Abstract
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.
Highlights
The search for new antimicrobial agents remains a crucial and urgent task, which is largely due to the existence and endless emergence of resistant bacterial strains with various mechanisms of acquired resistance to most clinically relevant antibiotics.These mechanisms include mutations in the drug target site, enzymatic modification or degradation of antibiotics, and active efflux through porins and other permeability barriers [1,2,3].One promising approach to creating new antibiotics is the development of the socalled twin-drugs–dual-acting compounds, which contain two pharmacophores covalently linked in one molecule
These compounds were designed with the idea that the amphenicol moiety would anchor the compound in the canonical CHL binding site within the PTC of the bacterial ribosome, and an additional group would form multiple interactions with the walls of the nascent peptide exit tunnel (NPET)
In the case of chloramphenicol amine (CAM)-C4-TPP [51], we showed how this analog binds to the bacterial ribosome and inhibits bacterial protein synthesis, both in vitro and in vivo
Summary
The search for new antimicrobial agents remains a crucial and urgent task, which is largely due to the existence and endless emergence of resistant bacterial strains with various mechanisms of acquired resistance to most clinically relevant antibiotics.These mechanisms include mutations in the drug target site, enzymatic modification or degradation of antibiotics, and active efflux through porins and other permeability barriers [1,2,3].One promising approach to creating new antibiotics is the development of the socalled twin-drugs–dual-acting compounds, which contain two pharmacophores covalently linked in one molecule. The search for new antimicrobial agents remains a crucial and urgent task, which is largely due to the existence and endless emergence of resistant bacterial strains with various mechanisms of acquired resistance to most clinically relevant antibiotics. These mechanisms include mutations in the drug target site, enzymatic modification or degradation of antibiotics, and active efflux through porins and other permeability barriers [1,2,3]. While each of the two pharmacophores in such a hybrid drug molecule is expected to act independently of the original biological target, the non-cleavable covalent linker tethering the two active moieties endows the drug with a dual mechanism of action. These pharmacophores can be either two antibiotics or an antibiotic with an adjuvant that increases the access of the drug to its intracellular target (e.g., an efflux pump inhibitor or membrane and cell wall-penetrating group, or a moiety that changes the physical properties of the molecule)
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