The Antimicrobial Activity of Human Defensins at Physiological Non-Permeabilizing Concentrations Is Caused by the Inhibition of the Plasma Membrane H+-ATPases
Abstract
:1. Introduction
2. Results
2.1. Determination of Antimicrobial Non-Permeabilizing Concentrations of Human Defensins
2.2. Effect of Human Defensins on Cellular K+-Homeostasis
2.2.1. Effect of High Extracellular K+-Concentration on Antimicrobial Activity
2.2.2. Evaluation of K+-Efflux Induced by Defensins
2.2.3. Effect of the Inhibition of the K+-Channel Tok1p on Candidacidal Activity
2.3. Influence of Bioenergetics on the Microbicidal Activity of Defensins
2.3.1. Influence of Cellular Respiration on the Microbicidal Activity of Defensins
2.3.2. Effect of CCCP on the Defensin Bactericidal Activity
2.3.3. Role of Mitochondrial ATP Synthase in the Candidacidal Activity of Defensins
2.4. Human Defensins Inhibit Fungal Pma1p H+-ATPase
2.4.1. Evaluation of Cellular ATP Levels in Relation to Candidacidal Activity of Defensins
2.4.2. Effect of Defensins on The Electrical Potential of the Plasma Membrane
2.4.3. Effect of Defensins on H+-Extrusion by Pma1p H+-ATPase
3. Discussion
Human α-Defensins | Human β-Defensins | Human Transferrins | |||
---|---|---|---|---|---|
HNP-1 | HNP-4 | hBD-2 | hBD-3 | Human Lactoferrin | |
Number of amino acids | 30 | 33 | 41 | 45 | 691 (protein) |
Archetypal antimicrobial structures γ-core motif (number) Isomeric form (type) | Yes (one) Levomeric (2) | Yes (one) Levomeric (2) | Yes (one) Levomeric (2) | Yes (one) Levomeric (2) | Yes (two) Levomeric (1) |
Antimicrobial activity NPIC (μM) Cidal/static Membrane depolarization Membrane permeabilization Partial K+-efflux ATP increment/ATP-efflux Inhibition of H+-extrusion (yeast) Antimicrobial range | 0.25 a, 0.5 b Cidal [24,62] Yes [26] Yes [14] Yes Yes [47]/Yes [47] Yes Gm +,Gm −,F,V,P | 0.25 a,b Cidal [62,63] Yes [12] Yes [23] Yes Yes/ND Yes Gm +,Gm −,F,V | 0.25 a,b Cidal [20] Yes [11] Yes [11,13]/No [20] Yes Yes/ND Yes Gm +,Gm −,F,V | 0.125 a, 0.25 b Cidal [12,20] Yes [11] No [20]/Yes [11] Yes Yes/ND Yes Gm +,Gm −, F,V,P | 5 a, 1 b Cidal [34,35,64]/Static [65,66] Yes [43,67] No [31,34,42] Yes [31,42,43,44] Yes [35]/ND Yes Gm +,Gm −,F,V,P |
Cell death inhibitors Extracellular inhibitors: K+ or Na+ Ca2+ or Mg2+ Tok1p inhibitors (TEA) Anoxia Intracellular inhibitors: CCCP or DNP Azide Antimycin A (+SHAM) Piericidin A Oligomycin A | Yes [68] Yes (Ca2+)/No (Mg2+) [24] Yes Yes [24] Yes [24] Yes [20,24] Yes [24] Yes Yes | Yes [69] ND Yes ND ND ND ND ND ND | Yes [20] Yes [20] Yes ND Yes Yes [20] ND Yes Yes | No [11,12]/Yes [20] No [20] Yes ND ND Yes [20] ND ND ND | Yes [31,36,43] Yes [43] Yes [36,44] Yes [34,35] Yes [34] No [34] ND Yes [34,35] Yes [35] |
Cellular target | PM H+-ATPase | PM H+-ATPase | PM H+-ATPase Phospholipids [13] | PM H+-ATPase | PM H+-ATPase [34,35,36] PM (V) H+-ATPase [39] |
Cell death type (yeast) | ND Permeabilization [14] | ND Permeabilization [23] | ND Permeabilization (No [20]/Yes [11,13]) | ND Permeabilization (No [20]/Yes [11,20]) | Apoptosis-like cell death [36,44] No permeabilization [31,42] |
4. Materials and Methods
4.1. Materials
4.2. Strains and Growth Conditions
4.3. Antimicrobial Assays
4.4. Permeability Assay
4.5. Extracellular Potassium Measurement
4.6. Oxygen Consumption Measurement
4.7. Measurement of ATP
4.8. Membrane Potential Monitoring
4.9. Measurements of Acidification of the External Medium
4.10. Statistics
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Amino Acid Sequence | Aa (No.) | mav | z | HR | |
---|---|---|---|---|---|
α-defensins | |||||
HNP-1 | 30 | 3448 | +3 | 38 | |
HNP-4 | 33 | 3802 | +4 | 39 | |
β-defensins | |||||
hBD-2 | 41 | 4328 | +6 | 29 | |
hBD-3 | 45 | 5155 | +11 | 23 |
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Andrés, M.T.; Fierro, P.; Antuña, V.; Fierro, J.F. The Antimicrobial Activity of Human Defensins at Physiological Non-Permeabilizing Concentrations Is Caused by the Inhibition of the Plasma Membrane H+-ATPases. Int. J. Mol. Sci. 2024, 25, 7335. https://doi.org/10.3390/ijms25137335
Andrés MT, Fierro P, Antuña V, Fierro JF. The Antimicrobial Activity of Human Defensins at Physiological Non-Permeabilizing Concentrations Is Caused by the Inhibition of the Plasma Membrane H+-ATPases. International Journal of Molecular Sciences. 2024; 25(13):7335. https://doi.org/10.3390/ijms25137335
Chicago/Turabian StyleAndrés, María T., Patricia Fierro, Victoria Antuña, and José F. Fierro. 2024. "The Antimicrobial Activity of Human Defensins at Physiological Non-Permeabilizing Concentrations Is Caused by the Inhibition of the Plasma Membrane H+-ATPases" International Journal of Molecular Sciences 25, no. 13: 7335. https://doi.org/10.3390/ijms25137335