TABLE 1.
Antibacterial activities of novel macrolone compounds against key respiratory pathogens, grouped by species and resistance mechanisma
| Compound (compound no.) | MIC90 (μg/ml) |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
|
S. pneumoniae |
S. pyogenes |
S. aureus |
H. influenzae (n = 12) | ||||||||
| Erys (n = 10) | M (n = 13) | MLSb (n = 13) | Erys (n = 10) | M (n = 12) | iMLSb (n = 14) | cMLbS (n = 13) | Erys (n = 11) | M (n = 10) | iMLSb (n = 12) | ||
| Azithromycin | 0.03 | 8 | >64 | 0.06 | 4 | >64 | >64 | 1 | >64 | >64 | 2 |
| Clarithromycin | 0.03 | 8 | >64 | ≤0.015 | 4 | >64 | >64 | 0.125 | 32 | >64 | 16 |
| Telithromycin | ≤0.015 | 0.5 | 0.5 | ≤0.015 | 0.5 | 4 | 32 | 0.06 | 0.25 | 0.06 | 2 |
| Clindamycin | ≤0.015 | 0.03 | >64 | 0.03 | 0.03 | 0.3 | >64 | 0.06 | 0.125 | 0.125 | 32 |
| Ciprofloxacin | 0.5 | 1 | 1 | 0.25 | 0.5 | 1 | 0.5 | >64 | 0.5 | >64 | ≤0.015 |
| azi-NN-Cl (1) | 0.125 | 0.5 | 0.125 | 0.06 | 1 | 0.25 | 0.5 | 2 | 1 | 2 | 8 |
| azi-NMeN-Cl (2) | ≤0.015 | ≤0.015 | 0.25 | ≤0.015 | 0.25 | 0.125 | 1 | 1 | 2 | 2 | 8 |
| azi-NmeN (3) | ≤0.015 | 0.03 | 0.03 | ≤0.015 | 0.25 | 0.25 | 2 | 2 | 2 | 2 | 8 |
| azi-NEtN-Cl (4) | 0.03 | 1 | 1 | 0.06 | 2 | 0.25 | 2 | 1 | 4 | 4 | 32 |
| azi-NN-Cl-Qme (5) | ≤0.015 | 0.06 | 0.06 | 0.03 | 0.5 | 0.25 | 0.25 | 1 | >8 | 64 | 16 |
| azi-NMeN-Cl-Qme (6) | ≤0.015 | 0.06 | 0.06 | 0.06 | 0.03 | 0.25 | 1 | 4 | 16 | 32 | 16 |
| azi-ON-Cl (7) | ≤0.015 | ≤0.015 | 0.125 | ≤0.015 | 0.03 | ≤0.015 | 0.25 | 0.5 | 0.5 | 0.5 | 2 |
| azi-ON (8) | ≤0.015 | 0.06 | 1 | ≤0.015 | 0.06 | 0.03 | 1 | 0.5 | 1 | 1 | 2 |
| clari-ON-Cl (9) | ≤0.015 | ≤0.015 | 0.25 | ≤0.015 | ≤0.015 | 0.03 | 0.5 | 0.5 | 0.5 | 1 | 4 |
| clari-ON (10) | ≤0.015 | ≤0.015 | 4 | ≤0.015 | 0.25 | 0.06 | 2 | 4 | 0.5 | 2 | 8 |
| claric-ON-Cl (11) | ≤0.015 | ≤0.015 | 0.25 | ≤0.015 | ≤0.015 | 0.06 | 0.5 | 0.5 | 1 | 2 | 4 |
| claric-ON (12) | ≤0.015 | 0.03 | 0.125 | ≤0.015 | ≤0.015 | 0.06 | 0.25 | 0.5 | 1 | 2 | 2 |
| azi-OO-Cl (13) | ≤0.015 | ≤0.015 | 0.5 | ≤0.015 | 0.03 | ≤0.015 | 1 | 0.5 | 1 | 0.5 | 2 |
| azi-OO (14) | ≤0.015 | 0.03 | 0.25 | ≤0.015 | 0.06 | ≤0.015 | 1 | 0.25 | 0.5 | 1 | 2 |
| clari-OO-Cl (15) | ≤0.015 | 0.06 | 1 | ≤0.015 | 0.06 | 0.06 | 2 | 0.5 | 0.5 | 1 | 8 |
| clari-OO (16) | ≤0.015 | ≤0.015 | 0.5 | ≤0.015 | ≤0.015 | ≤0.015 | 1 | 1 | 0.25 | 4 | 8 |
| claric-OO-Cl (17) | ≤0.015 | ≤0.015 | 0.25 | ≤0.015 | ≤0.015 | 0.03 | 0.5 | 1 | 1 | 1 | 8 |
| claric-OO (18) | ≤0.015 | 0.03 | 0.25 | ≤0.015 | 0.125 | 0.125 | 1 | 0.5 | 1 | 4 | 4 |
| azi-OON-Cl (19) | ≤0.015 | ≤0.015 | 0.25 | ≤0.015 | ≤0.015 | ≤0.015 | 0.5 | 0.5 | 0.5 | 0.5 | 2 |
| azi-OON (20) | ≤0.015 | 0.03 | 0.5 | ≤0.015 | 0.06 | ≤0.015 | 0.25 | 0.25 | 0.25 | 0.25 | 8 |
| azi-OON-F (21) | ≤0.015 | 0.03 | 1 | 0.03 | 0.25 | 0.06 | 4 | 0.5 | 0.5 | 1 | 32 |
| clari-OON-Cl (22) | ≤0.015 | 0.06 | 4 | 0.03 | 0.125 | 2 | 2 | 1 | 2 | 8 | 8 |
| claric-OON-Cl (23) | ≤0.015 | ≤0.015 | 0.125 | ≤0.015 | ≤0.03 | ≤0.015 | 0.25 | 0.25 | 0.5 | 1 | 4 |
| 8a-OON-Cl (24) | ≤0.015 | ≤0.015 | 0.125 | ≤0.015 | 0.03 | 0.03 | 0.5 | 0.25 | 0.25 | 0.25 | 4 |
| eox-OON-Cl (25) | ≤0.015 | ≤0.015 | 0.5 | ≤0.015 | ≤0.015 | ≤0.015 | 0.5 | 0.25 | 0.25 | 0.5 | 2 |
| rox-OON-Cl (26) | 0.06 | 0.125 | 2 | 0.06 | 0.06 | 0.25 | 2 | 0.5 | 1 | 4 | 4 |
The structures of all compounds are provided in the supplemental material. n, number of isolates tested; Erys, erythromycin susceptible; iMLSb, inducible resistance to macrolide, lincosamide, and streptogramin B antibiotics; cMLSb, constitutive resistance to macrolide, lincosamide, and streptogramin B antibiotics; M, efflux-mediated macrolide. Boldface data represent compounds that were evaluated in vivo. The abbreviations of the compounds represent the scaffold heteroatom composition of the linker and the presence of the halogen atom at the quinolone moiety. Macrolide scaffolds are as follows: azi, azithromycin; clari, clarithromycin; claric, clarithromycin carbamate; 8-a, 8-a-lactame; eox, erythromycin oxime; rox, roxithromycin.