Synthesis and evaluation of biological activity for dual-acting antibiotics on the basis of azithromycin and glycopeptides

Tevyashova, Anna N.; Bychkova, E. N.; Королев, А. М.; Исакова, Е. П.; Mirchink, Elena P.; Osterman, Ilya А.; Erdei, Réka; Szűcs, Zsolt; Batta, Gyula

doi:10.1016/j.bmcl.2018.11.038

Cited by 18 publications

(27 citation statements)

References 31 publications

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“…Many studies on the development of dual-acting compounds have been conducted on aminoglycosides by linking these molecules to quinolones, as well as to β-lactam antibiotics, CHL, oxazolidinones, or short amphiphilic peptides. Some dual-acting glycopeptide antibiotics have been synthesized, including β-lactam, macrolide moieties, and fragments of natural antimicrobial peptides [ 6 , 7 , 8 ]. Many of these compounds exhibited a high antibacterial activity not only against Gram-positive strains, but also against Gram-negative bacteria, had a broad spectrum of activity and reduced the toxicity to the mammalian host, compared to the original antibiotics, and were also active against bacterial drug-resistant strains.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, benzoxaboroles are known to enhance the transport of macromolecules into the cell as a result of the interaction with 1,2- and 1,3-diol polysaccharides located on the cell surface. These properties, as well as the ability of some heterocyclic boronic acids and benzoxaborole derivatives to exhibit activity against Gram-negative bacteria with multi-drug resistance, were considered when developing chimeric antibiotics based on glycopeptides or polyene macrocyclic antibiotics containing benzoxaboroles in their structure [ 6 , 12 ] and benzoxaborole derivatives of azithromycin [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…We have recently designed and prepared novel conjugates of azithromycin, the macrozones, in order to overcome the bacterial resistance mechanisms [12]. Some azithromycin conjugates have already proven useful to treat pathogenic bacteria [13][14][15][16][17][18][19][20][21][22][23][24]. The macrozones, hybrid compounds of azithromycin and thiosemicarbazones, have shown excellent antibacterial activities against susceptible and resistant strains [12].…”

Section: Resultsmentioning

confidence: 99%

Rapid Structure Determination of Bioactive 4″-Tetrahydrofurfuryl Macrozone Reaction Mixture Components by LC-SPE/Cryo NMR and MS

et al. 2021

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LC-SPE/cryo NMR and MS methodologies have been developed and employed for a rapid structure determination of 4″-tetrahydrofurfuryl macrozone reaction mixture components. Macrozones, novel conjugates of azithromycin, and thiosemicarbazones have shown very good in vitro antibacterial activities against susceptible and some resistant bacterial strains and are promising agents for further development. The post-column multiple trapping of the chromatographically separated reaction mixture components on the SPE cartridges increased the sensitivity and together with cryogenically cooled NMR probe made it possible to identify and structurally characterize main 4″-tetrahydrofurfuryl macrozone reaction mixture compounds including those present at very low concentration level. This approach has several advantages over a classical off-line procedure, efficiency and low solvent consumption being the two most important ones. All identified components were process-related. It has been demonstrated that two different kinds of compounds with respect to structure were identified, i.e., macrolide-related and thiosemicarbazone-related ones. This methodology can serve as a platform for reliable and effective macrolides reaction components structure profiling, serving as both isolation and identification tools.

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“…Many studies on the development of dualacting compounds have been conducted on aminoglycosides by linking these molecules to quinolones, as well as to β-lactam antibiotics, CHL, oxazolidinones, or short amphiphilic peptides. Some dual-acting glycopeptide antibiotics have been synthesized, including β-lactam, macrolide moieties, and fragments of natural antimicrobial peptides [6][7][8]. Many of these compounds exhibited a high antibacterial activity not only against Gram-positive strains, but also against Gram-negative bacteria, had a broad spectrum of activity and reduced the toxicity to the mammalian host, compared to the original antibiotics, and were also active against bacterial drug-resistant strains.…”

Section: Introductionmentioning

confidence: 99%

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

Pavlova¹,

Khairullina²,

Tereshchenkov³

et al. 2021

Preprint

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In the current work, in continuation of our recent research [1] we synthesized and studied new chimeric compounds comprising the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP) connected by alkyl linkers 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 decrease membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP on bacterial ribosomes differ from that of CHL. By simulating the dynamics of complexes of CAM-Cn-TPP with bacterial ribosomes, we have proposed a possible explanation for the specificity of the action of these analogs on the translation process. CAM-C10-TPP and CAM-C14-TPP stronger inhibit the growth of the Gram-positive bacteria in comparison to the CHL and suppress some strains of CHL-resistant bacteria. Thus, we have shown that TPP derivatives of CHL are dual-acting compounds that target the ribosomes and the cellular membranes of bacteria. The TPP fragment of CAM-Cn-TPP compounds contributes to the inhibitory effect on bacteria. Moreover, since the mitochondria of eukaryotic cells have qualities similar to those of their prokaryotic ancestors, we demonstrate the possibility of targeting chemoresistant cancer cells with these compounds.

show abstract

Synthesis and evaluation of biological activity for dual-acting antibiotics on the basis of azithromycin and glycopeptides

Cited by 18 publications

References 31 publications

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

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

Rapid Structure Determination of Bioactive 4″-Tetrahydrofurfuryl Macrozone Reaction Mixture Components by LC-SPE/Cryo NMR and MS

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

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