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Chapter 27 : New Antibacterial Drugs in Development That Act on Novel Targets

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Abstract:

This chapter presents a survey of some new antibacterial agents that act on novel targets. In recent years, bacterial resistance to antibacterial drugs has become a global public health threat and has been increasing due to the use, overuse, and misuse of broad-spectrum antibiotics and the ability of bacteria to exchange resistance genes. Cationic peptides exhibit a broad spectrum of activity against various targets, including gram-negative and gram-positive bacteria, fungi, enveloped viruses, and parasites. Aminoacyl-tRNA synthetases play a crucial role in protein synthesis in all organisms, and selective inhibition of the bacterial enzymes has potential for the discovery of new antibacterial agents. Uropathogenic strains of Escherichia coli are the primary causative agents of urinary tract infections in humans. Combinatorial chemistry has had a significant impact on the discovery of new antibacterial drugs. Most of the successes have come from the use of small libraries to explore a specific pharmacophore. This kind of application has been exemplified in the chapter with the discovery of actinonin, a selective peptide deformylase inhibitor. The traditional method for obtaining new antibacterial drugs has been to synthesize analogues of existing antibacterial drugs and evaluate them for improved therapeutic activity by using in vitro and in vivo methods that detect antibacterial activity against gram-positive and gram-negative organisms.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.1
Figure 27.1

Some of the novel targets for new antibacterial agents currently under development.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.2
Figure 27.2

Schematic representation of the active site of PDF.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.3
Figure 27.3

Classification of peptidases according to the site of amide bond cleavage.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.4
Figure 27.4

Standard nomenclature for substrate residues and their corresponding binding sites. Reprinted from I. Schechter and A. Berger, Biochem. Biophys. Res. Commun. 27:157–162, 1967, with permission from the publisher.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.5
Figure 27.5

Structure of PCLNA.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.6
Figure 27.6

Proposed mechanism of PDF-mediated deformylation based on the native (top left) and complexed (bottom right) structures. Reprinted from B. Hao, W. Gong, P. T. Ravi Rajagopalan, Y. Zhou, D. Pei, and M. K. Chan, Biochemistry 38:4712–4719, 1999, with permission from the publisher.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.7
Figure 27.7

Structure of 2-thiomethyl- Nle-Arg-OCH3 (TNR) as the trifluorocetate salt.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.8
Figure 27.8

Chemical structures of compounds 1 through 5.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.9
Figure 27.9

Chemical structure of actinonin.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.10
Figure 27.10

Chemical structure of (R)-3-(phenylsulfonyl) heptanoic acid hydroxamide.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.11
Figure 27.11

Figure 27.11 General structure of (5-chloro-2-oxo-1,4- dihydro-2H-quinazolin-3-yl)acetic acid hydrazide derivatives.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.12
Figure 27.12

Structures of the compounds developed by Thorarensen and coworkers.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.13
Figure 27.13

Chemical structure of BB-3497

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.14
Figure 27.14

Chemical structure of N-CBZ-Leu-norleucinal (calpeptin).

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.15
Figure 27.15

(Left) General structure of biaryl acid analogs. (Middle and right) Chemical structures of compounds 1 and 4.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.16
Figure 27.16

A typical TCS. Reprinted from J. F. Barrett and J. A. Hoch, Antimicrob. Agents Chemother. 42:1529–1536, 1998, with permission from the American Society for Microbiology.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.17
Figure 27.17

Chemical structures of closantel, and 3,3',4',5-tetrachlorosalicylanilide.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.18
Figure 27.18

Chemical structures of bisamidino indole derivative 1, amidino benzimidazole derivative 2, and diaryltriazole 3.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.19
Figure 27.19

Peptide stack self-assembly of flat, cyclic, eight-residue D,L-α-peptides forms β-sheet-like, tubular, open-ended supramolecular structures. Reprinted from S. Fernandez-Lopez, H. S. Kim, E. C. Choi, M. Delgado, J. R. Granja, A. Khasanov, K. Kraehenbuehl, G. Long, D. A. Weinberger, K. M. Wilcoxen, and M. R. Ghadiri, Nature 412:452–455, 2001, with permission from the publisher.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.20
Figure 27.20

(a) Chemical structures of channel-forming cyclic β-peptide subunits 1 through 3 represented in a flat ring-shaped conformation. (b) Putative structure of selfassembled transmembrane channels formed from cyclic β-peptides 1 through 3. The tubular channel ensemble is represented with the expected parallel ring stacking and extensive intersubunit hydrogen bonding. (For clarity, most side chains are omitted.) Reprinted from T. D. Clark, L. K. Buehler, and M. R. Ghadiri, J. Am. Chem. Soc. 120:651–656, 1998, with permission from the publisher.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.21
Figure 27.21

Fatty acid synthesis in E. coli.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.22
Figure 27.22

Chemical structures of cerulenin, thiolactomycin, diazaborine, isoniazid, triclosan, 2,9-disubstituted 1,2,3,4-tetrahydropyrido[3,4-b]indoles, 1,4-disubstituted imidazoles, and the aminopyridine derivative (compound 9).

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.23
Figure 27.23

Chemical structures of compounds 4, 29, and 30.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.24
Figure 27.24

Chemical structures of compounds 1 and 5.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.25
Figure 27.25

Chemical structures of compounds 1 (SB-219383), 2, 3, and 11.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.26
Figure 27.26

Chemical structure of phosphinate derivative 1 (compound 1).

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.27
Figure 27.27

Chemical structure of the compound SProC5.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.28
Figure 27.28

Bicyclic β-lactam compounds of the general structure 1 superimpose well with the structure of a peptide whose crystal structure complexed with PapD was determined by X-ray crystallography.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.29
Figure 27.29

A unique deacetylase catalyzes the second step of lipid A biosynthesis. The LpxA-catalyzed acylation that occurs before deacetylation is reversible and has an unfavorable equilibrium constant.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.30
Figure 27.30

Structures of the LpxC inhibitors BB-78484 and BB-78485.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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Image of Figure 27.31
Figure 27.31

Steps in the research and development process for antibacterial agents. Reprinted from I. Chopra, Curr. Opin. Microbiol. 1:495–501, 1998, with permission from the publisher.

Citation: Mascaretti O. 2003. New Antibacterial Drugs in Development That Act on Novel Targets, p 329-354. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch27
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