Dibasic Derivatives of Phenylcarbamic Acid as Prospective Antibacterial Agents Interacting with Cytoplasmic Membrane
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Antibacterial Activity
2.3. In Vitro Antiproliferative Assay
2.4. Structure–Activity Relationships
2.5. Advanced Antimicrobial Evaluation
2.5.1. Synergistic Effect
2.5.2. Time-Kill Studies
2.5.3. Crystal Violet Uptake
2.5.4. Antibiofilm Activity
3. Materials and Methods
3.1. Chemistry
3.2. Minimum Inhibitory Concentration Determination
3.3. Synergy Effect with Clinically Used Drugs
3.4. Time-Kill Study
3.5. Crystal Violet Uptake
3.6. Biofilm Inhibition Assay
3.7. Biofilm Susceptibility to Compounds
3.8. Calculations and Statistical Analyses
3.9. In Vitro Antiproliferative Assay
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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| ||||||
---|---|---|---|---|---|---|
Comp. | R | X | Y | log kw | γ (N/m) | log ε2 (Ch-T) |
1a | 2-OC4H9 | A | C | 3.7688 | 0.06464 | 4.19 |
1b | 2-OC5H11 | A | C | 4.0454 | 0.06366 | 4.05 |
1c | 2-OC6H13 | A | C | 4.6049 | 0.06222 | 4.52 |
1d | 2-OC7H15 | A | C | 4.9487 | 0.05985 | 4.08 |
1e | 3-OC4H9 | A | D | 4.0258 | 0.06316 | 4.24 |
1f | 3-OC5H11 | A | D | 4.6722 | 0.06285 | 4.27 |
1g | 3-OC6H13 | A | D | 4.9446 | 0.06105 | 4.13 |
1h | 3-OC7H15 | A | D | 5.5384 | 0.05786 | 4.27 |
1i | 2-OC4H9 | B | C | 4.4679 | 0.06302 | 4.08 |
1j | 2-OC5H11 | B | C | 4.8466 | 0.06206 | 4.22 |
1k | 2-OC6H13 | B | C | 5.2359 | 0.06065 | 4.10 |
1l | 2-OC7H15 | B | C | 5.8966 | 0.05853 | 4.14 |
1m | 3-OC4H9 | B | D | 4.7099 | 0.06298 | 4.09 |
1n | 3-OC5H11 | B | D | 5.2087 | 0.06154 | 4.18 |
1o | 3-OC6H13 | B | D | 5.6569 | 0.05925 | 4.01 |
1p | 3-OC7H15 | B | D | 6.1749 | 0.05692 | 4.20 |
Comp. | MICs (µg/mL (µM)) | Tox IC50 (μM) | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
SA | MRSA1 | MRSA2 | MRSA3 | EF | VRE1 | VRE2 | VRE3 | CA | ||
1a | >256 (>427) | >256 (>427) | >256 (>427) | >256 (>427) | >256 (>427) | >256 (>427) | >256 (>427) | >256 (>427) | >128 (>213) | 10.80 ± 1.11 |
1b | >256 (>417) | >256 (>417) | >256 (>417) | >256 (>417) | >256 (>417) | >256 (>417) | >256 (>417) | >256 (>417) | >128 (>208) | 12.53 ± 1.22 |
1c | >256 (>407) | >256 (>407) | >256 (>407) | >256 (>407) | >256 (>407) | >256 (>407) | >256 (>407) | >256 (>407) | >128 (>203) | 15.42 ± 0.22 |
1d | >256 (>398) | >256 (>398) | >256 (>398) | >256 (>398) | >256 (>398) | >256 (>398) | >256 (>398) | >256 (>398) | >128 (199) | 16.32 ± 0.70 |
1e | 64 (129) | 64 (129) | 64 (129) | 64 (129) | 128 (259) | 32 (65.1) | 64 (129) | 32 (65.1) | >128 (>259) | 4.20 ± 0.79 |
1f | 16 (31.6) | 16 (31.6) | 32 (63.2) | 16 (31.6) | 32 (63.2) | 16 (31.6) | 16 (31.6) | 16 (31.6) | 128 (252) | 4.19 ± 0.54 |
1g | 8 (15.4) | 8 (15.4) | 16 (30.8) | 8 (15.4) | 16 (30.8) | 8 (15.4) | 8 (15.4) | 8 (15.4) | 16 (30.8) | 3.50 ± 0.31 |
1h | 8 (15.0) | 8 (15.0) | 8 (15.0) | 8 (15.0) | 8 (15.0) | 4 (7.51) | 4 (7.51) | 4 (7.51) | 8 (15.0) | 3.67 ± 0.01 |
1i | >256 (>407) | >256 (>407) | >256 (>407) | >256 (>407) | >256 (>407) | >256 (>407) | >256 (>407) | >256 (>407) | >128 (>203) | 23.06 ± 0.95 |
1j | >256 (>398) | >256 (>398) | >256 (>398) | >256 (>398) | >256 (>398) | >256 (>398) | >256 (>398) | >256 (>398) | >128 (>199) | 26.45 ± 1.91 |
1k | >256 (>390) | >256 (>390) | >256 (>390) | >256 (>390) | >256 (>390) | >256 (>390) | >256 (>390) | >256 (>390) | >128 (>195) | 31.24 ± 2.24 |
1l | >256 (>382) | >256 (>382) | >256 (>382) | >256 (>382) | >256 (>382) | >256 (>382) | >256 (>382) | >256 (>382) | >128 (>191) | 29.75 ± 0.14 |
1m | 128 (245) | 32 (61.5) | 64 (122) | 64 (122) | 32 (61.5) | 32 (61.5) | 64 (122) | 16 (30.7) | >128 (>245) | 4.90 ± 0.19 |
1n | 128 (239) | 64 (119) | 128 (239) | 256 (478) | 16 (29.9) | 32 (59.9) | 64 (119) | 16 (29.9) | >128 (>239) | 4.99 ± 0.99 |
1o | >256 (>466) | 128 (233) | >256 (>466) | >256 (>466) | 16 (29.2) | 32 (58.3) | 256 (466) | 8 (14.6) | >128 (>233) | 4.71 ± 0.07 |
1p | >256 (>455) | 256 (455) | >256 (>455) | >256 (>455) | 8 (14.2) | 64 (113) | 256 (455) | 16 (28.4) | >128 (>227) | 6.32 ± 0.58 |
AMP | 2 (5.72) | 16 (45.8) | >16 (>45.8) | >16 (>45.8) | 4 (11.5) | 4 (11.5) | 4 (11.5) | 2 (5.72) | – | >30 |
CPX | 0.5 (1.51) | >16 (>45.8) | >16 (>45.8) | >16 (>45.8) | 1 (3.02) | 1 (3.02) | 1 (3.02) | 64 (193) | – | 0.71 ± 0.09 |
VAN | 1 (0.69) | 2 (1.38) | 1 (0.69) | 1 (0.69) | – | 512 (353) | 512 (353) | 1024 (706) | – | >30 |
5-FC | – | – | – | – | – | – | – | – | 1 (7.75) | – |
CMP | – | – | – | – | – | – | – | – | – | 0.20 ± 0.07 |
SDS | 128 (443) | 128 (443) | 64 (222) | 64 (222) | 128 (443) | 256 (887) | 128 (443) | 128 (443) | – | 148.43 ± 8.42 |
CRB | 0.25 (0.59) | 0.25 (0.59) | 0.5 (1.18) | 2 (4.73) | 0.5 (1.18) | 0.5 (1.18) | 0.25 (0.59) | 0.5 (1.18) | – | 1.73 ± 0.08 |
CTC | 0.25 (0.63) | 0.25 (0.63) | 0.5 (1.26) | 1 (2.53) | 1 (2.53) | 0.5 (1.26) | 0.5 (1.26) | 0.5 (1.26) | – | 1.29 ± 0.07 |
PRC | >256 (>1083) | >256 (>1083) | >256 (>1083) | >256 (>1083) | >256 (>1083) | >256 (>1083) | >256 (>1083) | >256 (>1083) | – | >300 |
TRC | >256 (>1030) | >256 (>1030) | >256 (>1030) | >256 (>1030) | >256 (>1030) | >256 (>1030) | >256 (>1030) | >256 (>1030) | – | >300 |
TEC | >256 (>968) | >256 (>968) | >256 (>968) | >256 (>968) | >256 (>968) | >256 (>968) | >256 (>968) | >256 (>968) | – | 224.13 ± 6.52 |
Isolate | Combination (MIC (μg/mL)) | FIC Index | Comb. Effect (MICs (μg/mL)) |
---|---|---|---|
MRSA 63718 | Comp. 1g + CPX (16/16) | 1.000 | IND |
Comp. 1h + CPX (8/16) | 0.531 | ADD 0.25/0.032 | |
Comp. 1g + OXA (8/512) | 0.500 | SYN 2/128 | |
Comp. 1h +OXA (4/512) | 0.562 | ADD 2/32; 1/256 | |
MRSA SA 3202 | Comp. 1g + CPX (16/16) | 1.000 | IND |
Comp. 1h + CPX (8/16) | 1.000 | IND | |
Comp. 1g + OXA (8/512) | 1.000 | IND | |
Comp. 1h+ OXA (8/512) | 0.750 | ADD 4/128 | |
VRE 342B | Comp. 1g + VAN (8/1024) | 0.625 | ADD 4/128 |
Comp. 1h + VAN (8/1024) | 0.500 | SYN 2/256 | |
Comp. 1g + GEN (8/32) | 0.750 | ADD 4/8 | |
Comp. 1h+ GEN (8/32) | 1.000 | IND | |
VRE 368 | Comp. 1g + VAN (8/512) | 0.750 | ADD 4/128 |
Comp. 1h + VAN (4/512) | 0.750 | ADD 2/256 | |
Comp. 1g + GEN (8/64) | 1.000 | IND | |
Comp. 1h+ GEN (2/128) | 1.016 | IND |
Strain | Conc. | Log10 Difference in CFU/mL from Inoculum | |||
---|---|---|---|---|---|
4 h | 6 h | 8 h | 24 h | ||
SA | 1 × MIC | 1.54 | 1.98 | 2.33 | 2.74 |
2 × MIC | 0.87 | 0.98 | 1.26 | 2.24 | |
4 × MIC | −0.26 | −0.04 | 0.10 | 1.85 | |
MRSA1 | 1 × MIC | 0.00 | 0.66 | 1.00 | 1.99 |
2 × MIC | −1.33 | −0.93 | −0.26 | 1.29 | |
4 × MIC | −2.57 * | −1.99 * | −1.26 * | 1.21 | |
EF | 1 × MIC | −1.63 | −1.01 | −0.61 | 0.27 |
2 × MIC | −3.37 * | −3.43 * | −2.68 | 1.04 | |
4 × MIC | −5.62 * | −5.14 * | −5.92 * | −0.31 | |
VRE1 | 1 × MIC | −0.14 | 0.97 | 1.01 | 1.11 |
2 × MIC | −0.36 | −1.89 | −0.64 | 1.51 | |
4 × MIC | −0.92 | −1.00 | −1.09 | 0.77 | |
VRE2 | 1 × MIC | −2.00 | 0.29 | 0.25 | −0.16 |
2 × MIC | −2.34 | −1.97 | −1.01 | 0.32 | |
4 × MIC | −2.72 * | −2.71 * | −2.45 | 0.97 | |
VRE3 | 1 × MIC | −0.09 | −0.29 | 0.19 | 2.41 |
2 × MIC | −0.75 | −0.74 | 0.56 | 0.43 | |
4 × MIC | −1.85 | −1.85 | −2.15 | −2.27 |
Strain | Conc. | Log10 Difference in CFU/mL from Inoculum | |||
---|---|---|---|---|---|
4 h | 6 h | 8 h | 24 h | ||
SA | 1 × MIC | 0.08 | 0.31 | 0.50 | 2.07 |
2 × MIC | 0.05 | 0.10 | 0.05 | 2.01 | |
4 × MIC | −0.25 | −0.13 | −0.08 | 1.93 | |
MRSA1 | 1 × MIC | −0.73 * | −0.11 | 0.98 | 1.58 |
2 × MIC | −0.92 * | −0.42 * | −0.13 | 1.62 | |
4 × MIC | −2.48 * | −2.40 * | −2.08 * | 1.35 | |
EF | 1 × MIC | −0.64 | 0.16 | 0.24 | 0.34 |
2 × MIC | −1.87 | −1.36 | −0.86 | 0.42 | |
4 × MIC | −2.57 * | −2.23 * | −1.62 | 0.49 | |
VRE1 | 1 × MIC | 0.07 | 1.08 | −0.08 | 1.42 |
2 × MIC | 0.09 | 0.41 | −0.02 | 0.47 | |
4 × MIC | −0.78 | −0.99 | −0.66 | 0.85 | |
VRE2 | 1 × MIC | 0.46 | 0.71 | 1.25 | 1.13 |
2 × MIC | 0.28 | 0.54 | −0.37 | 0.66 | |
4 × MIC | −0.32 | 0.05 | 0.22 | 0.37 | |
VRE3 | 1 × MIC | −0.70 | 0.08 | −0.05 | 0.92 |
2 × MIC | −1.81 | −1.31 | −0.81 | 0.95 | |
4 × MIC | −1.75 * | −0.76 | −0.76 | 1.08 |
Strain | Conc. | Log10 Difference in CFU/mL from Inoculum | |||
---|---|---|---|---|---|
4 h | 6 h | 8 h | 24 h | ||
SA | 1 × MIC | −0.37 | −0.65 | −0.84 | 2.90 |
2 × MIC | −0.26 | −0.59 | −1.12 | −3.67 | |
4 × MIC | −0.27 | −0.38 | −1.18 | −5.47 | |
MRSA1 | 1 × MIC | −1.00 | −1.50 | −1.76 | 0.55 |
2 × MIC | −0.91 | −1.43 | −1.97 | −5.18 | |
4 × MIC | −1.31 | −1.75 | −3.89 | −5.19 |
Sample | (µg/mL) | ||
---|---|---|---|
MIC | MBIC80 | MBEC80 | |
1f | 16 | 32 | 64 |
1g | 8 | 8 | 16 |
1h | 8 | 8 | 16 |
SDS | 128 | 32 | 128 |
CRB | 0.25 | 0.25 | 64 |
CTC | 0.25 | 0.25 | >256 |
PRC | >256 | >256 | >256 |
TRC | >256 | >256 | >256 |
TEC | >256 | >256 | >256 |
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Pospíšilová, Š.; Malík, I.; Bezouskova, K.; Kauerova, T.; Kollar, P.; Csöllei, J.; Oravec, M.; Cizek, A.; Jampilek, J. Dibasic Derivatives of Phenylcarbamic Acid as Prospective Antibacterial Agents Interacting with Cytoplasmic Membrane. Antibiotics 2020, 9, 64. https://doi.org/10.3390/antibiotics9020064
Pospíšilová Š, Malík I, Bezouskova K, Kauerova T, Kollar P, Csöllei J, Oravec M, Cizek A, Jampilek J. Dibasic Derivatives of Phenylcarbamic Acid as Prospective Antibacterial Agents Interacting with Cytoplasmic Membrane. Antibiotics. 2020; 9(2):64. https://doi.org/10.3390/antibiotics9020064
Chicago/Turabian StylePospíšilová, Šárka, Ivan Malík, Kristyna Bezouskova, Tereza Kauerova, Peter Kollar, Jozef Csöllei, Michal Oravec, Alois Cizek, and Josef Jampilek. 2020. "Dibasic Derivatives of Phenylcarbamic Acid as Prospective Antibacterial Agents Interacting with Cytoplasmic Membrane" Antibiotics 9, no. 2: 64. https://doi.org/10.3390/antibiotics9020064