Table 2. Assessing resistance acquisition by various gram-positive and -negative bacteria in vitro and in mice for standard antibiotics and new peptidomimetics.
| Gram-positive clinical isolates | Gram-negative clinical isolates | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MSSA | MRSA | P. aeruginosa 15643 | E. coli K12 | E. coli 13090 | E. coli MCR1 | |||||||||
| d0 | d14 | d0 | d14 | d4 mice with septic kidneys |
d6 mice with skin abscess |
d0 | d14 | d0 | d14 | d0 | d14 | d0 | d14 | |
| Pep15 | 4 (4.6) | 4 (4.6) | 2 (2.3) | 2 (2.3) | - | - | 8 (9.2) | 32 (36.8) | 4 (4.6) | 16 (18.4) | 8 (9.2) | 16 (18.4) | 8 (9.2) | 16 (18.4) |
| Pep16 | 4 (4.5) | 4 (4.5) | 4 (4.5) | 4 (4.5) | 4 (4.5) | 8 (9) | 8 (9) | 16 (18) | 4 (4.5) | 16 (18) | 8 (9) | 16 (18) | 8 (9) | 8 (9) |
| Pep18 | 16 (16.4) |
64 (65.6) | 8 (8.2) | 16 (16.4) | - | - | 16 (16.4) | 16 (16.4) | 16 (16.4) | 64 (65.6) | 16 (16.4) | 64 (65.6) | 16 (16.4) | 64 (65.6) |
| Pep19 | 4 (4.4) | 4 (4.4) | 4 (4.4) |
8 (8.8) |
8 (8.8) |
16 (16.2) |
8 (8.8) | 16 (16.2) | 4 (4.4) | 8 (8.8) | 8 (8.8) | 8 (8.8) | 8 (8.8) | 8 (8.8) |
| Vancomycin |
0.5 (0.7) |
1 (1.4) |
1 (1.4) | 1 (1.4) | 1 (1.4) | 1 (1.4) | - | - | - | - | - | - | ||
| Rifampicin |
0.03 (0.025) |
1,024 (843) |
1,024 (843) |
1,024 (843) |
- | - | - | - | - | - | - | - | ||
| Polymyxin B | - | - | - | - | - | - | 0.5 (0.65) | 1 (1.3) | 0.5 (0.65) | 1 (1.3) | 1 (1.3) | 1 (1.3) | 2 (2.6) | 8 (10.4) |
| Colistin | 0.5 (0.65) | 1 (1.3) | 1 (1.3) | 1 (1.3) | - | - | ||||||||
| Fosfomycin | - | - | - | - | - | - | 0.2 mM (0.027 g.L−1) |
405 mM (56 g.L−1) |
0.2 mM (0.027 g.L−1) |
405 mM (56 g.L−1) |
0.2 mM (0.027 g.L−1) |
202 mM (28 g.L−1) |
0.2 mM (0.027 g.L−1) |
202 mM (28 g.L−1) |
Concentrations are provided in μM and corresponding mg. L−1 in parentheses unless otherwise indicated. In vitro testing: 14 d serial passages with a sub-MIC of drug on MDR gram-positive and -negative pathogens; rifampicin and fosfomycin were positive controls for resistance acquisition by gram-positive and -negative bacteria, respectively. The greatest frequency of resistance acquisition occurred with Pep18, which lacks amino acid analogs. Testing resistance in infected mice: IV (approximately 5 × 108 CFUs) or subcutaneous (approximately 5 × 109 CFUs) MRSA injections, and subsequent treatments with 1.5 mg.kg−1 of Pep16, Pep19, or vancomycin. MIC assessments were done on sets of 15 independent colonies, 5 per mouse, and the results for both treatments times were similar. IV: on colonies isolated from mice kidneys, extracted 4 d after the infection, treated for a mild sepsis by a single injection at either 3 h or 15 h post infection. Subcutaneous: on colonies isolated from cutaneous abscesses from mice, extracted 6 d after the infection, treated once by IV 24 h post infection. Data associated with this Table can be found in S5 Fig. The data are representative of independent biological triplicates.
Abbreviations: “-,” undetermined; CFU, colony-forming unit; MIC, minimal inhibitory concentration; MRSA (Mu3), methicillin-resistant S. aureus; MSSA (Newman), methicillin-susceptible S. aureus