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Antibiotics
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New Ribosome-Acting Antibiotic Derivatives
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New Ribosome-Acting Antibiotic Derivatives

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Novel Antimicrobial Agents".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 22956

Special Issue Editor

Dr. George Dinos

E-Mail Website
Guest Editor
Laboratory of Biochemistry, School of Medicine, University of Patras, 26500 Patras, Greece
Interests: antibiotics; ribosome structure and function; protein biosynthesis; antibiotics development and evaluation; Chloramphenicol Derivatives
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The discovery of novel antibiotics has nearly halted in the past 30 years, leading to the exhaustion of the pipeline reserve. This has resulted in some “shelved” antibiotics returning either to clinical practice or to the use of the derivatization procedure as a scaffold for new effective compounds development. One of such old shelved antibiotics is chloramphenicol (CAM). Discovered in 1949, CAM was the first broad spectrum antibiotic introduced, covering a wide range of Gram-positive and Gram-negative pathogens. When issued for clinical use, the drug became immediately popular not only for its low cost and effectiveness, but also for its few and mild side effects. However, shortly after the mild side effects, serious hematological disorders were recorded, like bone marrow depression and aplastic anemia. As a result, the toxicity of the drug and the development of safer alternative antibiotics narrowed the indications of CAM prescriptions and its use declined. The unwanted side effects prompted early searches for chloramphenicol derivatization concerning characteristics, antimicrobial activity, and toxici side effects. To date, numerous derivatives have been designed and synthesized but none have been evaluated as superior compared to CAM. Although the derivatization method has not been successful up to now, efforts have been ongoing since it is one of the most productive methods for the novel generation of antibiotics to combat resistant pathogens.

This Special Issue seeks manuscript submissions that improve our understanding of CAM derivatives, covering both chemistry and antimicrobial activity, and combining better structure–activity relationships. Antibacterial studies using ribosome profiling or proteomics are especially encouraged for submission.

Dr. George Dinos
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Antibiotics
  • Chloramphenicol
  • Cloramphenicol derivatives
  • Ribosome
  • Protein biosynthesis inhibitors
  • Pathogens Resistant

Published Papers (4 papers)

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22 pages, 2726 KiB  
Article
Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents
by Julia A. Pavlova, Zimfira Z. Khairullina, Andrey G. Tereshchenkov, Pavel A. Nazarov, Dmitrii A. Lukianov, Inna A. Volynkina, Dmitry A. Skvortsov, Gennady I. Makarov, Etna Abad, Somay Y. Murayama, Susumu Kajiwara, Alena Paleskava, Andrey L. Konevega, Yuri N. Antonenko, Alex Lyakhovich, Ilya A. Osterman, Alexey A. Bogdanov and Natalia V. Sumbatyan
Antibiotics 2021, 10(5), 489; https://doi.org/10.3390/antibiotics10050489 - 23 Apr 2021
Cited by 14 | Viewed by 3491
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue New Ribosome-Acting Antibiotic Derivatives)
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11 pages, 4570 KiB  
Article
New Chloramphenicol Derivatives with a Modified Dichloroacetyl Tail as Potential Antimicrobial Agents
by Artemis Tsirogianni, Georgia G. Kournoutou, Anthony Bougas, Eleni Poulou-Sidiropoulou, George Dinos and Constantinos M. Athanassopoulos
Antibiotics 2021, 10(4), 394; https://doi.org/10.3390/antibiotics10040394 - 06 Apr 2021
Cited by 7 | Viewed by 2600
Abstract
To combat the dangerously increasing pathogenic resistance to antibiotics, we developed new pharmacophores by chemically modifying a known antibiotic, which remains to this day the most familiar and productive way for novel antibiotic development. We used as a starting material the chloramphenicol base, [...] Read more.
To combat the dangerously increasing pathogenic resistance to antibiotics, we developed new pharmacophores by chemically modifying a known antibiotic, which remains to this day the most familiar and productive way for novel antibiotic development. We used as a starting material the chloramphenicol base, which is the free amine group counterpart of the known chloramphenicol molecule antibiotic upon removal of its dichloroacetyl tail. To this free amine group, we tethered alpha- and beta-amino acids, mainly glycine, lysine, histidine, ornithine and/or beta-alanine. Furthermore, we introduced additional modifications to the newly incorporated amine groups either with protecting groups triphenylmethyl- (Trt) and tert-butoxycarbonyl- (Boc) or with the dichloroacetic group found also in the chloramphenicol molecule. The antimicrobial activity of all compounds was tested both in vivo and in vitro, and according to the results, the bis-dichloroacetyl derivative of ornithine displayed the highest antimicrobial activity both in vivo and in vitro and seems to be a dynamic new pharmacophore with room for further modification and development. Full article
(This article belongs to the Special Issue New Ribosome-Acting Antibiotic Derivatives)
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16 pages, 3778 KiB  
Article
Binding and Action of Triphenylphosphonium Analog of Chloramphenicol upon the Bacterial Ribosome
by Chih-Wei Chen, Julia A. Pavlova, Dmitrii A. Lukianov, Andrey G. Tereshchenkov, Gennady I. Makarov, Zimfira Z. Khairullina, Vadim N. Tashlitsky, Alena Paleskava, Andrey L. Konevega, Alexey A. Bogdanov, Ilya A. Osterman, Natalia V. Sumbatyan and Yury S. Polikanov
Antibiotics 2021, 10(4), 390; https://doi.org/10.3390/antibiotics10040390 - 05 Apr 2021
Cited by 14 | Viewed by 5365
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue New Ribosome-Acting Antibiotic Derivatives)
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13 pages, 3894 KiB  
Perspective
Recent Trends in Synthesis of Chloramphenicol New Derivatives
by Anna N. Tevyashova
Antibiotics 2021, 10(4), 370; https://doi.org/10.3390/antibiotics10040370 - 31 Mar 2021
Cited by 14 | Viewed by 10483
Abstract
Chloramphenicol (CAM), the bacteriostatic broad-spectrum antibiotic, isolated from Streptomyces venezuelae during the “golden era” of antibiotic discovery, nowadays has limited clinical potential due to adverse side effects and frequent antimicrobial resistance. Numerous CAM analogs were synthesized in order to find the derivatives with [...] Read more.
Chloramphenicol (CAM), the bacteriostatic broad-spectrum antibiotic, isolated from Streptomyces venezuelae during the “golden era” of antibiotic discovery, nowadays has limited clinical potential due to adverse side effects and frequent antimicrobial resistance. Numerous CAM analogs were synthesized in order to find the derivatives with improved pharmacological properties and activity on resistant bacterial strains. This work aims to summarize the most recent achievements in obtaining new CAM analogs reported during the last five years. Current investigations are mainly focused on elucidating the molecular basis of the mode of CAM action and determining the mechanisms of resistance to this class of antibiotics or on studies of the possible use of the CAM scaffold to search for therapeutic agents with different CAM modes of action—such as selective antiproliferative agents or bacterial cell wall biosynthesis inhibitors. Hopefully, a deeper understanding of the CAM interactions with the target and its specificity will generate research ideas for developing new effective drugs. Full article
(This article belongs to the Special Issue New Ribosome-Acting Antibiotic Derivatives)
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