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. 2019 Jul 9;17(7):e3000337. doi: 10.1371/journal.pbio.3000337

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