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Chapter 39 : Peptidyl Deformylase Inhibitors

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Abstract:

The chapter mainly focuses on peptidyl deformylase (PDF) inhibitors. Bacterial peptidyl deformylase (PDF) belongs to subfamily 3, with at least two other members: thermolysin and matrix metalloproteases (MMPs), namely, matricins and/or metzincins. Two classes of aminopeptidases are described: MAP-1 and MAP-2. MAP-1 and MAP-2 have similar specificities, with methionine cleavage depending on the nature of the second amino acid. MAP-2 is inhibited by fumagillin and TNP-470. Bacterial PDFs are small monomers composed of about 160 to 200 amino acids with few variations in the lengths of their N- and C-terminal extremities. Deformylase inhibitors can be classified in three groups: natural compounds, hydroxamate derivatives, and miscellaneous compounds. The hydroxamic moiety is crucial for the antibacterial activity, but the pseudopeptide backbone can be altered, such as the methionine-like structure. In addition to the antibacterial activity, it has been shown that actinonin inhibits several aminopeptidases, such as human seminal alanyl aminopeptidase, as well as tumor growth. A series of β-sulfonyl and β-sulfinyl hydroxamic acid derivatives has been shown to be potent PDF inhibitors with in vitro antibacterial activity. A macrocyclic deformylase peptide inhibitor was reported. The improved affinity for PDF is probably due to the rigidity introduced by cyclization. Some compounds exhibited good activity against , , and but weak activity against ; they were inactive against .

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39

Key Concept Ranking

Chemicals
0.9670189
Antibacterial Agents
0.9470203
Amino Acids
0.8508245
Hydroxamic Acids
0.7445489
Proteins
0.69189733
Gram-Negative Bacteria
0.68184614
0.9670189
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Figures

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Figure 1

Fumagillin and TNP-470

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 2

Ferrous ion binding

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 3

Formylation-deformylation cycle

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 4

Protein synthesis process

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 5

Basic structure of hydroxamic acid

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 6

Classification of inhibitors of PDF

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 7

Actinonin

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 8

Actinonin interactions in PDF active site

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 9

Galardin

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 10

VRC-3324 and VRC-3852

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 11

VRC-4232 and VRC-4307

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 12

Metabolism of VRC-4232

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 13

VRC-3375

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 14

Interaction of VRC-4237 with the active site

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 15

VRC-4249 and VRC-4299

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 16

LBM-415

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 17

BB-3497

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 18

BB-3497 in the PDF active site

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 19

BB-83698

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 20

Phosphonate derivatives

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 21

PCLNA and active site

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 22

Derivatives from Pharmacia

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 23

NB series of anti-PDF

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 24

Structure of PDF inhibitors

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 25

β-Sulfonyl and β-sulfinyl hydroxamate derivatives

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 26

Thyropropic analogs

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 27

General structure of biaryl analogs

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 28

Biaryl acid

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 29

Biaryl derivatives

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 30

Thiopeptides (1)

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 31

Thiopeptides (2)

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 32

Isoxazole hydroxamates

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 33

Benzothiazole hydroxamic acid derivatives

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 34

Quinazoline derivatives

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 35

Bicyclic peptide PDF inhibitors

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 36

Sch-382583

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 37

Thioxo-4-thiazolidinone

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Figure 38

Macrocyclic peptide PDF inhibitors

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Tables

Generic image for table
Table 1

Structure of PDFs of two higher plants

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
Generic image for table
Table 2

PDF versus metal ions

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
Generic image for table
Table 3

In vitro activity of actinonin

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 4

Inhibition of various metalloproteases by actinonin

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 5

values for various groups

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 6

Pharmacokinetics of VRC-4232 and VRC-4307 in mice

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 7

In vitro activity of VRC-3375

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 8

Pharmacokinetics of VRC-3375 in mice

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 9

In vitro activity of the α-fluoro succinate hydroxamate

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 10

In vitro activity of VRC-4887

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 11

In vitro activity of VRC-4887 against resistant isolates

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 12

In vitro activity against mycobacteria and intracellular and atypical pathogens

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 13

In vivo efficacy of VRC-4887

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 14

Antipneumococcal activity of VRC-4887 (administered orally)

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 15

Pharmacokinetics of VRC-4887 in mice

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 16

In vitro activity of LBM-415 against common pathogens

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 17

Pharmacokinetics of LBM-415 in rodents

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 18

In vitro activity of BB-3497 against common pathogens causing respiratory tract infections

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 19

In vitro activities against spp.

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 20

In vitro activities of keto PDF inhibitors against intracellular and atypical pathogens

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 21

In vitro activity of BB-83698

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 22

Pharmacokinetics of BB-83698 in humans after intravenous administration

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 23

Stability of anti-PDF analogs in various media

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 24

In vitro activities of Ro-66-0376 and Ro-66-6976

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 25

Binding affinity for PDFs

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39
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Table 26

Kinetic parameters of dithiol compounds as time-dependent inhibitors

Citation: Bryskier A, Lowther J. 2005. Peptidyl Deformylase Inhibitors, p 991-1010. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch39

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