Evaluation of the Effects of Heteroaryl Ethylene Molecules in Combination with Antibiotics: A Preliminary Study on Control Strains
Abstract
:1. Introduction
2. Results
2.1. Structural Design of Heteroaryl Ethylenes
2.1.1. QSAR Model for the Screening of the In Vitro Activity against S. aureus ATCC29213
2.1.2. QSAR Model for Cytotoxic Activity towards CaCo-2 Colon–Rectal Cancer Cell Line
2.2. Impact on Biological Activity and Antimicrobial Susceptibility Test
2.3. Evaluation of Heteroaryl Ethylene Compound Cell Cytotoxicity
Evaluation of Antibiotic Cytotoxicity
3. Discussion
4. Materials and Methods
4.1. Dataset of the QSAR models
4.2. Compound Synthesis
4.3. Bacterial Strains
4.4. Bacterial Growth Conditions
4.5. Antimicrobial Susceptibility Test
4.6. Evaluation of the Cytotoxic Activity of the Compounds on Human Colorectal Adenocarcinoma Cells
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
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PB4 | BCM4 | BCM6 | GC-VII-39 | GC-VI-70 | GC-VII-50 | GC-VI-10 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Species | Strain | mg/L | µM | mg/L | µM | mg/L | µM | mg/L | µM | mg/L | µM | mg/L | µM | mg/L | µM |
E. faecalis | ATCC 29212 | 0.5 | 0.98 | ≥128 | ≥349.5 | 32 | 65.93 | 16 | 30.45 | 2 * | 3.32 | 8 * | 18.5 | 4 * | 5.2 |
S. aureus | ATCC 29213 | 0.125 | 0.24 | 128 | 349.5 | 4 * | 8.2 | 128 | 243.6 | 16 | 26.6 | 0.5 * | 1.1 | 128 | 168.9 |
S. aureus | ATCC 12598 | 0.25 | 0.49 | 64 | 174.7 | 4 * | 8.23 | 32 | 60.9 | 16 | 26.6 | 0.25 * | 0.5 | 64 | 84.4 |
S. aureus | ATCC BAA-1556 USA300 | ≤0.125 | ≤0.24 | 64 | 174.7 | 8 * | 16.4 | >128 | >243.6 | 4 * | 6.65 | 2 * | 4.6 | 128 | 168.9 |
K. pneumoniae | ATCC 700603 | 64 | 125.1 | >128 | ≥349.5 | >128 | >263.7 | ≥128 | ≥243.6 | >128 | >212.7 | >128 | >297.4 | >128 | >168.9 |
A. baumannii | ATCC 17978 | ≤0.125 | ≤0.24 | ≥128 | ≥349.5 | 64 | 131.8 | ≥128 | ≥243.6 | 32 | 53.19 | 16 | 37.18 | >128 | >168.9 |
P. aeruginosa | ATCC 27853 | >128 | >250.2 | >128 | ≥349.5 | >128 | >263.7 | ≥128 | ≥243.6 | >128 | >212.7 | >128 | >297.4 | >128 | >168.9 |
S. enterica | ATCC 14028 | 64 | 125.1 | >128 | ≥349.5 | >128 | >263.7 | ≥128 | ≥243.6 | >128 | >212.7 | >128 | >297.4 | >128 | >168.9 |
E. coli | ATCC 25922 | 2 | 3.91 | ≥128 | ≥349.5 | 128 | 263.7 | ≥128 | ≥128 | 128 | 212.7 | 64 | 148.7 | >128 | >168.9 |
Species | Strain | Gentamycin | |
---|---|---|---|
mg/L | CLSI Range | ||
E. faecalis | ATCC 29212 | 8 | 4–16 |
S. aureus | ATCC 29213 | 0.5 | 0.125–1 |
P. aeruginosa | ATCC 27853 | 2 | 0.5–2 |
E. coli | ATCC 25922 | 0.5 | 0.25–1 |
Species | Strain | LNZ | LNZ + PB4 | RD | RD + PB4 | E | E + PB4 | CN | CN + PB4 | AMP | AMP + PB4 | IMI | IMI + PB4 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
E. faecalis | ATCC 29212 | 4 | 2 | 0.25 * | 0.06 * | 2 | 1 | 4 * | 1 * | 0.25 | 0.125 | - | - |
S. aureus | ATCC 29213 | 4 | 4 | 0.125 | 0.125 | 0.5 | 0.5 | 0.5 | 0.5 | 2 | 8 | - | - |
ATCC 12598 | 4 | 4 | 0.125 | 0.125 | 0.5 | 0.5 | 0.5 | 0.5 | 0.125 | 0.125 | - | - | |
USA 300 | 2 | 1 | 0.125 * | 0.006 * | 32 | 32 | 0.5 | 0.5 | 8 | 8 | - | - | |
K. pneumoniae | ATCC 700603 | - | - | - | - | - | - | 8 * | 2 * | >128 | >128 | 0.03 | 0.03 |
A. baumannii | ATCC 17978 | - | - | - | - | - | - | 2 | 2 | 32 | 32 | 0.06 | 0.06 |
P. aeruginosa | ATCC 27853 | - | - | - | - | - | - | 2 * | 0.5 * | >128 | >128 | 0.25 | 0.25 |
S. enterica | ATCC 14028 | - | - | - | - | - | - | 1 | 1 | 2 | 2 | 0.06 | 0.06 |
E. coli | ATCC 25922 | - | - | - | - | - | - | 0.5 | 0.5 | 8 | 8 | 0.06 | 0.06 |
PB4 | GC-VI-70 | PB4 + GC-VI-70 | |||||
---|---|---|---|---|---|---|---|
Species | Strain | mg/L | µM | mg/L | µM | mg/L | µM |
E. faecalis | ATCC 29212 | 0.5 | 0.98 | 2 | 3.3 | 0.06 * | 0.2 * |
S. aureus | ATCC 29213 | 0.125 | 0.24 | 16 | 26.5 | 1 | 1.66 |
S. aureus | ATCC 12598 | 0.25 | 0.49 | 16 | 26.5 | 0.06 * | 0.2 * |
S. aureus | ATCC BAA-1556 USA 300 | ≤0.125 | ≤0.24 | 4 | 6.6 | 2 | 3.3 |
Molecule | IC50 at 24 h (µM) | IC50 at 48 h (µM) |
---|---|---|
BCM4 | 0.72 | 0.10 |
BCM6 | 0.16 | 0.18 |
GC-VII-39 | 0.23 | 0.18 |
GC-VII-50 | 0.17 | 0.07 |
GC-VI-70 | 0.94 | 3.76 |
GC-VI-10 | 1.35 | 0.99 |
5-FU | 27.36 | 12.91 |
PB4 | 0.31 | 0.3 |
Antibiotic | Antibiotic + PB4 0.2 µM | ||||
---|---|---|---|---|---|
24 h | 48 h | 24 h | 48 h | ||
Linezolid | MIC | 153.5 | 252.9 | 144.0 | 145.7 |
sub-MIC | 143.4 | 247.6 | 132.0 | 130.6 | |
Gentamicin | MIC | 158.2 | 247.5 | 125.6 | 141.1 |
sub-MIC | 132.3 | 271.7 | 132.4 | 99.2 | |
Ampicillin | MIC | 147.7 | 321.1 | 133.8 | 127.7 |
sub-MIC | 155.6 | 247.5 | 135.6 | 137.0 | |
Erythromycin | MIC | 148.2 | 269.0 | 133.6 | 117.5 |
sub-MIC | 159.5 | 280.6 | 124.9 | 155.8 | |
Rifampin | MIC | 133.7 | 282.6 | 126.9 | 158.9 |
sub-MIC | 146.6 | 265.6 | 130.6 | 163.7 | |
Mean | 147.9 | 268.6 | 131.9 | 137.7 | |
PB4 0.2 µM | |||||
24h | 48h | ||||
68.8 | 72.7 |
Strain | Species | |
---|---|---|
Gram + | ATCC 29212 | Enterococcus faecalis |
ATCC 29213 | Staphylococcus aureus | |
ATCC 12598 | Staphylococcus aureus | |
ATCC BAA-1556 | Staphylococcus aureus sub. Rosenbach (USA300 clone) | |
Gram − | ATCC 700603 | Klebsiella pneumoniae |
ATCC 17978 | Acinetobacter baumannii | |
ATCC 27853 | Pseudomonas aeruginosa | |
ATCC 14028 | Salmonella enterica | |
ATCC 25922 | Escherichia coli |
Compounds | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
PB4 | BCM4 | BCM6 | GC-VII-39 | GC-VII-50 | GC-VI-10 | 5-FU | GC-VI-70 | |||
Concentrations Tested | 100 µM, 10 µM, 1 µM, 0.1 µM, and 0.01 µM | |||||||||
Antibiotic | ||||||||||
Linezolid | Gentamicin | Ampicillin | Erythromycin | Rifampin | ||||||
mg/L | µM | mg/L | µM | mg/L | µM | mg/L | µM | mg/L | µM | |
MIC Concentrations Tested | 4 | 11.85 | 4 | 7.74 | 0.25 | 0.72 | 2 | 2.73 | 0.25 | 0.30 |
Sub-MIC Concentrations Tested | 2 | 5.93 | 2 | 3.87 | 0.125 | 0.36 | 1 | 1.36 | 0.125 | 0.15 |
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Bonomo, C.; Bonacci, P.G.; Bivona, D.A.; Mirabile, A.; Bongiorno, D.; Nicitra, E.; Marino, A.; Bonaccorso, C.; Consiglio, G.; Fortuna, C.G.; et al. Evaluation of the Effects of Heteroaryl Ethylene Molecules in Combination with Antibiotics: A Preliminary Study on Control Strains. Antibiotics 2023, 12, 1308. https://doi.org/10.3390/antibiotics12081308
Bonomo C, Bonacci PG, Bivona DA, Mirabile A, Bongiorno D, Nicitra E, Marino A, Bonaccorso C, Consiglio G, Fortuna CG, et al. Evaluation of the Effects of Heteroaryl Ethylene Molecules in Combination with Antibiotics: A Preliminary Study on Control Strains. Antibiotics. 2023; 12(8):1308. https://doi.org/10.3390/antibiotics12081308
Chicago/Turabian StyleBonomo, Carmelo, Paolo Giuseppe Bonacci, Dalida Angela Bivona, Alessia Mirabile, Dafne Bongiorno, Emanuele Nicitra, Andrea Marino, Carmela Bonaccorso, Giuseppe Consiglio, Cosimo Gianluca Fortuna, and et al. 2023. "Evaluation of the Effects of Heteroaryl Ethylene Molecules in Combination with Antibiotics: A Preliminary Study on Control Strains" Antibiotics 12, no. 8: 1308. https://doi.org/10.3390/antibiotics12081308