Transformation of Helicobacter pylori into Coccoid Forms as a Challenge for Research Determining Activity of Antimicrobial Substances
Abstract
:1. Introduction
2. Review Strategy and Literature Included
3. Results
3.1. Antibiotics and Proton Pump Inhibitors
3.2. Plant Extracts and Plant-derived Compounds
3.3. Synthetic Compounds
3.4. Fatty Acids and Fatty Acid Derivatives
3.5. Peptides
4. Discussion
4.1. Culture Methods in the Viability Assessing
4.2. Extending Techniques to Determine the Viability
4.2.1. Amount of ATP in the Viability Assessment
4.2.2. Morphostructure Determined by TEM in the Viability Assessment
4.2.3. Degradation of Genetic Material and eDNA Amount in the Viability Assessment
4.2.4. Fluorescence Determination in the Viability Assessment
4.3. Difficulties in Determining the Viability of H. pylori in the Context of Applied Research Techniques
4.4. Future Research Determining the Viability of H. pylori
4.5. Implications for Scientists and Clinicians
5. Conclusions
- Apply several methods determining the viability of H. pylori.
- Search for new, more accurate techniques determining the viability of H. pylori.
- Test the activity of substances against preformed coccoid H. pylori forms (regardless of studies on spiral forms).
- Use coccoid H. pylori forms, not treated with antimicrobial substances, as a control of the activity of substances against these morphological forms (without reference to spiral forms characterized by different physiology).
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Compound | H. pylori Strain(s) | Technic Determining Morphology | Technic Determining Viability | Main Results Covering the Morphological Transformation of H. pylori | Authors Interpretation | Bibliography |
---|---|---|---|---|---|---|
SUL TAZ CLV AMX AMX + CLV | ATCC 43504 | Light microscopy, TEM | Culture | - Viability ↓ <1 log, 6 h, 10× MIC (CLV, SUL, and TAZ) - Coccoid forms with CLV, SUL, and TAZ (6 h, 10× MIC) - Viability ↓ 1 log, 3 h, MIC (AMX, AMX+CLV) - Coccoid forms with AMX and AMX+CLV (3 h, MIC) - Separation of membranes for all antimicrobials (3–6 h, MIC) | Bactericidal activity | [37] |
AMX | ATCC 43504 | TEM | Culture, Fluorescence (membrane integrity) | - Viability ↓ (3 log, 24 h, MIC) - Coccoid forms (2 h, MIC) - Membrane permeabilization (2 h, MIC) | Bactericidal activity | [38,39] * |
CLR TET MTZ AMX | Tx30a | Light microscopy | Culture | - Total viability ↓ for all antibiotics (72 h, MIC) - ≥85% of coccoid forms for all antibiotics (72 h, MIC) - Approx. 30% (¼× MIC) and 70% (½× MIC) of coccoid forms with AMX (72 h) - <15% (¼× MIC) and 25–30% (½× MIC) of coccoid forms with CLR, TET, or MTZ (72 h) | Bactericidal activity, AMX is the strongest inducer of a spiral-to-coccoid form transformation | [40,41] * |
AMX MTZ CLR | ATCC 700392 | Light microscopy | Flow cytometry (membrane integrity) | - Approx. 30%, 40%, and 95% of coccoid forms with CLR, MTZ, and AMX, respectively (72 h, ½× MIC) - Viability ↓ of coccoid forms by 99.8%, 62.6%, and 0.03% with CLR, MTZ, and AMX, respectively (24 h, 2× MIC) | Bactericidal activity, lower susceptibility of coccoid forms to antibiotics (especially to AMX) | [42] |
AMX | SS1 | SEM | Culture, Fluorescence (membrane integrity) | - Total viability ↓ of spiral forms (24 h, MIC) - Viability ↓ of coccoid forms only by 20% (24 h, 20× MIC) | Bactericidal activity, coccoid forms are more tolerant to AMX than spiral forms | [43] * |
Omeprazole | Clinical isolates | Light microscopy | Culture | - Viability ↓ was directly associated with an amount of coccoid forms - 10%, 40%, and 90% of coccoid forms after 3, 6, and 9 days, respectively (½× MIC) - Viability and spiral shape were recovered after 9–12 days of the omeprazole removal | Inhibitory activity with the reversibility of morphology | [44] |
Compound | H. pylori Strain(s) | Technic Determining Morphology | Technic Determining Viability | Main Results Covering the Morphological Transformation of H. pylori | Authors Interpretation | Bibliography |
---|---|---|---|---|---|---|
Cranberry extract | NCTC 11637 | SEM | Culture | - Viability ↓ (2 log, 48 h, MIC) - 33% of coccoid forms (48 h, MIC) | Inhibitory activity | [45] |
Eugenol Cinnamaldehyde | ATCC 700392 | Light microscopy | Culture | - Total viability ↓ (9 h, MBC or 6 h, 2× MBC) - Viability ↓ (>3 log, 4 h, 2× MBC) - 70% of coccoid forms (4 h, 2× MBC) | Inhibitory activity | [46] |
Boropinol A | B128 | SEM | Culture | - Viability ↓ (several times lower OD, 48 h, MIC) - Spiral forms with shorter length and blebbing (24 h, MIC) | Inhibitory activity | [47] |
7-O-Butylnaringenin | ATCC 700392 | SEM | Culture | - Viability ↓ (<3 log, 24 h, MIC) - Coccoid-like cells with irregular shapes (24 h, MIC) | Inhibitory activity | [48] |
β-ACPM | ATCC 43504 | TEM | Culture | - Total viability ↓ (18 h, MIC) - Coccoid forms with blebbing, detachment of the outer cell membrane, and membrane invaginations (24 h, MIC) | Bactericidal activity | [49] |
Methyl gallate Benzoic acid PGG Paeonol | ATCC 43504 | Light microscopy | Culture | - Viability ↓ (1–2 log, 48 h, MIC) - Viability ↓ (≥5 log, 48 h, 2× MIC) - 43–52% of coccoid forms (48 h, MIC) - 74–91% of coccoid forms (48 h, 2× MIC) | Bactericidal activity | [50] |
DCL from Magnolia sieboldii leaves | ATCC 43504 | SEM | Culture | - Total viability ↓ (36 h, 2× MIC) - Viability ↓ (2 log, 48 h, MIC) - 49% and 94% of coccoid forms (48 h, MIC and 2× MIC, respectively) | Bactericidal activity | [51] |
Isocoumarin paepalantine | ATCC 43504 | SEM | Culture | - Total viability ↓ (72 h, MIC) - Spiral forms (72 h, ½× MIC) - Coccoid forms (72 h, MIC) | Bactericidal activity | [52] |
Patchouli alcohol | NCTC 11637 | SEM, TEM | Culture | - Viability ↓ (1 log, 6 h, 2× MIC) - Mix of both spiral and coccoid forms (72 h, sub-MICs) - Coccoid forms with blebbing, cell wall damage, and lysis of the cytoplasmic membrane (1 h, MIC or 2 h, 2× MIC) | Bactericidal activity | [53] |
Chrysin (CH) Pinocembrin (P) Galangin (G) Caffeic acid (CA) | ATCC 43504 | TEM | Culture | - Viability ↓ (4 log, 12 h, FIC of CH+P) - Viability ↓ (3 log, 12 h, FIC of G+CA) - Ghost (degenerative) cells with coccoid-like shape, membrane damage, and membrane vesicles formation (12 h, FIC of CH+P or G+CA) | Bactericidal activity | [54] |
Daphnetin | ATCC 43504 | SEM, TEM | Culture, Fluorescence + CLSM + Flow cytometry (membrane integrity) | - Spiral forms (72 h, ¼× MIC) - Single coccoid forms (72 h, ½× MIC) - Budding, rough outer membrane, peculiar detachments between membrane and cytoplasm, and numerous membrane vesicles (72 h, ½× MIC) - No membrane permeability and depolarization (24 h, ½× MIC) - DNA damage (24 h, ½× MIC) | Daphnetin has a potential to be an effective anti-H. pylori agent | [55] |
Compound | H. pylori Strain(s) | Technic Determining Morphology | Technic Determining Viability | Main Results Covering the Morphological Transformation of H. pylori | Authors Interpretation | Bibliography |
---|---|---|---|---|---|---|
DFMO | SS1 | Light microscopy, TEM | Culture, Luminescence (ATP level) | - Viability ↓ (<1 log, 24 h, MIC) - Coccoid forms (6 h, MIC) - Reversion from coccoid to spiral forms (6 h after the DFMO removal) - ↑ iATP level (0–12 h, MIC), no difference later (24 h, MIC) | Inhibitory activity with the reversibility of morphology | [56] |
Niclosamide | ATCC 49503 | SEM | Culture, Fluorescence (membrane integrity) | - Viability ↓ (approx. 1.5 log, 24 h, 4× MIC) - Coccoid forms produced in a dose-dependent manner (3 h, MIC to 8× MIC) - No membrane permeabilization (1 h, 64× MIC) | Inhibitory activity | [57] |
Polyethyleneimine functionalized zinc oxide | ATCC 700392 | SEM, TEM | Culture, Luminescence (ATP level), qRT-PCR (RNA degradation), Fluorescence (membrane integrity) | - Viability ↓ (1 log, 24 h, MIC) - 10% (0.5 h, MIC) and 33% (3 h, MIC) of coccoid forms - Membrane damage (3 h, MIC) - ↓ iATP level (3 h, MIC) - Degradation of rRNA (time-dependent, MIC) | Inhibitory activity | [58] |
Polyoxometalates: As4W40 Sb9W21 SiVW11 | ATCC 43504 | SEM | Culture | - Total viability ↓ for As4W40 and Sb9W21 (10× MIC, 24 h and 12 h, respectively) - Stable viability for SiVW11 (10× MIC, 24 h) - Intensive formation of coccoids for As4W40 and Sb9W21 (36 h, > MICs) - Weak formation of coccoids for SiVW11 (36 h, > MICs) | Bactericidal (As4W40 and SB9W21) or bacteriostatic (SiVW11) activity | [59] |
NE-2001 | ATCC 43504 | TEM | Culture | - Viability ↓ (1 log, 24 h, MIC) - Coccoid forms with an intact membrane (6 h, ½× MIC) - Ghost (degenerative) cells with coccoid-like shape with a loosening of the outer membrane (6 h, MIC) | Bactericidal activity | [60] |
TG44 | ATCC 43504 | SEM, TEM | Culture | - Total viability ↓ (24 h, 8× MIC) - Viability ↓ (<1 log, 24 h, MIC to 4× MIC) - Spiral forms with membrane vesicles around (3 h, ½× MIC to 4× MIC) - Coccoid forms with blebbing and outer membrane detachment (3 h, 64× MIC) | Bactericidal activity | [61] |
SQ109 | G27 | TEM | Culture, Fluorescence (membrane integrity) | - Total viability ↓ (8 h, 2× MBC) - Coccoid forms (98–99%) with disintegration of the inner membrane (8 h, 2× MBC) - Ghost (degenerative) cells (1–2%) (8 h, 2× MBC) - No membrane disruption using fluorescence analysis (10 h, 2× MBC) | Bactericidal activity | [62] |
3-Bromopyruvate | Tx30a J99 | Light microscopy, SEM | Culture, Fluorescence (membrane integrity) | - Total viability ↓ (6 h, 4 h, and 2 h for MIC, 2× MIC, and 4× MIC, respectively) - 33.5% (Tx30a) and 57.5% (J99) of coccoid forms (2 h, 4× MIC) - 97–98% of coccoid forms for both (24 h, 4× MIC) - ↓ green/red fluorescence (time-dependent, MIC to 4× MIC) | Bactericidal activity | [40] |
Sertraline | Tx30a J99 | Light microscopy, SEM | Culture, Fluorescence (membrane integrity) | - Total viability ↓ (8 h, 4× MIC for J99 or 24 h, 4× MIC for Tx30a) - Viability ↓ (2–4 log, 24 h, MIC) - > 85% of coccoid forms (8 h, 4× MIC for J99 or 24 h, 4× MIC for Tx30a) - ↓ green/red fluorescence (time-dependent, MIC to 4× MIC) | Bactericidal activity | [41] |
Compound | H. pylori Strain(s) | Technic Determining Morphology | Technic Determining Viability | Main Results Covering the Morphological Transformation of H. pylori | Authors Interpretation | Bibliography |
---|---|---|---|---|---|---|
Docosahexaenoic acid | ATCC 700392, SS1 | SEM | Culture | - Viability ↓ (<2 log, 48 h, MIC) - Mixed population of spiral and coccoid forms (48 h, MIC) | Inhibitory activity | [63] |
Sodium butyrate | TK1402 | SEM | Culture, PCR (eDNA detection) | - Stable viability (24 h, MBC) - Viability ↓ (4 log, 48 h, MBC) - Coccoid forms with blebs and cell envelope alternations (24 h, MBC) - ↑ eDNA amount (24 h, MBC) | Bactericidal activity | [64] |
Zinc linolenate | G27 | TEM | Culture, Luminescence (ATP level), Fluorescence (membrane integrity) | - Total viability ↓ (70 min, MIC) - Coccoid forms with membrane detachments, cytoplasmic content leakage, and vesiculation (2 h, MIC) - Membrane permeabilization (2 h, MIC) - ↓ iATP (2 h, MIC) and ↑ eATP (2 h, MIC) | Bactericidal activity | [65] |
Liposomal linolenic acid | SS1 | SEM | Culture, Fluorescence (membrane integrity) | - Total viability ↓ influenced by the morphology - MBC was higher for coccoid forms than spiral forms and killed cells more slowly (24 h, 400 µg/mL vs. 0.5 h, 67 µg/mL) - Disruption of bacterial membranes and cell clusters formation (0.5 h, MBC) | Bactericidal activity with coccoid forms being more tolerant | [43] |
Compound | H. pylori Strain(s) | Technic Determining Morphology | Technic Determining Viability | Main Results Covering the Morphological Transformation of H. pylori | Authors Interpretation | Bibliography |
---|---|---|---|---|---|---|
C12K-2β12 | G27 | TEM | Culture, Fluorescence (membrane integrity) | - Viability ↓ (>2 log, 8 h, 3× MIC) - Membrane permeabilization (8 h, 3× MIC) - Ghost (degenerative) cells with coccoid-like shape, blebbing, vesicularization, and loosening of the outer membrane (16 h, 3× MIC) | Bactericidal activity | [66] |
Epinecidin-1 | ATCC 43504 | TEM | Culture, Fluorescence (membrane integrity) | - Viability ↓ (2 log, 12 h, 2× MIC or 2 log, 24 h, MIC) - Membrane permeabilization (6 h, MIC) - Ghost (degenerative) cells with coccoid-like shape, pore formation, blebbing, vesicularization, and loosening of the outer membrane (8 h, MIC) | Bactericidal activity | [38] |
Tilapia Piscidin 4 | ATCC 43504 | TEM | Culture, Fluorescence (membrane integrity) | - Viability ↓ (2 log, 3 h, MIC or 3 log, 3 h, 2× MIC) - Membrane permeabilization (6 h, MIC) - Ghost (degenerative) cells with coccoid-like shape, micellization, and loosening of the outer membrane (2 h, MIC) | Bactericidal activity | [39] |
Cbf-K16 | SS1 | TEM | Culture, Fluorescence + CLSM + Flow cytometry (membrane integrity) | - Viability ↓ (0.5 log, 8 h, 4× MIC or 1 log, 12 h, 4× MIC) - Ghost (degenerative) cells with coccoid-like shape, separation of membranes, and a total loss of cytoplasmic content (8 h, 4× MIC) - Membrane permeabilization (time-dependent, 4× MIC) | Bactericidal activity | [67] |
(PGA)m-r-(PHLG-MHH)n | SS1 | SEM | Culture, Fluorescence (membrane integrity) | - Total viability ↓ in pH = 3 (1 h, MIC) - Coccoid forms with membrane damage in pH = 3 (0.5 h, MIC) - Membrane permeabilization in pH = 3 (1 h, MIC) | Bactericidal activity in acidic environment | [68] |
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Krzyżek, P.; Grande, R. Transformation of Helicobacter pylori into Coccoid Forms as a Challenge for Research Determining Activity of Antimicrobial Substances. Pathogens 2020, 9, 184. https://doi.org/10.3390/pathogens9030184
Krzyżek P, Grande R. Transformation of Helicobacter pylori into Coccoid Forms as a Challenge for Research Determining Activity of Antimicrobial Substances. Pathogens. 2020; 9(3):184. https://doi.org/10.3390/pathogens9030184
Chicago/Turabian StyleKrzyżek, Paweł, and Rossella Grande. 2020. "Transformation of Helicobacter pylori into Coccoid Forms as a Challenge for Research Determining Activity of Antimicrobial Substances" Pathogens 9, no. 3: 184. https://doi.org/10.3390/pathogens9030184
APA StyleKrzyżek, P., & Grande, R. (2020). Transformation of Helicobacter pylori into Coccoid Forms as a Challenge for Research Determining Activity of Antimicrobial Substances. Pathogens, 9(3), 184. https://doi.org/10.3390/pathogens9030184