.13439, PMID 30484959
65. Giurrandino M. Polyphosphate Kinase from Intracellular Pathogens as a Novel Antibacterial Target (Doctoral Dissertation, University of Southampton); 2017.
66. Matern WM, Parker H, Danchik C, Hoover L, Bader JS, Karakousis PC. Genetic determinants of intrinsic antibiotic tolerance in Mycobacterium avium. Microbiol Spectr. 2021 Oct 31;9(2):e0024621. doi: 10.1128/ Spectrum.00246-21, PMID 34523947
67. Harita D, Kanie K, Kimura Y. Enzymatic properties of Myxococcus xanthus exopolyphosphatases mxPpx1 and mxPpx2. Biochim Biophys Acta Proteins Proteom. 2021 Aug 1;1869(8):140660. doi: 10.1016/j. bbapap.2021.140660, PMID 33857634
68. Tkachenko AG, Kashevarova NM, Sidorov RY, Nesterova LY, Akhova AV, Tsyganov IV, et al. A synthetic diterpene analogue inhibits mycobacterial persistence and biofilm formation by targeting (p) ppGpp synthetases. Cell Chem Biol. 2021 Oct 21;28(10):1420-32.e9. doi: 10.1016/j.chembiol.2021.01.018, PMID 33621482
69. Sala A, Bordes P, Genevaux P. Multiple toxin-antitoxin systems in Mycobacterium tuberculosis. Toxins. 2014 Mar 6;6(3):1002-20. doi: 10.3390/toxins6031002, PMID 24662523
70. Chuang YM, Dutta NK, Gordy JT, Campodónico VL, Pinn ML, Markham RB, et al. Antibiotic treatment shapes the antigenic environment during chronic TB infection, offering novel targets for therapeutic vaccination. Front Immunol. 2020 Apr 28;11:680. doi: 10.3389/fimmu.2020.00680, PMID 32411131
71. Chuang YM, Bandyopadhyay N, Rifat D, Rubin H, Bader JS, Karakousis PC. Deficiency of the novel exopolyphosphatase Rv1026/ PPX2 leads to metabolic downshift and altered cell wall permeability in Mycobacterium tuberculosis. mBio. 2015 May 1;6(2):e02428. doi: 10.1128/mBio.02428-14, PMID 25784702
72. Belardinelli JM, Verma D, Li W, Avanzi C, Wiersma CJ, Williams JT, et al. Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus. Sci Transl Med. 2022 Feb 23;14(633):eabj3860. doi: 10.1126/scitranslmed.abj3860, PMID 35196022
73. Njire M, Wang N, Wang B, Tan Y, Cai X, Liu Y, et al. Pyrazinoic acid inhibits a bifunctional enzyme in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2017 Jul;61(7):e00070-17. doi: 10.1128/AAC.00070-17, PMID 28438933
74. Syal K, Flentie K, Bhardwaj N, Maiti K, Jayaraman N, Stallings CL, et al. Synthetic (p) ppGpp analogue is an inhibitor of stringent response in mycobacteria. Antimicrob Agents Chemother. 2017 Jun;61(6):e00443-17. doi: 10.1128/AAC.00443-17, PMID 28396544
75. Vesga P, Flury P, Vacheron J, Keel C, Croll D, Maurhofer M. Transcriptome plasticity underlying plant root colonization and insect invasion by Pseudomonas protegens. ISME J. 2020 Nov;14(11):2766- 82. doi: 10.1038/s41396-020-0729-9, PMID 32879461
76. Roberge N, Neville N, Douchant K, Noordhof C, Boev N, Sjaarda C, et al. Broad-spectrum inhibitor of bacterial polyphosphate homeostasis attenuates virulence factors and helps reveal novel physiology of Klebsiella pneumoniae and Acinetobacter baumannii. Front Microbiol. 2021 Oct 26;12:764733. doi: 10.3389/fmicb.2021.764733, PMID 34764949
77. Song Y, Lv H, Xu L, Liu Z, Wang J, Fang T, et al. In vitro and in vivo activities of scutellarein, a novel polyphosphate kinase 1 inhibitor against Acinetobacter baumannii infection. Microb Cell Factories. 2024 Oct 8;23(1):269. doi: 10.1186/s12934-024-02540-9, PMID 39379932
78. Neville NA. Polyphosphate: A New Target to Fight Bacterial Infections and Regulate Eukaryotic Protein Activity (Doctoral Dissertation, Queen’s University (Canada)); 2023.
79. Lehotsky K, Neville N, Martins I, Poole K, Jia Z. Lysine polyphosphate modifications contribute to virulence factors in Pseudomonas aeruginosa. mBio. 2025 May 14;16(5):e0085525. doi: 10.1128/ mbio.00855-25, PMID 40243364
80. Shah R, Narh JK, Urlaub M, Jankiewicz O, Johnson C, Livingston B, et al. Pseudomonas aeruginosa kills Staphylococcus aureus in a polyphosphate-dependent manner. mSphere. 2024 Oct 29;9(10):e0068624. doi: 10.1128/ msphere.00686-24, PMID 39365057
81. Liao C, Huang X, Wang Q, Yao D, Lu W. Virulence factors of Pseudomonas aeruginosa and antivirulence strategies to combat its drug resistance. Front Cell Infect Microbiol. 2022 Jul 6;12:926758. doi: 10.3389/fcimb.2022.926758, PMID 35873152
82. Varas M, Valdivieso C, Mauriaca C, Ortíz-Severín J, Paradela A, Poblete- Castro I, et al. Multi-level evaluation of Escherichia coli polyphosphate related mutants using global transcriptomic, proteomic and phenomic analyses. Biochim Biophys Acta Gen Subj. 2017 Apr 1;1861(4):871- 83. doi: 10.1016/j.bbagen.2017.01.007, PMID 28069396
83. Zhang R, Zhang K. Mitochondrial NAD kinase in health and disease. Redox Biol. 2023 Apr 1;60:102613. doi: 10.1016/j.redox.2023.102613, PMID 36689815
84. Vilchèze C, Jacobs WR Jr. The isoniazid paradigm of killing, resistance, and persistence in Mycobacterium tuberculosis. J Mol Biol. 2019 Aug 23;431(18):3450-61. doi: 10.1016/j.jmb.2019.02.016, PMID 30797860
85. Walter ND, Dolganov GM, Garcia BJ, Worodria W, Andama A, Musisi E, et al. Transcriptional adaptation of drug-tolerant Mycobacterium tuberculosis during treatment of human tuberculosis. J Infect Dis. 2015 Sep 15;212(6):990-8. doi: 10.1093/infdis/jiv149, PMID 25762787
86. Chugh S, Tiwari P, Suri C, Gupta SK, Singh P, Bouzeyen R, et al. Polyphosphate kinase-1 regulates bacterial and host metabolic pathways involved in pathogenesis of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2024 Jan 9;121(2):e2309664121. doi: 10.1073/pnas.2309664121, PMID 38170746
87. Gautam LK, Sharma P, Capalash N. Structural insight into substrate binding of Acinetobacter baumannii polyphosphate-AMP phosphotransferase (PPK2), a novel drug target. Biochem Biophys Res Commun. 2022 Oct 20;626:107-13. doi: 10.1016/j.bbrc.2022.07.090, PMID 35987095
88. Janet-Maitre M, Pont S, Masson FM, Sleiman S, Trouillon J, Robert- Genthon M, et al. Genome-wide screen in human plasma identifies multifaceted complement evasion of Pseudomonas aeruginosa. PLoS Pathog. 2023 Jan 25;19(1):e1011023. doi: 10.1371/journal. ppat.1011023, PMID 36696456
89. Tawiah PO, Gaessler LF, Anderson GM, Oladokun EP, Dahl JU. A novel silver-ruthenium-based antimicrobial kills Gram-negative bacteria through oxidative stress-induced macromolecular damage. mSphere. 2025 Jun 25;10(6):e0001725. doi: 10.1128/msphere.00017-25, PMID 40444966
90. McCarthy L, Baijal K, Downey M. A framework for understanding and investigating polyphosphate-protein interactions. Biochem Soc Trans. 2025 Feb;53(01):BST20240678. doi: 10.1042/BST20240678, PMID 39836110
91. Li C, Lev S, Saiardi A, Desmarini D, Sorrell TC, Djordjevic JT. Identification of a major IP5 kinase in Cryptococcus neoformans confirms that PP-IP5/IP7, not IP6, is essential for virulence. Sci Rep. 2016 Apr 1;6(1):23927. doi: 10.1038/srep23927
92. Wei Z, Zhang Y, Duan X, Fan Y. En hancing l-asparagine bioproduction efficiency through l-asparagine synthetase and polyphosphate kinase-coupled conversion and ATP regeneration. Appl Biochem Biotechnol. 2024 Sep;196(9):6342-62. doi: 10.1007/s12010-024-04856-z, PMID 38358456
93. Mandal S, Flood BE, Lunzer M, Kumar D, Bailey JV. Fluoride and gallein regulate polyphosphate accumulation in dental caries-associated Lacticaseibacillus. Microbiology (Reading). 2024 Nov 28;170(11):001519. doi: 10.1099/mic.0.001519, PMID 39607745
94. Brown MR, Kornberg A. The long and short of it-polyphosphate, PPK and bacterial survival. Trends Biochem Sci. 2008 Jun 1;33(6):284-90. doi: 10.1016/j.tibs.2008.04.005, PMID 18487048
95. Candon HL, Allan BJ, Fraley CD, Gaynor EC. Polyphosphate kinase 1 is a pathogenesis determinant in Campylobacter jejuni. J Bacteriol. 2007 Nov 15;189(22):8099-108. doi: 10.1128/JB.01037-07, PMID 17827292
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