Table 1 Minimum inhibitory concentrations (MICs), in vivo efficacy and nephrotoxicity of polymyxin B, colistin, and representative synthetic lipopeptides.

From: A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens

 

MIC (µg/mL)

  
 

P. aeruginosa

A. baumannii

K. pneumoniae

  

Lipopeptide

Position

ATCC 27853

FADDI-PA025

FADDI-PA038*

ATCC 19606

FADDI-AB030*

FADDI-AB034*

FADDI-KP032*

FADDI-KP065*

Δlog10 CFU/mLblood**

Kidney histopathology (SQS Score)***

N-terminus

3

6

7

PMB

6-MO/7-MH

Dab

D-Phe

Leu

0.5

2

1

1

0.25

0.5

0.5

0.25

−2.69

+2 → +5 (3/3 mice)

COL

6-MO/7-MH

Dab

D-Leu

Leu

0.5

2

1

1

0.5

0.5

1

0.25

−2.39

+2 → +5 (3/3 mice)

Modification of positions 6 and 7

 F100

Octanoyl

Dab

D-Leu

Thr

0.5

>32

0.5

4

1

2

0.25

<0.125

−3.01

0 (3/3 mice)

 F124

Octanoyl

Dab

D-Leu

Ala

0.5

>32

0.5

1

1

0.5

0.25

<0.125

−2.92

0 (3/3 mice)

 F224

Octanoyl

Dab

D-Phe

Thr

1

16

0.5

1

0.25

0.5

0.5

<0.125

−3.38

0 (3/3 mice)

 F225

Octanoyl

Dab

D-Leu

Val

1

4

1

0.5

0.25

0.25

<0.125

<0.125

−2.86

0 (3/3 mice)

 F226

Octanoyl

Dab

D-Nle

Thr

1

16

1

2

0.5

1

<0.125

<0.125

−3.24

+1 (1/3 mice)

 F227

Octanoyl

Dab

D-Leu

Ser

0.5

>32

>32

8

4

4

0.25

0.25

−1.04

0 (3/3 mice)

 F228

Octanoyl

Dab

D-Thr

Leu

0.25

32

32

>32

16

32

2

16

−3.39

+1 (1/3 mice)

 F229

Octanoyl

Dab

D-Val

Thr

>32

>32

>32

>32

32

>32

1

2

n.d.

0 (3/3 mice)

 F230

Octanoyl

Dab

D-Thr

Thr

>32

>32

>32

>32

>32

>32

16

32

n.d.

0 (3/3 mice)

 F319

Octanoyl

Dab

D-Leu

Abu

0.5

4

4

0.5

0.5

<0.125

0.25

<0.125

−3.44

+1 (1/3 mice)

Modification of positions 3, 6, and 7

 F085

Octanoyl

D-Dab

D-Leu

Thr

0.5

8

0.5

1

0.25

2

0.25

<0.125

−2.16

+2 (2/2 mice)†

 F183

Octanoyl

D-Ser

D-Leu

Thr

4

>32

4

1

<0.125

0.25

<0.125

0.25

n.d.

0 (3/3 mice)

 F251

Octanoyl

Dap

D-Leu

Thr

0.5

8

0.5

0.5

0.25

0.25

<0.125

<0.125

−1.57

0 (3/3 mice)

 F252

Octanoyl

Orn

D-Leu

Thr

0.5

>32

2

1

0.5

1

<0.125

0.5

−1.98

+1 (2/3 mice)

 F271

Octanoyl

Dap

D-Leu

Ala

0.5

16

1

0.5

0.25

0.25

<0.125

<0.125

−2.27

0 (3/3 mice)

 F287

Octanoyl

Dap

D-Leu

Abu

0.5

2

0.5

0.25

0.25

<0.125

<0.125

<0.125

−2.42

0 (3/3 mice)

 F300

Octanoyl

D-Dap

D-Leu

Thr

0.25

4

1

0.25

<0.125

<0.125

<0.125

<0.125

−1.53

+2 (3/3 mice)

Modification of N-terminus positions 3, 6 and 7

 F314

Nonanoyl

Dap

D-Leu

Abu

1

>32

2

0.5

0.5

2

<0.125

0.25

−2.82

+1 (3/3 mice)

 F342

Hexanoyl

Dap

D-Leu

Abu

0.5

2

1

2

1

1

0.25

0.5

0.17

0 (3/3 mice)

 F350

2-Chlorobenzoyl

Dap

D-Leu

Abu

0.5

4

2

8

4

4

1

0.5

n.d.

n.d.

 F360

2,6-Dichlorobenzoyl

Dap

D-Leu

Abu

0.5

4

4

16

4

8

1

0.5

−0.07

0 (3/3 mice)

 F365

2,4-Dichlorobenzoyl

Dap

D-Leu

Abu

0.5

0.5

0.5

0.25

0.25

0.25

<0.125

<0.125

−3.44

0 (3/3 mice)

 F371

3-Chlorobenzoyl

Dap

D-Leu

Abu

0.5

1

2

4

1

1

0.5

1

−3.33

0 (3/3 mice)

 F378

4-Chlorobenzoyl

Dap

D-Leu

Abu

0.5

2

1

1

1

0.25

0.25

1

−3.23

0 (3/3 mice)

 F379

Benzoyl

Dap

D-Leu

Abu

1

>32

4

8

2

8

2

2

−2.67

n.d.

 F381

3,5-Dichlorobenzoyl

Dap

D-Leu

Abu

0.25

0.5

1

0.5

0.25

0.25

<0.125

0.5

−3.45

+1 (1/3 mice)

 F383

4-Methylbenzoyl

Dap

D-Leu

Abu

0.5

2

1

2

2

2

1

1

−3.02

0 (3/3 mice)

 F448

4-Chloro-2-fluorobenzoyl

Dap

D-Leu

Abu

0.5

1

0.5

2

1

0.5

<0.125

0.25

−3.06

0 (3/3 mice)

 F449

2-Chloro-4-fluorobenzoyl

Dap

D-Leu

Abu

0.5

2

1

4

1

1

0.25

0.25

−2.32

0 (3/3 mice)

 F477

Biphenyl

Dap

D-Leu

Abu

1

1

1

1

0.5

0.25

0.25

0.25

−3.89

+1 (1/3 mice)

  1. PMB polymyxin B, COL colistin, 6-MO (S)-6-methyloctanoyl, 7-MH 7-methylheptanoyl, n.d. not determined.
  2. *Carbapenem-resistant isolates. ** Reduction in bacterial load of P. aeruginosa ATCC 27853 in blood (CFU/mL blood) at 4 h in a neutropenic mouse bloodstream infection model after a single IV dose of the lipopeptide (4 mg/kg, n = 3). Only lipopeptides with an MIC < 2 μg/mL against P. aeruginosa ATCC 27853 were tested. Δlog10 CFU/mL blood = log10 [treated] CFU/mL blood – log10 [control] CFU/mL blood. Mean values of three replicates are shown. ***Mouse nephrotoxicity model (n = 3). Lipopeptides were dosed 72 mg/kg/d subcutaneously in six divided doses every 2 h.
  3. Semi-Quantitative Score (SQS): SQS 0 = no significant change (overall score, <1); SQS + 1 = mild damage (overall score, 1 to <15);  SQS + 2 = mild to moderate damage (overall score, 15 to <30); SQS + 3 = moderate damage (overall score, 30 to <45); SQS + 4 = moderate to severe damage (overall score, 45 to <60); and SQS + 5 = severe damage (overall score, >60)16.
  4. †One mouse had to be humanely euthanized before completion of the study.
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