Biofilm of Helicobacter pylori: History
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Yasmine Elshenawi
,
Shuai Hu
,
Skander Hathroubi

Helicobacter pylori is a gastric pathogen that infects nearly half of the global population and is recognized as a group 1 carcinogen by the Word Health Organization. The global rise in antibiotic resistance has increased clinical challenges in treating H. pylori infections. Biofilm growth has been proposed to contribute to H. pylori’s chronic colonization of the host stomach, treatment failures, and the eventual development of gastric diseases. Several components of H. pylori have been identified to promote biofilm growth, and several of these may also facilitate antibiotic tolerance, including the extracellular matrix, outer membrane proteins, shifted morphology, modulated metabolism, efflux pumps, and virulence factors.

  • Helicobacter pylori
  • biofilms
  • planktonic
  • antibiotic resistance
  • extra polymeric substance

1. Introduction

Helicobacter pylori is a Gram-negative, spiral-shaped, bacterial pathogen that colonizes the gastric epithelium [1][2][3]. H. pylori has been globally recognized as a high priority pathogen as it has been associated with various gastric diseases, including peptic ulcers, chronic gastritis [4][5], gastric mucosa-associated tissue lymphomas [6], and gastric adenocarcinomas [7][8][9][10]. Mechanisms of transmission remain unknown [10], but antibiotic therapies used to treat H. pylori infection have alarmingly been losing efficacy in regions with high infection burden [11]. Antibiotic-resistant H. pylori was reported to disproportionately affect children in Asian, African, and European countries [12], and in underserved communities in the US [13]. One current perspective is that H. pylori in biofilms, a low growth state, may substantially promote antibiotic resistance and persistence in the host stomach [14]. H. pylori were initially observed in vitro to form water-insoluble biofilms which are defined as stationary aggregates of cells encased in extra polymeric substances (EPS) [15][16]. H. pylori with biofilm state have also been observed in the gastric mucosa of patients with peptic ulcers [17][18].

2. General Features of H. pylori Biofilms

H. pylori biofilms consist of stationary aggregates of cells encased by an extracellular matrix composed of proteins [19], extracellular DNA [20], and polysaccharides [21]. H. pylori biofilm formation starts from planktonic cells that adhere to either abiotic or biotic surfaces, leading to the formation of microcolonies with three-dimensional structures [22][23]. Additionally, H. pylori cells can cluster together as non-surface-attached aggregates, a form that has been recently observed and recognized as a biofilm format in other bacterial studies [24]. Once adhered, H. pylori biofilm formation was found to occur optimally under conditions lacking nutrients, such as fetal bovine serum [25][26].
Aside from biofilm growth on abiotic surfaces, additional studies have also suggested that H. pylori can form a microcolony network that adhered and grew between epithelial cell junctions on human cells [27][28] and in murine gastric glands [29]. Mature H. pylori biofilms consist of different cell shapes within one multicellular population. For example, both spiral and coccoid H. pylori cells were simultaneously observed from one gastric biopsy [17]. Similarly, on abiotic surfaces, most cells adopt the coccoid morphology, with the minority displaying a rod shape [30][31]. As found in other bacteria, H. pylori biofilm formation exhibits a similar multiple-step process, including bacterial adherence, biofilm assembly, mature biofilm formation, and dispersion (Scheme 1). In the next sections, researchers dissect the features of each step in H. pylori biofilm growth.
Antibiotics 12 01260 sch001 550
Scheme 1. Helicobacter pylori Biofilm Lifecycle. H. pylori adheres to both abiotic and biotic surfaces, where it forms microcolonies that susbquently assemble into mature biofilms characterized by the presence of extracellular polymeric susbtances (EPSs). Dispersion allows bacteria to colonizes new niches.

3. H. pylori Clinical Treatment Strategies Become Less Efficient, Highlighting the Requirement of Alternative Strategies

Due to the persistence of disease development in H. pylori infections that has been exacerbated due to the COVID-19 pandemic, a recent consensus report states a need for consistent updates in clinical treatments, including effective testing and preventative measures for gastric illness [32]. Globally, different geographic regions have variable patterns of anti-microbial resistance [12], a component which should be used to determine treatment strategies according to recent European [32], Chinese [33], and Canadian [34] consensus reports. A challenge to developing effective treatments strategies for these infections is the rising rate of antibiotic resistance and the diversity of clinical and symptom scenarios associated with H. pylori infections [32].
In regions with a high prevalence in H. pylori infection, current clinical guidelines recommend a quadruple therapy that consists of bismuth, proton pump inhibitor (PPI) or potassium-competitive acid blocker and two different antibiotics (i.e., including clarithromycin, metronidazole, levofloxacin, or amoxicillin) [12][32][33][35]. Non-bismuth quadruple therapies are also recommended and have the following components: PPI and three antibiotics [32][35]. However, this classical therapeutic strategy has been being less effective due to the continuing global rise of antibiotic resistance [36]. For example, in 2016 a national consensus on Chinese management of H. pylori infections where quadruple therapy is used reported that metronidazole, levofloxacin, and clarithromycin resistance was 40–70%, 20–50%, and 20–50%, respectively [33]. Similarly, the elevation of antibiotic resistance was also noticed in other countries, like Indonesia, that apply the triple therapy approach consisting of PPI and two antibiotics [37]. Metronidazole and levofloxacin, two commonly applied antibiotics, were observed to be resisted by 46.7% and 31.2% of H. pylori-infected population, respectively; while those less commonly applied antibiotics exhibited relative lower resistance prevalence, including amoxicillin (5.2%), tetracycline (2.6%), and clarithromycin (9.1%) [37]. In 2020, a case study reported that triple therapies in Indonesia were further decreased to only 67.6% efficient [38].Aside from Indonesia and China, alarming clarithromycin resistance rates are observed in the Americas (10%), the African region (15%), Eastern Mediterranean region (29%), Europe (32%) which is why the WHO has designated clarithromycin-resistant H. pylori as a high priority research pathogen [36].
A meta-analysis review based on global WHO regions reported that clarithromycin resistance decreased the efficacy empiric eradications to less than 80%; additionally, metronidazole resistance was observed in >27% strains and levofloxacin resistance in >14% strains from all surveyed WHO regions in 2018 [36]. To counter potential therapy failure caused by antibiotic resistance, clinicians have proposed using a tailored treatment approach based on antibiotics susceptibility tests and localized resistance [34][38][39][40][41]. A clinical study that analyzed the failure of treatment revealed that isolated H. pylori has either individually or populationally developed multidrug resistance [42]. A study genotyped 112 H. pylori strains isolated from a region with prevalent H. pylori infection that apply quadruple treatment found strains with dual resistance to metronidazole and levofloxacin (20.5%) and triple resistance to metronidazole, clarithromycin, and levofloxacin (~7%) [11]. A study investigating the tailored treatment strategy found that out of 40 patients, some patients were infected with multiple strains or singular strains that exhibited different resistance phenotypes depending on the region of stomach the strain was isolated from [42]. Clarithromycin resistance is attributed to mutations in the 23S rRNA [43]; metronidazole resistance was associated to the mutations in rdxA and frxA loci [44]; levofloxacin resistance was caused by gyrA and gyrB mutations [45]. These mutations are naturally occurring, but increased prevalence in the population can occur by exposing strains to sub-MIC levels of antibiotics, such as levofloxacin [46]. To address these resistance-based challenges, a clinical trial evaluated the effectiveness of tailored therapies in comparison with the traditional bismuth quadruple therapy, and it was demonstrated that the tailored bismuth/quadruple therapy was more effective [34]. Intriguingly, another case study examined 101 clinical H. pylori isolates from Indonesian patients with gastritis (90.1%), peptic ulcer disease (8.9%), and gastric cancer (1%) and discovered that 93% of the isolates formed biofilms [38]. These studies strongly suggest that biofilm formation may plays a vital role in facilitating H. pylori to acquire high antibiotic tolerance; therefore, the eradication of H. pylori biofilm is likely a key process for clinical therapy. Nevertheless, there are challenges in clinal therapies: (1) planktonic susceptibility of minimal inhibitory concentration (MIC) may not be a reliable indicator of Minimal Biofilm Eradication Concentration (MBEC) with certain antibiotics [38][47][48]; (2) the isolation of clinical strains is not always a simple procedure as it requires the acquisition of gastric biopsies through endoscopic procedures which are not recommended as first line treatments for H. pylori-infected patients [11][32]. Therefore, it would be very interesting to understand if targeting biofilm formation would enhance H. pylori treatment.

4. Regulation in H. pylori Biofilm

Accumulating evidence suggests that H. pylori biofilm formation is under complicated regulations. It includes the small molecules-mediated signaling, such as AI-2 induced quorum sensing [22] and (p)ppGpp-mediated stringent response [49], two component systems, such as ArsRS acid response system [19][50][51], and transcriptional re-programing [52]. For example, dysfunction of autoinducer molecule AI-2 secretion coding gene luxS lead to the more robust biofilm, indicating that quorum sensing plays a regulatory role in biofilms [22]. Similarly, increased (p)ppGpp production and transcriptional upregulation of its coding gene spoT was both found in H. pylori biofilm. In turn, the absence of spoT results in a biofilm defect, indicating that (p)ppGpp-mediated stringent response may play an important role in regulating H. pylori biofilm formation [49]. In addition, mutations in the ArsRS acid response system also leads to hyper biofilm formation. In H. pylori, biofilm formation has also been suggested to regulations of several transcriptional regulators, such as fliA, flgR, hp1021, fur, nikR, and crdR [52].

This entry is adapted from the peer-reviewed paper 10.3390/antibiotics12081260

References

  1. Dubois, A.; Fiala, N.; Heman-Ackah, L.M.; Drazek, E.; Tarnawski, A.; Fishbein, W.N.; Perez-Perez, G.I.; Blaser, M.J. Natural gastric infection with Helicobacter pylori in monkeys: A model for spiral bacteria infection in humans. Gastroenterology 1994, 106, 1405–1417.
  2. Hooi, J.K.Y.; Lai, W.Y.; Ng, W.K.; Suen, M.M.Y.; Underwood, F.E.; Tanyingoh, D.; Malfertheiner, P.; Graham, D.Y.; Wong, V.W.S.; Wu, J.C.Y.; et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology 2017, 153, 420–429.
  3. Malfertheiner, P.; Camargo, M.C.; El-Omar, E.; Liou, J.M.; Peek, R.; Schulz, C.; Smith, S.I.; Suerbaum, S. Helicobacter pylori infection. Nat. Rev. Dis. Primers 2023, 9, 19.
  4. Labenz, J.; Borsch, G. Evidence for the essential role of Helicobacter pylori in gastric ulcer disease. Gut 1994, 35, 19–22.
  5. Blaser, M.J. Helicobacter pylori Phenotypes Associated with Peptic Ulceration. Scand. J. Gastroenterol. Suppl. 1994, 205, 1–5.
  6. Pereira, M.-I. Role of Helicobacter pylori in gastric mucosa-associated lymphoid tissue lymphomas. World J. Gastroenterol. 2014, 20, 684–698.
  7. Asaka, M.; Kimura, T.; Kato, M.; Kudo, M.; Miki, K.; Ogoshi, K.; Kato, T.; Tatsuta, M.; Graham, D.Y. Possible role of Helicobacter pylori infection in early gastric cancer development. Cancer 1994, 73, 2691–2694.
  8. van Zanten, S.J.V.; Sherman, P.M. Helicobacter pylori infection as a cause of gastritis, duodenal ulcer, gastric cancer and nonulcer dyspepsia: A systematic overview. CMAJ 1994, 150, 177–185.
  9. Isaacson, P.G. Gastric Lymphoma and Helicobacter pylori. N. Engl. J. Med. 1994, 330, 1310–1311.
  10. Ma, J.; Yu, M.; Shao, Q.; Yu, X.; Zhang, C.; Zhao, J.; Yuan, L.; Qi, Y.; Hu, R.; Wei, P.; et al. Both family-based Helicobacter pylori infection control and management strategy and screen-and-treat strategy are cost-effective for gastric cancer prevention. Helicobacter 2022, 27, e12911.
  11. Liu, Y.; Wang, S.; Yang, F.; Chi, W.; Ding, L.; Liu, T.; Zhu, F.; Ji, D.; Zhou, J.; Fang, Y.; et al. Antimicrobial resistance patterns and genetic elements associated with the antibiotic resistance of Helicobacter pylori strains from Shanghai. Gut Pathog. 2022, 14, 14.
  12. Karbalaei, M.; Keikha, M.; Abadi, A.T.B. Prevalence of Primary Multidrug-resistant Helicobac-ter pylori in Children: A Systematic Review and Meta-analysis. Arch. Med. Res. 2022, 53, 634–640.
  13. Brown, H.; Cantrell, S.; Tang, H.; Epplein, M.; Garman, K.S. Racial Differences in Helicobacter pylori Prevalence in the US: A Systematic Review. Gastro Hep Adv. 2022, 1, 857–868.
  14. Cellini, L.; Grande, R.; Di Campli, E.; Traini, T.; Di Giulio, M.; Lannutti, S.N.; Lattanzio, R. Dynamic colonization of Helicobacter pylori in human gastric mucosa. Scand. J. Gastroenterol. 2008, 43, 178–185.
  15. Mackay, W.; Gribbon, L.; Barer, M.; Reid, D. Biofilms in drinking water systems: A possible reservoir for Helicobacter pylori. J. Appl. Microbiol. 1998, 85, 52S–59S.
  16. Stark, R.M.; Gerwig, G.J.; Pitman, R.S.; Potts, L.F.; Williams, N.A.; Greenman, J.; Weinzweig, I.P.; Hirst, T.R.; Millar, M.R. Biofilm for-mation by Helicobacter pylori. Lett. Appl. Microbiol. 1999, 28, 121–126.
  17. Carron, M.A.; Tran, V.R.; Sugawa, C.; Coticchia, J.M. Identification of Helicobacter pylori biofilms in human gas-tric mucosa. J. Gastrointest. Surg. 2006, 10, 712–717.
  18. Coticchia, J.M.; Sugawa, C.; Tran, V.R.; Gurrola, J.; Kowalski, E.; Carron, M.A. Presence and Density of Helicobacter pylori Biofilms in Human Gastric Mucosa in Patients with Peptic Ulcer Disease. J. Gastrointest. Surg. 2006, 10, 883–889.
  19. Windham, I.H.; Servetas, S.L.; Whitmire, J.M.; Pletzer, D.; Hancock, R.E.; Merrell, D.S. Helicobacter pylori bio-film formation is differentially affected by common culture conditions, and proteins play a central role in the biofilm matrix. Appl. Environ. Microbiol. 2018, 84, e00391-18.
  20. Grande, R.; Di Giulio, M.; Bessa, L.J.; Di Campli, E.; Baffoni, M.; Guarnieri, S.; Cellini, L. Extracellular DNA in Hel-icobacter pylori biofilm: A backstairs rumour. J. Appl. Microbiol. 2011, 110, 490–498.
  21. Li, P.; Chen, X.; Shen, Y.; Li, H.; Zou, Y.; Yuan, G.; Hu, P.; Hu, H. Mucus penetration enhanced lipid polymer nanopar-ticles improve the eradication rate of Helicobacter pylori biofilm. J. Control. Release 2019, 300, 52–63.
  22. Cole, S.P.; Harwood, J.; Lee, R.; She, R.; Guiney, D.G. Characterization of monospecies biofilm formation by Heli-cobacter pylori. J. Bacteriol. 2004, 186, 3124–3132.
  23. Hathroubi, S.; Hu, S.; Ottemann, K.M. Genetic requirements and transcriptomics of Helicobacter pylori biofilm formation on abiotic and biotic surfaces. npj Biofilms Microbiomes 2020, 6, 56.
  24. Sauer, K.; Stoodley, P.; Goeres, D.M.; Hall-Stoodley, L.; Burmølle, M.; Stewart, P.S.; Bjarnsholt, T. The biofilm life cycle: Expanding the conceptual model of biofilm formation. Nat. Rev. Genet. 2022, 20, 608–620.
  25. Hathroubi, S.; Zerebinski, J.; Ottemann, K.M. Helicobacter pylori Biofilm Involves a Multigene Stress-Biased Response, Including a Structural Role for Flagella. mBio 2018, 9, e01973-18.
  26. Williams, J.C.; McInnis, K.A.; Testerman, T.L. Adherence of Helicobacter pylori to Abiotic Surfaces Is Influenced by Serum. Appl. Environ. Microbiol. 2008, 74, 1255–1258.
  27. Tan, S.; Tompkins, L.S.; Amieva, M.R. Helicobacter pylori Usurps Cell Polarity to Turn the Cell Surface into a Replicative Niche. PLOS Pathog. 2009, 5, e1000407.
  28. Anderson, J.K.; Huang, J.Y.; Wreden, C.; Sweeney, E.G.; Goers, J.; Remington, S.J.; Guillemin, K. Chemorepulsion from the Quorum Signal Autoinducer-2 Promotes Helicobacter pylori Biofilm Dispersal. mBio 2015, 6, e00379-15.
  29. Sigal, M.; Rothenberg, M.E.; Logan, C.Y.; Lee, J.Y.; Honaker, R.W.; Cooper, R.L.; Passarelli, B.; Camorlinga, M.; Bouley, D.M.; Alvarez, G.; et al. Helicobacter pylori Activates and Expands Lgr5+ Stem Cells Through Direct Colonization of the Gastric Glands. Gastroenterology 2015, 148, 1392–1404.e21.
  30. Cellini, L.; Grande, R.; Di Campli, E.; Di Bartolomeo, S.; Di Giulio, M.; Traini, T.; Trubiani, O. Characterization of an Helicobacter pylori environmental strain. J. Appl. Microbiol. 2008, 105, 761–769.
  31. Bugli, F.; Palmieri, V.; Torelli, R.; Papi, M.; De Spirito, M.; Cacaci, M.; Galgano, S.; Masucci, L.; Paroni Sterbini, F.; Vella, A.; et al. In vitro effect of clarithromycin and alginate lyase against Helicobacter pylori biofilm. Biotechnol. Prog. 2016, 32, 1584–1591.
  32. Malfertheiner, P.; Megraud, F.; Rokkas, T.; Gisbert, J.P.; Liou, J.-M.; Schulz, C.; Gasbarrini, A.; Hunt, R.H.; Leja, M.; O’Morain, C.; et al. Management of Helicobacter pylori infection: The Maastricht VI/Florence consensus report. Gut 2022, 71, 1724–1762.
  33. Liu, W.Z.; Xie, Y.; Lu, H.; Cheng, H.; Zeng, Z.R.; Zhou, L.Y.; Chen, Y.; Bin Wang, J.; Du, Y.Q.; Lu, N.H. Fifth Chinese National Consensus Report on the management of Helicobacter pylori infection. Helicobacter 2018, 23, e12475.
  34. Pan, J.; Shi, Z.; Lin, D.; Yang, N.; Meng, F.; Lin, L.; Jin, Z.; Zhou, Q.; Wu, J.; Zhang, J.; et al. Is tailored therapy based on antibiotic susceptibility effective ? a multicenter, open-label, randomized trial. Front. Med. 2020, 14, 43–50.
  35. Malfertheiner, P.; Megraud, F.; O’Morain, C.A.; Gisbert, J.P.; Kuipers, E.J.; Axon, A.T.; Bazzoli, F.; Gasbarrini, A.; Atherton, J.; Graham, D.Y.; et al. Management of Helicobacter pylori infection—The Maastricht V/Florence Consensus Report. Gut 2017, 66, 6–30.
  36. Savoldi, A.; Carrara, E.; Graham, D.Y.; Conti, M.; Tacconelli, E. Prevalence of Antibiotic Resistance in Helicobacter pylori: A Systematic Review and Meta-analysis in World Health Organization Regions. Gastroenterology 2018, 155, 1372–1382.e17.
  37. Miftahussurur, M.; Syam, A.F.; Nusi, I.A.; Makmun, D.; Waskito, L.A.; Zein, L.H.; Akil, F.; Uwan, W.B.; Simanjuntak, D.; Wibawa, I.D.N.; et al. Surveillance of Helicobacter pylori Antibiotic Susceptibility in Indonesia: Different Resistance Types among Regions and with Novel Genetic Mutations. PLoS ONE 2016, 11, e0166199.
  38. Fauzia, K.A.; Miftahussurur, M.; Syam, A.F.; Waskito, L.A.; Doohan, D.; Rezkitha, Y.A.A.; Matsumoto, T.; Tuan, V.P.; Akada, J.; Yonezawa, H.; et al. Biofilm Formation and Antibiotic Resistance Phenotype of Helicobacter pylori Clinical Isolates. Toxins 2020, 12, 473.
  39. Fallone, C.A.; Chiba, N.; van Zanten, S.V.; Fischbach, L.; Gisbert, J.P.; Hunt, R.H.; Jones, N.L.; Render, C.; Leontiadis, G.I.; Moayyedi, P.; et al. The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults. Gastroenterology 2016, 151, 51–69.e14.
  40. De Palma, G.Z.; Mendiondo, N.; Wonaga, A.; Viola, L.; Ibarra, D.; Campitelli, E.; Salim, N.; Corti, R.; Goldman, C.; Catalano, M. Occurrence of mutations in the antimicrobial target genes related to levofloxacin, clarithromycin, and amoxicillin re-sistance in Helicobacter pylori isolates from Buenos Aires city. Microb. Drug Resist. 2017, 23, 351–358.
  41. Li, H.; Shen, Y.; Song, X.; Tang, X.; Hu, R.; Marshall, B.J.; Tang, H.; Benghezal, M. Need for standardization and harmonization of Helicobacter pylori antimicrobial susceptibility testing. Helicobacter 2022, 27, e12873.
  42. Mascellino, M.T.; Oliva, A.; De Angelis, M.; Pontone, S.; Porowska, B. Helicobacter pylori infection: Antibiotic resistance and eradi-cation rate in patients with gastritis showing previous treatment failures. New Microbiol. 2018, 41, 306–309.
  43. Redondo, J.J.; Keller, P.M.; Zbinden, R.; Wagner, K. A novel RT-PCR for the detection of Heli-cobacter pylori and identification of clarithromycin resistance mediated by mutations in the 23S rRNA gene. Diagn. Microbiol. Infect. Dis. 2018, 90, 1–6.
  44. Lee, S.M.; Kim, N.; Kwon, Y.H.; Nam, R.H.; Kim, J.M.; Park, J.Y.; Lee, Y.S.; Lee, D.H. rdxA, frxA, and efflux pump in metronidazole-resistant Helicobacter pylori: Their relation to clinical out-comes. J. Gastroenterol. Hepatol. 2018, 33, 681–688.
  45. Miftahussurur, M.; Shrestha, P.K.; Subsomwong, P.; Sharma, R.P.; Yamaoka, Y. Emerging Helicobacter pylori levofloxacin resistance and novel genetic mutation in Nepal. BMC Microbiol. 2016, 16, 256.
  46. Hanafi, A.; Lee, W.C.; Loke, M.F.; Teh, X.; Shaari, A.; Dinarvand, M.; Lehours, P.; Mégraud, F.; Leow, A.H.R.; Vadivelu, J.; et al. Molecular and Proteomic Analysis of Levofloxacin and Metronidazole Resistant Helicobacter pylori. Front. Microbiol. 2016, 7, 2015.
  47. Attaran, B.; Falsafi, T. Identification of factors associated with biofilm formation ability in the clinical iso-lates of Helicobacter pylori. Iran. J. Biotechnol. 2017, 15, 58.
  48. Attaran, B.; Falsafi, T.; Ghorbanmehr, N. Effect of biofilm formation by clinical isolates of Helicobacter pylori on the efflux-mediated resistance to commonly used antibiotics. World J. Gastroenterol. 2017, 23, 1163.
  49. Ge, X.; Cai, Y.; Chen, Z.; Gao, S.; Geng, X.; Li, Y.; Jia, J.; Sun, Y. Bifunctional Enzyme SpoT Is Involved in Biofilm Formation of Helicobacter pylori with Multidrug Resistance by Upregulating Efflux Pump Hp1174 (gluP). Antimicrob. Agents Chemother. 2018, 62, e00957-18.
  50. Servetas, S.L.; Kim, A.; Su, H.; Cha, J.; Merrell, D.S. Comparative analysis of the Hom family of outer membrane proteins in isolates from two geographically distinct regions: The United States and South Korea. Helicobacter 2018, 23, e12461.
  51. Servetas, S.L.; Doster, R.S.; Kim, A.; Windham, I.H.; Cha, J.H.; Gaddy, J.A.; Merrell, D.S. ArsRS-dependent regulation of homB contributes to Helicobacter pylori biofilm formation. Front. Microbiol. 2018, 2, 1497.
  52. De la Cruz, M.A.; Ares, M.; Von Bargen, K.; Panunzi, L.G.; Martínez-Cruz, J.; Valdez-Salazar, H.-A.; Jiménez-Galicia, C.; Torres, J. Gene Expression Profiling of Transcription Factors of Helicobacter pylori under Different Environmental Conditions. Front. Microbiol. 2017, 8, 615.
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