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

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

Schematic representation of the active site of PDF.

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

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.

Structure of PCLNA.

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.

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

Chemical structures of compounds 1 through 5.

Chemical structure of actinonin.

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

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

Structures of the compounds developed by Thorarensen and coworkers.

Chemical structure of BB-3497

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

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

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.

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

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

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.

(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.

Fatty acid synthesis in E. coli.

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).

Chemical structures of compounds 4, 29, and 30.

Chemical structures of compounds 1 and 5.

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

Chemical structure of phosphinate derivative 1 (compound 1).

Chemical structure of the compound SProC5.

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.

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.

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

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.