TABLE 1 .
Interaction of 4′-O-alkyl derivatives with polymorphic residues 1408 and 1491 in the drug binding pocket
| Drug | IC50 (mg/liter) with mutant bacterial A sites in the ribosomea: |
|||
|---|---|---|---|---|
| Wild-type | G1491C | G1491A | A1408G | |
| Paromomycin | 0.02 ± 0.01 | 10.42 ± 2.86 | 0.57 ± 0.09 | 0.26 ± 0.04 |
| 4′ Deoxy paromomycin | 0.05 ± 0.01 | 28.6 ± 0.9 | 2.4 ± 0.1 | 0.89 ± 0.4 |
| 4′,6′-O-(3-Phenylpropylidene) paromomycin | 0.10 ± 0.03 | 124.1 ± 0.1 | 43.0 ± 11.3 | 3.8 ± 2.4 |
| 4′-O-(3-Phenylpropyl) paromomycin | 0.20 ± 0.07 | 200.73 ± 25.84 | 51.26 ± 15.72 | 14.52 ± 5.77 |
| Compound 13 | 0.40 ± 0.11 | 229.92 ± 32.26 | 62.13 ± 9.35 | 21.73 ± 5.04 |
| Compound 12 | 0.30 ± 0.03 | 348.38 ± 23.69 | 90.87 ± 16.44 | 24.33 ± 5.82 |
| Compound 11 | 0.14 ± 0.02 | 288.85 ± 148.66 | 45.54 ± 23.65 | 11.74 ± 4.94 |
| Compound 14 | 0.14 ± 0.04 | 268.65 ± 18.91 | 44.68 ± 3.15 | 12.34 ± 1.57 |
| Compound 10 | 0.08 ± 0.03 | 258.93 ± 31.67 | 40.77 ± 16.93 | 8.83 ± 3.10 |
| Compound 22 | 0.12 ± 0.08 | 180.47 ± 45.33 | 41.77 ± 7.39 | 5.42 ± 1.23 |
| Compound 9 | 0.22 ± 0.05 | 242.42 ± 6.20 | 68.99 ± 11.53 | 14.21 ± 6.74 |
| Compound 21 | 0.89 ± 0.24 | 522.20 ± 44.59 | 119.58 ± 49.65 | 32.57 ± 9.13 |
| Compound 16 | 0.05 ± 0.02 | 152.22 ± 51.28 | 5.99 ± 1.19 | 1.93 ± 0.38 |
| Compound 15 | 0.73 ± 0.19 | >700 | 143.69 ± 15.86 | 38.12 ± 5.73 |
| Compound 17 | 0.03 ± 0.01 | 67.35 ± 21.25 | 2.57 ± 0.48 | 0.87 ± 0.07 |
| Compound 18 | 0.20 ± 0.03 | 167.43 ± 11.30 | 11.45 ± 0.55 | 4.48 ± 0.32 |
| Compound 19 | 1.57 ± 0.42 | 585.91 ± 16.81 | 83.71 ± 18.04 | 5.47 ± 1.24 |
| Compound 20 | 10.87 ± 0.53 | >700 | 529.40 ± 76.03 | 80.44 ± 20.17 |
a
The interaction of 4′-O-alkyl derivatives with the bacterial A site of the drug binding pocket is measured by the drug concentrations (in milligrams per liter) required to inhibit in vitro synthesis of functional firefly luciferase to 50% (IC50s). The values are means ± standard deviations (SD) for experiments performed in triplicate.