Table 2. In Vitro and Cell-Based Activities of AMA Analogs (10–23), Bearing Substitution at the C-Terminal Aspartic Acide,f.
| compound | Kd,Zn2 (nM) | IC50 (μM)a |
RC
(μg/mL) in MHBb,c |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|
| NDM-1 - Zn | NDM-1 + Zn | VIM-2 - Zn | IMP-7 - Zn | NDM-1 | VIM-1 | VIM-2 | IMP-7 | IMP-27 | ||
| AMA | 0.1 ± 0.02 | 12,800 ± 722 | 13 ± 0.2 | 3000 | 53,000 | 8 | 8 | 8 | 32 | 32 |
| 10 | <0.0003 | 173.3 ± 3.9 | 21.7 ± 3.9 | 136 ± 5 | >500 | 8 | 8 | 8 | 16 | 16 |
| 11 | 0.2 ± 0.05 | 21.5 ± 0.8 | 15.6 ± 0.2 | 22 ± 1 | 328 ± 15 | 32 | 32 | 16 | >64 | >64 |
| 12 | 4.4 ± 1.8 | 5.8 ± 0.5 | 403.8 ± 18.2 | -d | - | 32 | >64 | >64 | >64 | >64 |
| 13 | - | >1000 | >100 | - | - | 64 | >64 | 64 | >64 | >64 |
| 14 | 2.6 ± 0.4 | 184.6 ± 7.8 | 112.4 ± 4.8 | 246 ± 17 | >500 | 32 | 64 | 16 | 32 | >64 |
| 15e | 2.3 ± 0.4 | 98.6 ± 4.0 | 56.1 ± 2.5 | 361 ± 29 | >500 | 32 | 16 | 8 | 16 | 32 |
| 16 | 1.0 ± 0.1 | >1000 | 18.3 ± 0.7 | - | - | 16 | 16 | 16 | >64 | >64 |
| 17 | 24 ± 6 | >1000 | >100 | - | - | >64 | >64 | 64 | >64 | >64 |
| 18 | 18.0 ± 11.1 | >1000 | >100 | - | - | >64 | >64 | >64 | >64 | >64 |
| 19 | 4.5 ± 1.75 | >1000 | 80 ± 0.7 | - | - | 32 | 32 | 16 | >64 | >64 |
| 20 | 0.64 ± 0.17 | 172 ± 1.5 | 38 ± 1.8 | - | - | 16 | 16 | 8 | >64 | >64 |
| 21 | 10.8 ± 8.1 | 25.1 ± 8.3 | 54.0 ± 5.6 | - | - | 64 | >64 | 64 | >64 | >64 |
| 22 | 9.5 ± 6.5 | 23 ± 3.6 | 283 ± 27.4 | - | - | >64 | >64 | 64 | >64 | >64 |
| 23 | 4.2 ± 2.5 | 9.7 ± 1.7 | 42.2 ± 4.1 | - | - | 64 | 32 | 16 | >64 | >64 |
a
In vitro assay.
b
Rescue concentration was determined at the susceptibility breakpoint of meropenem (2 μg/mL).
c
Increases in rescue concentration values are highlighted as follows: ≤ 2 increases bolded.
d
Hyphens represent values not determined, as the RC against ndm-1-containing E. coli is ≥64 μg/mL.
e
MIC of 64 μg/mL.
f
RC, rescue concentration; MHB Mueller–Hinton Broth.