A Structural Model of the Chloramphenicol Receptor Site

Abstract

I . I NTRODUCTI ONHaving a relatively simple chemical structure, chloramphenicol became the first antibiotic to be synthesized by organic-chemical methods (Controulis, Rebstock and Crooks, 1949). A large number of chloramphenicol derivatives was subsequently prepared. Kolosov, Shemiakin, Khokhlov and Gurevich tabulated, in 1961, more than 500 such compounds, and the total number of known chloramphenicol derivatives is, by now, much greater.For many of these substances, data on their growth-inhibitory potencies for bacteria have been reported. Also, after it was recognized that chloramphenicol acts through specific inhibition of bacterial protein biosynthesis (Hahn and Wisseman, 1951; Gale and Folkes, 1953; Wisseman, Smadel, Hahn and Hopps, 1954) and cell-free model systems of protein synthesis were subsequently developed, chloramphenicol derivatives have been tested for inhibitions of such systems. Hence, the chloramphenicol series of compounds appears to be suited to the derivation of structure-activity relationships.The recent identification of a chloramphenicol binding protein which is a constituent of the 50s subunit of 70s ribosomes (Nierhaus and Nierhaus, 1973;Pongs, Bald and Erdmann, 1973) has renewed our interest in these structureactivity relationships and has encouraged us to analyze them with a view to deriving a structural model of a chloramphenicol receptor site which we infer to be located on the peptidyl transferase which is part of the 50s ribosomal subunit. II. STRUCTURE-ACTIVITY RELATIONSHIPS WHICH DETERMINE INHIBITION OF BACTERIAL GROWTHFirst systematic efforts to derive for chloramphenicol derivatives structureactivity rules for bacterial growth inhibition were made by Hahn (1955), Shemiakin, Kolosov, Levitov, Germanova, Karapetian, Shvetsov and Bamdas (1955, 1956) and Hahn, Hayes, Wisseman, Hopps and Smadel (1956). Both groups of workers arrived independently at the same conclusions; reviews of these conclusions represented the state of the art for several years (Kolosov et al., 1961;Hahn, 1967a). Both groups also called attention to the fact that data-on growth inhibitions by chloramphenicol derivatives had been obtained in many laboratories using varieties of methods and test organisms and could not be considered to be better than semi-quantitative approximations which did not lend themselves to the derivation of quantitative structure-activity relationships.

Effect of Glucose on Photodynamic Action of Methylene Blue in Escherichia coli Cells

“…We tested the effect of CP, which inhibits protein synthesis by inhibiting the peptidyl-transferase activity of the 50s ribosomal subunit (24,25), on the MB-PDA and observed that it did not modify the glucose effect (data not shown). This result suggests that the glucose effect occurs independently of protein synthesis after photodynamic treatment.…”

Three‐dimensional computer modeling as an aid to drug design

“…1): 4-phenylpiperidines (PP); 3,3-diphenylpropylamines (DPA); diamines (DA); and several miscellaneous classes. The problem of deciding whether or not these drugs bind to a unique receptor site remains obscure for both pharmacologists and s P 2 P 3 Douglas et al, 1977Gund and Shen, 1977Gund et al, 1979aSmith et al, 1979Gund and Veber, 1979bLumma et al, 1978Veber et al, 1978Veber, 1980Freidinger and Veber, 1979Hahn and Gund, 1974Stuper et al, 1979Dyott et al, 1980Eaton and Pensak, 1978Nordby and Hodges, 1975 Nordby (to be published) Nordby and Hodges, 1975Cohen, 1979Rohrer et al, 1979Fullerton et al, 1979Fullerton et al. 1980Nichols et al, 1978Marshall et al, 1979Marshall, 1978Gorin and Marshall, 1977Cobb et al, 1978Sufrin et al, 1979Weaver et al, 1979Andrews, 1979bPauling, 1978Cody, 1979Humber et al, 1979Philipp et al, 1979 4 While several uniform receptor models [Feinberg et al, 1976;Galt, 19771 have been proposed, none of them can provide an explanation for the activity encountered in every structural class.…”

Molecular Conformation of Crystalline and Amorphous Chloramphenicol

“…Chloramphenicol (CHL) is a broad-spectrum antibiotic, currently included in List of Essential Medicines (EML) published by the World Health Organization (WHO) [1]. Originally isolated from Streptomyces venezuelae in 1947 [2,3], its structure (shown in Fig. 1) was soon elucidated and became the first antibiotic to be synthesized by chemical means [2,3].…”

“…Originally isolated from Streptomyces venezuelae in 1947 [2,3], its structure (shown in Fig. 1) was soon elucidated and became the first antibiotic to be synthesized by chemical means [2,3]. CHL acts essentially as a bacteriostatic agent, inhibiting bacterial synthesis by binding to the 50S subunit of 70S ribosomes [2].…”

“…1) was soon elucidated and became the first antibiotic to be synthesized by chemical means [2,3]. CHL acts essentially as a bacteriostatic agent, inhibiting bacterial synthesis by binding to the 50S subunit of 70S ribosomes [2]. The bacterial activity of CHL has been suggested to depend on the conformation of the propanediol moiety [2,3].…”