Enhanced Antibacterial Activity of a Cationic Macromolecule by Its Complexation with a Weakly Active Pyrazole Derivative
Abstract
:1. Introduction
2. Materials and Methods
2.1. Synthesis and Characterization of P7, CB1H and CB1H-P7 NPs
2.2. Microbiology
2.2.1. Bacterial Species Considered in This Study
2.2.2. Determination of the Minimal Inhibitory Concentrations (MICs)
2.2.3. Time-Kill Experiments
2.3. Evaluation of Cytotoxicity of CB1H, P7 and CB1H-P7 NPs on Human Keratinocites (HaCaT)
2.3.1. Cell Culture
2.3.2. Viability Assay
2.4. Statistical Analyses
3. Results and Discussion
3.1. Antibacterial Effects of CB1H-P7 NPs
3.1.1. Determination of MIC Values
3.1.2. Time-Killing Curves
3.2. Cytotoxicity of P7, CB1H and CB1H-P7 NPs on HaCaT Human Keratinocytes Cells
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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36 Bacterial Species | ||||
---|---|---|---|---|
12 Gram-Positive | Resistance Information | 24 Gram-Negative | Resistance Information | |
6 Enterococci | 3 E. faecalis | VRE * | 9 MDR P. aeruginosa # | 1 colistin-resistant, 1 resistant to CAZ-AVI, 3 pyomelanin-producing, 4 from fibrosis cystic patients |
3 E. faecium | VRE * | |||
6 Staphylococci | 3 S. aureus | MRSA | 3 E. coli | 2 KPC-producing, 1 NDM carbapenemase-producing |
1 E. aerogenes | Carbapenems-resistant | |||
MRSE ** | 4 MDR S. maltophilia | 2 co-trimoxazole-resistant, 2 co-trimoxazole intermediates | ||
3 S. epidermidis | 4 K. pneumoniae | KPC-producing K. pneumoniae § | ||
3 MDR A. baumannii | 1 co-trimoxazole-resistant |
Samples | Concentrations (µM) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
CB1H | 0 | 1 | 5 | 10 | 15 | 20 | 25 | 50 | 75 | 100 |
CB1H-P7 | 0 | 0.02874 | 0.1437 | 0.2874 | 0.4311 | 0.5748 | 0.7185 | 1.4370 | 2.1555 | 2.8740 |
P7 | 0 | 0.02867 | 0.1433 | 0.2867 | 0.4300 | 0.5734 | 0.7167 | 1.4334 | 2.1501 | 2.8668 |
Original P7 (13,719) 1 | Original CB1H (371.9) 2 | CB1H-P7 NPs (26,624) 1 | Complexed P7 (13,719) 1 | Complexed CB1H (371.9) 2 | ||
---|---|---|---|---|---|---|
Strains | MIC µM (µg/mL) | MIC µM (µg/mL) | MIC µM (µg/mL) | MIC µM (µg/mL) | MIC µM (µg/mL) | Selectivity Indices 3 |
Enterococcus genus | ||||||
E. faecalis 1 *,# | 2.3 (32) | 344.2 (128) | 1.2 (32) | 1.2 (16.4) | 41.9 (15.6) | 1.2 |
E. faecalis 365 * | 2.3 (32) | 344.2 (128) | 2.4 (64) | 2.4 (32.9) | 83.6 (31.1) | 0.6 |
E. faecalis 450 * | 2.3 (32) | 344.2 (128) | 2.4 (64) | 2.4 (32.9) | 83.6 (31.1) | 0.6 |
E. faecium 21 * | 1.2 (16) | 344.2 (128) | 1.2 (32) | 1.2 (16.4) | 41.9 (15.6) | 1.2 |
E. faecium 325 * | 1.2 (16) | 344.2 (128) | 0.6 (16) | 0.6 (8.2) | 21.0 (7.8) | 2.4 |
E. faecium 341 *,# | 1.2 (16) | 344.2 (128) | 0.6 (16) | 0.6 (8.2) | 21.0 (7.8) | 2.4 |
Staphylococcus genus | ||||||
S. aureus 18 ** | 4.6 (64) | 344.2 (128) | 2.4 (64) | 2.4 (32.9) | 83.6 (31.1) | 0.6 |
S. aureus 187 ** | 4.6 (64) | 344.2 (128) | 4.8 (128) | 4.8 (65.8) | 167.2 (62.2) | 0.3 |
S. aureus 195 ** | 4.6 (64) | 344.2 (128) | 2.4 (64) | 2.4 (32.9) | 83.6 (31.1) | 0.6 |
S. epidermidis 22 ** | 1.2 (16) | 344.2 (128) | 0.6 (16) | 0.6 (8.2) | 21.0 (7.8) | 2.4 |
S. epidermidis 180 *** | 1.2 (16) | 344.2 (128) | 1.2 (32) | 1.2 (16.4) | 41.9 (15.6) | 1.2 |
S. epidermidis 181 *** | 1.2 (16) | 344.2 (128) | 0.6 (16) | 0.6 (8.2) | 21.0 (7.8) | 2.4 |
Original P7 (13,719) 1 | Original CB1H (371.9) 2 | CB1H-P7 NPs (26,624) 1 | Complexed P7 (13,719) 1 | Complexed CB1H (371.9) 2 | ||
---|---|---|---|---|---|---|
Strains | MIC µM (µg/mL) | MIC (µg/mL) | MIC µM (µg/mL) | MIC µM (µg/mL) | MIC µM (µg/mL) | Selectivity Indices 3 |
Enterobacteriaceae family | ||||||
E. coli 238 # | 4.6 (64) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 1.3 |
E. coli 477 # | 2.3 (32) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 1.3 |
E. coli 462 § | 2.3 (32) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 1.3 |
K. pneumoniae 375 # | 4.6 (64) | >688.4 (>256) | 4.8 (128) | 4.8 (65.8) | 167.2 (62.2) | 0.3 |
K. pneumoniae 376 # | 9.3 (128) | >688.4 (>256) | 9.6 (256) | 9.1 (124.4) | 35.4 (131.6) | 0.2 |
K. pneumoniae 377 # | 9.3 (128) | >688.4 (>256) | 4.8 (128) | 4.8 (65.8) | 167.2 (62.2) | 0.3 |
K. pneumoniae 490 CR # | 4.6 (64) | >688.4 (>256) | 2.4 (64) | 2.3 (32.9) | 83.6 (31.1) | 0.6 |
E. aerogenes 484 ## | 4.6 (64) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6)) | 1.3 |
Non-fermenting species | ||||||
A. baumannii 257 | 2.3 (32) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 1.3 |
A. baumannii 279 | 2.3 (32) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 1.2 |
A. baumannii 245 COR | 9.3 (128) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 1.3 |
P. aeruginosa 1V ## | 2.3 (32) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 1.3 |
P. aeruginosa 5V ## | 4.6 (64) | >688.4 (>256) | 2.4 (64) | 2.3 (32.9) | 83.6 (31.1) | 0.6 |
P. aeruginosa 6V ## | 4.6 (64) | >688.4 (>256) | 2.4 (64) | 2.3 (32.9) | 83.6 (31.1) | 0.6 |
P. aeruginosa 7G ## | 4.6 (64) | >688.4 (>256) | 2.4 (64) | 2.3 (32.9) | 83.6 (31.1) | 0.6 |
P. aeruginosa 265 CR ## | ≥18.6 (≥256) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 1.3 |
P. aeruginosa 432 py,## | 1.2 (16) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 1.3 |
P. aeruginosa 447 py,## | 4.6 (64) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 1.3 |
P. aeruginosa 244 py,## | 4.6 (64) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 1.3 |
P. aeruginosa 259 *,## | 9.3 (128) | >688.4 (>256) | 9.6 (256) | 9.1 (124.4) | 35.4 (131.6) | 0.2 |
S. maltophilia 2 COI | 2.3 (32) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 1.3 |
S. maltophilia 280 COI | 4.6 (64) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 1.3 |
S. maltophilia 384 COR | 2.3 (32) | >688.4 (>256) | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 1.3 |
S. maltophilia 390 COR | 2.3 (32) | >688.4 (>256) | 2.4 (64) | 2.3 (32.9) | 83.6 (31.1) | 0.6 |
Strains | CB1H-P7 NPs (26,624) 1 | Complexed P7 (13,719) 1 | Complexed CB1H (371.9) 2 | Reference Antibiotics |
---|---|---|---|---|
MIC µM (µg/mL) | MIC µM (µg/mL) | MIC µM (µg/mL) | MIC µM (µg/mL) | |
E. faecalis 1 *,# | 1.2 (32) | 1.2 (16.4) | 41.9 (15.6) | 366.3 (128) 3 |
E. faecalis 365 * | 2.4 (64) | 2.4 (32.9) | 83.9 (31.1) | 366.3 (128) 3 |
E. faecalis 450 * | 2.4 (64) | 2.4 (32.9) | 83.9 (31.1) | 366.3 (128) 3 |
E. faecium 21 | 1.2 (32) | 1.2 (16.4) | 41.9 (15.6) | 366.3 (128) 3 |
E. faecium 325 * | 0.6 (16) | 0.6 (8.2) | 21.0 (7.8) | 366.3 (128) 3 |
E. faecium 341 *,# | 0.6 (16) | 0.6 (8.2) | 21.0 (7.8) | 366.3 (128) 3 |
S. aureus 18 ** | 2.4 (64) | 2.4 (32.9) | 83.9 (31.1) | 386.4 (128) 4, 1275.5 (512) 5 |
S. aureus 187 ** | 4.8 (128) | 4.8 (65.8) | 167.2 (62.2) | 386.4 (128) 4, 1275.5 (512) 5 |
S. aureus 195 ** | 2.4 (64) | 2.4 (32.9) | 83.9 (31.1) | 386.4 (128) 4, 1275.5 (512) 5 |
S. epidermidis 22 ** | 0.6 (16) | 0.6 (8.2) | 21.0 (7.8) | 193.2 (64) 4, 637.8 (256) 5 |
S. epidermidis 180 *** | 1.2 (32) | 1.2 (16.4) | 41.9 (15.6) | 193.2 (64) 4, 637.8 (256) 5 |
S. epidermidis 181 *** | 0.6 (16) | 0.6 (8.2) | 21.0 (7.8) | 193.2 (64) 4, 637.8 (256) 5 |
Strains | CB1H-P7 NPs (26,624) 1 | Complexed P7 (13,719) 1 | Complexed CB1H (371.9) 2 | Reference Antibiotics |
---|---|---|---|---|
MIC µM (µg/mL) | MIC µM (µg/mL) | MIC µM (µg/mL) | MIC µM (µg/mL) | |
E. coli 238 # | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 96.6 (32) 3 |
E. coli 477 # | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 96.6 (32) 3 |
E. coli 462 § | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 96.6 (32) 3 |
K. pneumoniae 375 # | 4.8 (128) | 4.8 (65.8) | 167.2 (62.2) | 96.6 (32) 3 |
K. pneumoniae 376 # | 9.3 (256) | 9.6 (131.6) | 334.5 (124.4) | 96.6 (32) 3 |
K. pneumoniae 377 # | 4.8 (128) | 4.8 (65.8) | 167.2 (62.2) | 96.6 (32) 3 |
K. pneumoniae 490 CR # | 2.4 (64) | 2.3 (32.9) | 83.9 (31.1) | 18.5 (16) 4 |
E. aerogenes 484 ## | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 96.6 (32) 3 |
A. baumannii 257 | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 193.2 (64) 3 |
A. baumannii 279 | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 193.2 (64) 3 |
A. baumannii 245 COR | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 193.2 (64) 3 |
P. aeruginosa 1V ## | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 76.2 (64) 5 |
P. aeruginosa 5V ## | 2.4 (64) | 2.3 (32.9) | 83.9 (31.1) | 76.2 (64) 5 |
P. aeruginosa 6V ## | 2.4 (64) | 2.3 (32.9) | 83.9 (31.1) | 76.2 (64) 5 |
P. aeruginosa 7G ## | 2.4 (64) | 2.3 (32.9) | 83.9 (31.1) | 76.2 (64) 5 |
P. aeruginosa 265 CR ## | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 18.5 (16) 4 |
P. aeruginosa 432 py,## | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 76.2 (64) 5 |
P. aeruginosa 447 py,## | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 76.2 (64) 5 |
P. aeruginosa 244 py,## | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 76.2 (64) 5 |
P. aeruginosa 259 *,## | 9.6 (256) | 9.6 (131.6) | 334.5 (124.4) | 76.2 (64) 5 |
S. maltophilia 2 COI | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 117.7 (64) 6 |
S. maltophilia 280 COI | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 117.7 (64) 6 |
S. maltophilia 384 COR | 1.2 (32) | 1.2 (16.5) | 41.9 (15.6) | 117.7 (64) 6 |
S. maltophilia 390 COR | 2.4 (64) | 2.3 (32.9) | 83.9 (31.1) | 117.7 (64) 6 |
Sample | Equations | R2 | LD50 (µM) | SI | |
---|---|---|---|---|---|
Gram-Positive | Gram-Negative | ||||
P7 | y = −25.7640x + 103.4 | 0.8972 | 2.1 | 0.5–1.8 | 0.1–1.8 |
CB1H | y = −0.6059x + 84.712 | 0.8648 | 57.3 | ≤0.4. | ≤0.2. |
CB1H-P7 NPs | y = −31.0430x + 94.949 | 0.9842 | 1.5 | 0.3–2.4 | 0.2–1.3 |
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Schito, A.M.; Caviglia, D.; Brullo, C.; Zorzoli, A.; Marimpietri, D.; Alfei, S. Enhanced Antibacterial Activity of a Cationic Macromolecule by Its Complexation with a Weakly Active Pyrazole Derivative. Biomedicines 2022, 10, 1607. https://doi.org/10.3390/biomedicines10071607
Schito AM, Caviglia D, Brullo C, Zorzoli A, Marimpietri D, Alfei S. Enhanced Antibacterial Activity of a Cationic Macromolecule by Its Complexation with a Weakly Active Pyrazole Derivative. Biomedicines. 2022; 10(7):1607. https://doi.org/10.3390/biomedicines10071607
Chicago/Turabian StyleSchito, Anna Maria, Debora Caviglia, Chiara Brullo, Alessia Zorzoli, Danilo Marimpietri, and Silvana Alfei. 2022. "Enhanced Antibacterial Activity of a Cationic Macromolecule by Its Complexation with a Weakly Active Pyrazole Derivative" Biomedicines 10, no. 7: 1607. https://doi.org/10.3390/biomedicines10071607