Conjugates of Desmycosin with Fragments of Antimicrobial Peptide Oncocin: Synthesis, Antibacterial Activity, Interaction with Ribosome.

Design and synthesis of conjugates consisting of the macrolide antibiotic desmycosin and fragments of the antibacterial peptide oncocin were performed in attempt to develop new antimicrobial compounds. New compounds were shown to bind to the E. coli 70S ribosomes, to inhibit bacterial protein synthesis in vitro, as well as to suppress bacterial growth. The conjugates of N-terminal hexa- and tripeptide fragments of oncocin and 3,2',4''-triacetyldesmycosin were found to be active against some strains of macrolide-resistant bacteria. By simulating molecular dynamics of the complexes of these compounds with the wild-type bacterial ribosomes and with ribosomes, containing A2059G 23S RNA mutation, the specific structural features of their interactions were revealed.

Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents.

In the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are linked by alkyl groups of different lengths. Using various biochemical assays, we showed that these CAM-Cn-TPP compounds bind to the bacterial ribosome, inhibit protein synthesis in vitro and in vivo in a way similar to that of the parent CHL, and significantly reduce membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP in bacterial ribosomes differs from that of CHL. By simulating the dynamics of CAM-Cn-TPP complexes with bacterial ribosomes, we proposed a possible explanation for the specificity of the action of these analogs in the translation process. CAM-C10-TPP and CAM-C14-TPP more strongly inhibit the growth of the Gram-positive bacteria, as compared to CHL, and suppress some CHL-resistant bacterial strains. Thus, we have shown that TPP derivatives of CHL are dual-acting compounds targeting both the ribosomes and cellular membranes of bacteria. The TPP fragment of CAM-Cn-TPP compounds has an inhibitory effect on bacteria. Moreover, since the mitochondria of eukaryotic cells possess qualities similar to those of their prokaryotic ancestors, we demonstrate the possibility of targeting chemoresistant cancer cells with these compounds.

Binding and Action of Triphenylphosphonium Analog of Chloramphenicol upon the Bacterial Ribosome.

Chloramphenicol (CHL) is a ribosome-targeting antibiotic that binds to the peptidyl transferase center (PTC) of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving the properties of this inhibitor, we explored ribosome binding and inhibitory properties of a semi-synthetic triphenylphosphonium analog of CHL-CAM-C4-TPP. Our data demonstrate that this compound exhibits a ~5-fold stronger affinity for the bacterial ribosome and higher potency as an in vitro protein synthesis inhibitor compared to CHL. The X-ray crystal structure of the Thermus thermophilus 70S ribosome in complex with CAM-C4-TPP reveals that, while its amphenicol moiety binds at the PTC in a fashion identical to CHL, the C4-TPP tail adopts an extended propeller-like conformation within the ribosome exit tunnel where it establishes multiple hydrophobic Van der Waals interactions with the rRNA. The synthesized compound represents a promising chemical scaffold for further development by medicinal chemists because it simultaneously targets the two key functional centers of the bacterial ribosome-PTC and peptide exit tunnel.

Why are reactions of 2- and 8-thioquinoline derivatives with iodine different?

The crystal structures of 1,2-dihydro-1,1'-bi[thiazolo[3,2-a]quinoline]-10a,10a'-diium diiodide hemihydrate, C22H16N2S22+·2I-·0.5H2O, and 1,2-dihydro-1,1'-bi[thiazolo[3,2-a]quinoline]-10a,10a'-diium iodide triiodide, C22H16N2S22+·I-·I3-, obtained during the reaction of 1,4-bis(quinolin-2-ylsulfanyl)but-2-yne (2TQB) with iodine, have been determined at 120 K. The crystalline products contain the dication as a result of the reaction proceeding along the iodocyclization pathway. This is fundamentally different from the previously observed reaction of 1,4-bis(quinolin-8-ylsulfanyl)but-2-yne (8TQB) with iodine under similar conditions. A comparative analysis of the possible conformational states indicates differences in the relative stabilities and free rotation for the 2- and 8-thioquinoline derivatives which lead to a disparity in the convergence of the potential reaction centres for 2TQB and 8TQB.