In Vivo Efficacy and Toxicity Studies of a Novel Antibacterial Agent: 14-O-[(2-Amino-1,3,4-thiadiazol-5-yl)Thioacetyl] Mutilin
Abstract
:1. Introduction
2. Results and Discussion
2.1. In Vivo Efficacy of ATTM
Compounds | Group | n | Dose (mg/kg b. w.) | Logarithmic Dose | Survival | Survival Rate (%) |
---|---|---|---|---|---|---|
ATTM | 1 | 10 | 2.5 | 0.4 | 2 | 20 |
2 | 10 | 5.0 | 0.7 | 4 | 40 | |
3 | 10 | 10.0 | 1.0 | 9 | 90 | |
4 | 10 | 20.0 | 1.3 | 10 | 100 | |
5 | 10 | 40.0 | 1.6 | 10 | 100 | |
Tiamulin fumarate | 1 | 10 | 2.5 | 0.4 | 2 | 20 |
2 | 10 | 5.0 | 0.7 | 4 | 40 | |
3 | 10 | 10.0 | 1.0 | 8 | 80 | |
4 | 10 | 20.0 | 1.3 | 10 | 100 | |
5 | 10 | 40.0 | 1.6 | 10 | 100 |
2.2. Acute Oral Toxicity Study
Group | n | Dose (mg/kg b. w.) | Logarithmic Dose | Mortality | Mortality Rate (%) |
---|---|---|---|---|---|
1 | 10 | 948.15 | 3.68 | 0 | 0 |
2 | 10 | 1422.22 | 3.51 | 2 | 20 |
3 | 10 | 2133.33 | 3.33 | 4 | 40 |
4 | 10 | 3200.00 | 3.15 | 7 | 70 |
5 | 10 | 4800.00 | 2.98 | 10 | 100 |
vehicle control group | 10 | 20 (mL/kg b. w.) | - | 0 | 0 |
2.3. Subchronic Oral Toxicity
2.3.1. Clinical Signs, Body Weights, and Food Consumption
Item | Control Group | ATTM-Treated Groups (mg/kg b. w./d) | Saline Group | ||
---|---|---|---|---|---|
Low-Dose (5) | Middle-Dose (25) | High-Dose (125) | |||
Females | |||||
Total body weight gain (g) | 74.4 ± 7.5 | 66.06 ± 5.8 | 63.07 ± 6.3 | 87.4 ± 4.9 | 65.7 ± 8.5 |
Daily food consumption (g) | 118.6 ± 7.2 | 107.1 ± 13.6 | 106.9 ± 10.8 | 106.8 ± 15.7 | 109.7 ± 9.9 |
Males | |||||
Total body weight gain (g) | 124.8 ± 10.4 | 123.8 ± 9.6 | 121.1 ± 8.2 | 114.5 ± 9.9 | 121.0 ± 5.6 |
Daily food consumption (g) | 148.4 ± 10.2 | 134.9 ± 7.5 | 147.7 ± 12.6 | 147.7 ± 12.6 | 157.1 ± 8.6 |
2.3.2. Hematological and Serum Biochemical Data
Hematological Parameters | Control group | ATTM-Treated Groups (mg/kg b. w./d) | Saline Group | ||
---|---|---|---|---|---|
Low-Dose (5) | Middle-Dose (25) | High-Dose (125) | |||
Females | |||||
WBC(109/L) | 14.2 ± 4.5 | 10.9 ± 3.6 | 9.3 ± 7.5 | 10.2 ± 2.5 | 15.2 ± 3.8 |
RBC (1012/L) | 8.33 ± 0.78 | 7.47 ± 0.65 | 7.85 ± 0.48 | 7.7 ± 0.54 | 8.9 ± 0.74 |
HGB (g/L) | 180 ± 7.4 | 179 ± 6.3 | 171 ± 5.2 | 170 ± 7.8 | 180 ± 7.1 |
HCT% | 0.504 ± 1.4 | 0.392 ± 1.7 | 0.464 ± 1.9 | 0.414 ± 1.6 | 0.519 ± 1.4 |
MCV (fL) | 60.5 ± 0.89 | 60.6 ± 0.92 | 59.1 ± 0.95 | 61.8 ± 0.91 | 58.3 ± 0.93 |
MCH (pg) | 21.6 ± 0.90 | 21.5 ± 0.88 | 21.8 ± 0.87 | 22.4 ± 0.79 | 21.6 ± 0.92 |
MCHC (g/L) | 357 ± 0.52 | 355 ± 0.48 | 369 ± 0.58 | 362 ± 0.41 | 347 ± 0.61 |
PLT (109/L) | 1211 ± 127.83 | 1154 ± 153.47 | 1137 ± 184.26 | 1224 ± 192.38 | 1237 ± 83.54 |
Males | |||||
WBC (109/L) | 10.6 ± 2.8 | 10.9 ± 2.3 | 12.5 ± 4.6 | 12.2 ± 3.5 | 13.3 ± 3.9 |
RBC (1012/L) | 8.37 ± 0.64 | 8.21 ± 0.61 | 8.64 ± 0.69 | 8.7 ± 0.66 | 8.18 ± 0.65 |
HGB (g/L) | 182 ± 5.4 | 172 ± 5.6 | 189 ± 5.9 | 178 ± 6.3 | 179 ± 7.1 |
HCT% | 0. 520 ± 1.3 | 0.461 ± 1.6 | 0.535 ± 1.9 | 0.474 ± 1.2 | 0.485 ± 1.7 |
MCV (fL) | 62.1 ± 0.75 | 56.2 ± 0.72 | 61.9 ± 0.79 | 62.8 ± 0.64 | 59.3 ± 0.68 |
MCH (pg) | 21.7 ± 0.83 | 21.0 ± 0.95 | 21.9 ± 0.78 | 22.4 ± 0.74 | 20.7 ± 0.87 |
MCHC (g/L) | 350 ± 0.56 | 373 ± 0.62 | 353 ± 0.64 | 362 ± 0.58 | 348 ± 0.64 |
PLT (109/L) | 1152 ± 118.54 | 1143 ± 178.56 | 1229 ± 139.72 | 1224 ± 157.56 | 1215 ± 137.83 |
Biochemical Parameters | Control Group | ATTM-Treated Groups (mg/kg b. w./d) | Saline Group | ||
---|---|---|---|---|---|
Low-Dose (5) | Middle-Dose (25) | High-Dose (125) | |||
Females | |||||
ALT (U/L) | 52 ± 5.2 | 48 ± 4.6 | 45 ± 5.8 | 44 ± 6.1 | 64 ± 6.5 |
ALP (U/L) | 266 ± 14.5 | 233 ± 13.6 | 251 ± 16.8 | 153 ± 19.2 ** | 278 ± 18.4 |
AST (U/L) | 110 ± 23.7 | 113 ± 27.5 | 112 ± 26.5 | 106 ± 23.4 | 112 ± 24.6 |
T-Bil (μmol/L) | 4.70 ± 0.36 | 4.3 ± 0.54 | 4.83 ± 0.82 | 3.71 ± 0.71 | 3.68 ± 0.59 |
LDH (U/L) | 761 ± 12.8 | 770 ± 11.6 | 785 ± 13.2 | 797 ± 14.1 | 721 ± 13.7 |
TC (mmol/L) | 2.6 ± 0.21 | 2.6 ± 0.17 | 2.3 ± 0.19 | 2.7 ± 0.20 | 1.9 ± 0.45 |
HDL-c (mmol/L) | 1.83 ± 0.14 | 1.86 ± 0.17 | 1.70 ± 0.12 | 2.03 ± 0.16 | 1.80 ± 0.19 |
LDL-c (mmol/L) | 0.47 ± 0.07 | 0.43 ± 0.05 | 0.36 ± 0.08 | 0.35 ± 0.04 | 0.32 ± 0.09 |
TG (mmol/L) | 0.68 ± 0.31 | 0.60 ± 0.45 | 0.74 ± 0.41 | 0.76 ± 0.62 | 0.80 ± 0.58 |
CK (U/L) | 2178 ± 33.6 | 2127 ± 37.6 | 2160 ± 41.4 | 2007 ± 32.9 | 1983 ± 36.4 |
CR (μmol/L) | 66 ± 4.7 | 66 ± 4.6 | 65 ± 5.3 | 73 ± 6.2 * | 68 ± 4.5 |
Urea (mmol/L) | 5.4 ± 5.6 | 6.0 ± 7.8 | 8.8 ± 8.1 | 6.1 ± 6.5 | 5.7 ± 6.2 |
UA (μmol/L) | 79.5 ± 0.24 | 82.6 ± 0.37 | 80.2 ± 0.19 | 80.2 ± 0.56 | 83.9 ± 0.47 |
TP (g/L) | 60.3 ± 4.7 | 57.9 ± 3.8 | 63.6 ± 5.3 | 65.6 ± 4.2 | 69.1 ± 4.9 |
ALB (g/L) | 30.2 ± 2.4 | 22.4 ± 2.7 | 33.6 ± 3.2 | 31.4 ± 3.8 | 30.8 ± 3.0 |
GLU (mmol/L) | 4.24 ± 0.35 | 3.94 ± 0.37 | 5.09 ± 0.32 | 6.7 ± 0.39 * | 5.11 ± 0.31 |
Ca (mmol/L) | 2.70 ± 0.10 | 2.90 ± 0.08 | 2.49 ± 0.12 | 2.41 ± 0.14 | 2.44 ± 0.13 |
P (mmol/L) | 2.7 ± 0.24 | 2.7 ± 0.33 | 3.9 ± 0.45 | 3.3 ± 0.38 | 2.4 ± 0.51 |
Males | |||||
ALT (U/L) | 41 ± 5.4 | 49 ± 6.4 | 48 ± 6.1 | 44 ± 4.8 | 47 ± 3.9 |
ALP (U/L) | 103 ± 14.7 | 116 ± 15.4 | 110 ± 17.4 | 113 ± 18.9 | 117 ± 16.8 |
AST (U/L) | 117 ± 23.5 | 112 ± 25.6 | 110 ± 21.9 | 106 ± 26.5 | 116 ± 27.8 |
T-Bil (μmol/L) | 5.12 ± 0.34 | 3.44 ± 0.37 | 4.49 ± 0.36 | 3.71 ± 0.45 | 4.8 ± 0.52 |
LDH (U/L) | 518 ± 12.3 | 512 ± 12.7 | 515 ± 11.8 | 517 ± 13.6 | 517 ± 14.2 |
TC (mmol/L) | 2.3 ± 0.25 | 2.3 ± 0.29 | 2.2 ± 0.21 | 2.7 ± 0.19 | 3.2 ± 0.35 |
HDL-c (mmol/L) | 1.77 ± 0.15 | 1.73 ± 0.16 | 1.59 ± 0.13 | 2.03 ± 0.17 | 2.24 ± 0.15 |
LDL-c (mmol/L) | 0.29 ± 0.08 | 0.35 ± 0.06 | 0.27 ± 0.04 | 0.35 ± 0.05 | 0.52 ± 0.10 |
TG (mmol/L) | 0.65 ± 0.36 | 0.69 ± 0.39 | 0.56 ± 0.32 | 0.76 ± 0.47 | 1.17 ± 0.35 |
CK (U/L) | 2208 ± 42.5 | 2178 ± 32.6 | 2116 ± 35.7 | 2207 ± 36.2 | 2287 ± 37.9 |
CR (μmol/L) | 69 ± 4.7 | 67 ± 4.5 | 68 ± 5.2 | 73 ± 6.7 * | 68 ± 5.8 |
Urea (mmol/L) | 6.6 ± 6.5 | 6.1 ± 7.2 | 6.2 ± 5.8 | 6.1 ± 4.9 | 6.3 ± 8.1 |
UA (μmol/L) | 89.4 ± 0.51 | 64.5 ± 0.27 | 82.9 ± 0.46 | 80.2 ± 0.35 | 84.0 ± 0.49 |
TP (g/L) | 68.7 ± 4.7 | 60.5 ± 5.6 | 66.8 ± 3.9 | 65.6 ± 6.1 | 64.1 ± 5.8 |
ALB (g/L) | 32.3 ± 2.5 | 29.5 ± 3.9 | 32.5 ± 3.2 | 31.4 ± 4.5 | 34.9 ± 3.7 |
GLU (mmol/L) | 5.20 ± 3.2 | 5.22 ± 3.8 | 5.29 ± 3.3 | 5.70 ± 3.5 * | 5.11 ± 3.1 |
Ca (mmol/L) | 2.64 ± 0.13 | 2.44 ± 0.17 | 2.39 ± 0.09 | 2.41 ± 0.13 | 2.60 ± 0.11 |
P (mmol/L) | 3.0 ± 0.36 | 2.8 ± 0.29 | 2.5 ± 0.37 | 2.4 ± 0.42 | 2.6 ± 0.24 |
2.3.3. Organ Weights
Item | Control Group | ATTM-Treated Groups (mg/kg b. w./d) | Saline Group | ||
---|---|---|---|---|---|
Low-Dose (5) | Middle-Dose (25) | High-Dose (125) | |||
Females | |||||
Heart | 0.40 ± 0.12 | 0.39 ± 0.28 | 0.39 ± 0.26 | 0.40 ± 0.18 | 0.37 ± 0.29 |
Liver | 3.06 ± 0.26 | 3.49 ± 0.35 | 3.52 ± 0.38 | 4.01 ± 0.25 * | 3.30 ± 0.17 |
Spleen | 0.28 ± 0.05 | 0.23 ± 0.04 | 0.24 ± 0.03 | 0.27 ± 0.02 | 0.26 ± 0.06 |
Lung | 0.60 ± 0.15 | 0.75 ± 0.13 | 0.62 ± 0.17 | 0.61 ± 0.19 | 0.66 ± 0.21 |
Kidney | 0.74 ± 0.13 | 0.73 ± 0.17 | 0.80 ± 0.14 | 0.80 ± 0.18 | 0.66 ± 0.17 |
Thymus | 0.20 ± 0.09 | 0.20 ± 0.06 | 0.16 ± 0.04 | 0.20 ± 0.05 | 0.21 ± 0.08 |
Ovaries | 0.06 ± 0.01 | 0.07 ± 0.03 | 0.06 ± 0.04 | 0.06 ± 0.07 | 0.04 ± 0.05 |
Males | |||||
Heart | 0.37 ± 0.14 | 0.34 ± 0.18 | 0.35 ± 0.26 | 0.34 ± 0.23 | 0.31 ± 0.27 |
Liver | 3.14 ± 0.25 | 3.16 ± 0.28 | 2.99 ± 0.24 | 3.98 ± 0.27 * | 3.03 ± 0.19 |
Spleen | 0.22 ± 0.06 | 0.17 ± 0.07 | 0.22 ± 0.03 | 0.20 ± 0.02 | 0.27 ± 0.08 |
Lung | 0.57 ± 0.14 | 0.63 ± 0.13 | 0.56 ± 0.18 | 0.60 ± 0.20 | 0.66 ± 0.25 |
Kidney | 0.86 ± 0.12 | 0.78 ± 0.15 | 0.83 ± 0.18 | 0.80 ± 0.21 | 0.76 ± 0.19 |
Thymus | 0.15 ± 0.04 | 0.10 ± 0.07 | 0.29 ± 0.11 | 0.19 ± 0.09 | 0.17 ± 0.12 |
Testes | 1.16 ± 0.12 | 1.33 ± 0.18 | 1.27 ± 0.24 | 1.30 ± 0.32 | 1.21 ± 0.25 |
2.3.4. Histopathology Examination
3. Experimental Section
3.1. Preparation of ATTM
3.2. Animals
3.3. In Vivo Efficacy in a Mouse Model
3.4. Acute Oral Toxicity in Mice
3.5. Subchronic Oral Toxicity
3.5.1. Experimental Design
3.5.2. Clinical Signs, Body Weights and Food Consumption
3.5.3. Blood Analysis
3.5.4. Necropsy, Organ Weight and Histopathology
3.6. Statistical Analysis
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Zhang, C.; Yi, Y.; Chen, J.; Xin, R.; Yang, Z.; Guo, Z.; Liang, J.; Shang, R. In Vivo Efficacy and Toxicity Studies of a Novel Antibacterial Agent: 14-O-[(2-Amino-1,3,4-thiadiazol-5-yl)Thioacetyl] Mutilin. Molecules 2015, 20, 5299-5312. https://doi.org/10.3390/molecules20045299
Zhang C, Yi Y, Chen J, Xin R, Yang Z, Guo Z, Liang J, Shang R. In Vivo Efficacy and Toxicity Studies of a Novel Antibacterial Agent: 14-O-[(2-Amino-1,3,4-thiadiazol-5-yl)Thioacetyl] Mutilin. Molecules. 2015; 20(4):5299-5312. https://doi.org/10.3390/molecules20045299
Chicago/Turabian StyleZhang, Chao, Yunpeng Yi, Jiongran Chen, Rensheng Xin, Zhen Yang, Zhiting Guo, Jianping Liang, and Ruofeng Shang. 2015. "In Vivo Efficacy and Toxicity Studies of a Novel Antibacterial Agent: 14-O-[(2-Amino-1,3,4-thiadiazol-5-yl)Thioacetyl] Mutilin" Molecules 20, no. 4: 5299-5312. https://doi.org/10.3390/molecules20045299
APA StyleZhang, C., Yi, Y., Chen, J., Xin, R., Yang, Z., Guo, Z., Liang, J., & Shang, R. (2015). In Vivo Efficacy and Toxicity Studies of a Novel Antibacterial Agent: 14-O-[(2-Amino-1,3,4-thiadiazol-5-yl)Thioacetyl] Mutilin. Molecules, 20(4), 5299-5312. https://doi.org/10.3390/molecules20045299