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Antibiotics
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Multitalented Synthetic Antimicrobial Compounds: From Design to Effect
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Multitalented Synthetic Antimicrobial Compounds: From Design to Effect

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

Deadline for manuscript submissions: 31 May 2025 | Viewed by 4321

Special Issue Editors

Dr. Tsz Tin Yu

E-Mail Website
Guest Editor
School of Chemistry, University of New South Wales (UNSW Sydney), Sydney, NSW 2052, Australia
Interests: medicinal chemistry; antimicrobials; peptidomimetics; quorum sensing; Antibiofilm
Special Issues, Collections and Topics in MDPI journals
Dr. Maria Fernanda N. N. Carvalho

E-Mail Website
Guest Editor
Instituto Superior Técnico, University of Lisbon, 1049-001 Lisbon, Portugal
Interests: synthesis of coordination and organic compounds; medicinal chemistry; drugs; bioactive compounds; redox properties
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The rapid emergence of antimicrobial resistance poses a serious threat to public health. The misuse and overuse of antibiotics has contributed to the development of antimicrobial resistance, rendering antibiotics ineffective for treating multi-drug-resistant bacterial and fungal infections. In addition, the lack of innovation in the development of novel therapeutic strategies in the last few decades has undermined efforts to circumvent multi-drug-resistant infections. Hence, there is an urgent need to design and develop new classes of antimicrobial compounds, particularly those with broad antibacterial and/or fungal activity.

This Special Issue will compile up-to-date research on novel antimicrobial compounds. Topics to be covered in this Special Issue include, but are not limited to, the design and synthesis of antimicrobial compounds, the development of synthetic analogues of natural products with antimicrobial activity, the in vitro and/or in vivo antimicrobial evaluation of synthetic compounds, and the mechanisms of action of novel antimicrobial compounds.

Prospective authors are invited to submit their research findings as full articles, communications, or reviews related to this topic.

Dr. Tsz Tin Yu
Dr. Maria Fernanda N. N. Carvalho
Guest Editors

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

  • antimicrobial resistance
  • antibiotic development
  • the design of antimicrobial compounds
  • the synthesis of antimicrobial compounds
  • medicinal chemistry
  • bioorganic chemistry
  • antimicrobial properties
  • the mechanisms of antimicrobial activity
  • bioinorganic

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Published Papers (4 papers)

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Research

17 pages, 5078 KiB  
Article
Synthesis and Antibacterial Activity of New 6″-Modified Tobramycin Derivatives
by Kseniya S. Shapovalova, Georgy V. Zatonsky, Elizaveta A. Razumova, Daria A. Ipatova, Dmitrii A. Lukianov, Petr V. Sergiev, Natalia E. Grammatikova, Alexander S. Tikhomirov and Andrey E. Shchekotikhin
Antibiotics 2024, 13(12), 1191; https://doi.org/10.3390/antibiotics13121191 - 6 Dec 2024
Viewed by 708
Abstract
Objectives: Aminoglycosides are one of the first classes of natural antibiotics which have not lost relevance due to their broad spectrum of action against Gram-positive, Gram-negative bacteria and mycobacteria. The high growth rate of antimicrobial resistance (AMR) together with the severe side effects [...] Read more.
Objectives: Aminoglycosides are one of the first classes of natural antibiotics which have not lost relevance due to their broad spectrum of action against Gram-positive, Gram-negative bacteria and mycobacteria. The high growth rate of antimicrobial resistance (AMR) together with the severe side effects of aminoglycosides increase the importance of developing improved semisynthetic derivatives. Methods: In this work, we proposed a synthetic route to new tobramycin derivatives modified at the 6″-position with aminoalkylamine or guanidinoalkylamine residues. Results: The antibacterial activity of the new compounds against reference strains of microorganisms was comparable to the parental tobramycin. In striking contrast to tobramycin (resistance index, >256), its 6″-modified derivatives were significantly more potent against resistant clinical isolates of P. aeruginosa strains (resistance index = 4–16) and they demonstrated a promising AMR circumvention in E. coli strains associated with mutations in the fusA gene encoding elongation factor G. All the obtained tobramycin derivatives exhibited reduced cytotoxicity for the eukaryotic HEK293T cells compared to the tobramycin and thereby they potentially may have improved therapeutic index. The proposed modification of the 6″-position of tobramycin does not change the mechanism of aminoglycoside’s antibacterial activity: new compounds induced translation errors which resulted in the inhibition of protein synthesis in bacterial cells. Conclusions: Taken together, we can suggest that further modifications of the 6″-position of tobramycin may be beneficial for circumvention of AMR to aminoglycosides or used for conjugation with other molecules of interest. Full article
(This article belongs to the Special Issue Multitalented Synthetic Antimicrobial Compounds: From Design to Effect)
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14 pages, 827 KiB  
Article
Mono-N-alkylation of Amphotericin B and Nystatin A1 and Its Amides: Effect on the In Vitro Activity, Cytotoxicity and Permeabilization of Model Membranes
by Olga Omelchuk, Elena Bychkova, Svetlana Efimova, Natalia Grammatikova, George Zatonsky, Lyubov Dezhenkova, Svetlana Solovieva, Olga Ostroumova, Anna Tevyashova and Andrey Shchekotikhin
Antibiotics 2024, 13(12), 1177; https://doi.org/10.3390/antibiotics13121177 - 4 Dec 2024
Viewed by 727
Abstract
Objectives: In 2022, the World Health Organization highlighted the necessity for the development of new antifungal agents. Polyene antibiotics are characterized by a low risk of drug resistance; however, their use is limited by low solubility and severe side effects. Methods: [...] Read more.
Objectives: In 2022, the World Health Organization highlighted the necessity for the development of new antifungal agents. Polyene antibiotics are characterized by a low risk of drug resistance; however, their use is limited by low solubility and severe side effects. Methods: A series of N-alkylated derivatives of amphotericin B and nystatin A1 as well as their N-(2-hydroxyethyl)amides were synthesized. Their antifungal activity was evaluated against various Candida strains and Aspergillus fumigatus using the broth microdilution method. Cytotoxicity was assessed using an MTT assay on human embryonic kidney cells HEK293 and human skin fibroblast cells hFB-hTERT6, as well as a hemolysis assay on erythrocytes. Membrane activity was analyzed by fluorimetric measurement of calcein leakage from model liposomes. Results: Derivatives containing the N-(hydroxyethyl)amino)ethyl fragment (compounds 3 and 4) exhibited relatively high antifungal activity, as did N-(2-hydroxyethyl)amides 5 and 9. Bis-modified compounds 6 and 10 did not outperform their mono-modified analogues in terms of activity or cytotoxicity. The mono-N-alkylated compound 3 showed the highest activity/toxicity ratio, which correlated well with its selectivity for ergosterol-containing model membranes. Discussion: Combining two successful modifications does not necessarily improve the activity/toxicity ratio of polyenes. Further studies can be performed for the optimization of carboxyl group of 3. Full article
(This article belongs to the Special Issue Multitalented Synthetic Antimicrobial Compounds: From Design to Effect)
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13 pages, 1626 KiB  
Article
Enhancing Antibacterial Efficacy: Combining Novel Bacterial Topoisomerase Inhibitors with Efflux Pump Inhibitors and Other Agents Against Gram-Negative Bacteria
by Maša Zorman, Maja Kokot, Irena Zdovc, Lidija Senerovic, Mina Mandic, Nace Zidar, Andrej Emanuel Cotman, Martina Durcik, Lucija Peterlin Mašič, Nikola Minovski, Marko Anderluh and Martina Hrast Rambaher
Antibiotics 2024, 13(11), 1081; https://doi.org/10.3390/antibiotics13111081 - 13 Nov 2024
Viewed by 1255
Abstract
Background: The novel bacterial topoisomerase inhibitors (NBTIs) developed in our laboratory show potent on-target enzyme inhibition but suffer from low activity against Gram-negative bacteria. Methods: With the aim of improving the antibacterial activity of our compounds against Gram-negative bacteria, we tested them in [...] Read more.
Background: The novel bacterial topoisomerase inhibitors (NBTIs) developed in our laboratory show potent on-target enzyme inhibition but suffer from low activity against Gram-negative bacteria. Methods: With the aim of improving the antibacterial activity of our compounds against Gram-negative bacteria, we tested them in combination with different efflux pump inhibitors (EPIs), a strategy that showed promise in several other classes of antimicrobials. We also investigated the combined effect of NBTIs with ATP-competitive inhibitors of bacterial type II topoisomerases (ACIs), as well as the antibiofilm properties of our compounds and the combination with EPIs against early and mature Acietobacter baumannii biofilm. Results: Our results demonstrate that combinations of NBTIs with EPI Phenylalanine-arginyl-β-naphthylamide significantly reduce the corresponding NBTIs’ minimal inhibitory concentration values and show potentiation of A. baumannii biofilm inhibition as compared to NBTIs alone. Although combinations of NBITs and ACIs did not show synergistic effects, the FIC index value calculations revealed additive effects for all the combinations of a selected NBTI in combination with three ACIs in all the assayed Gram-negative bacteria from the ESKAPE group. Conclusions: These results show for the first time that combinations of NBTIs with either EPIs or a different class of the topoisomerase inhibitors may be a beneficial strategy to combat difficult-to-treat bacterial infections. Full article
(This article belongs to the Special Issue Multitalented Synthetic Antimicrobial Compounds: From Design to Effect)
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26 pages, 3485 KiB  
Article
Synthesis and Antibacterial Activity of Alkylamine-Linked Pleuromutilin Derivatives
by Kerrin Hainsworth, Melissa M. Cadelis, Florent Rouvier, Jean Michel Brunel and Brent R. Copp
Antibiotics 2024, 13(11), 1018; https://doi.org/10.3390/antibiotics13111018 - 29 Oct 2024
Viewed by 870
Abstract
In an effort to expand the spectrum of the antibacterial activity of pleuromutilin, a series of amine- and polyamine-linked analogues were prepared and evaluated for activities against a panel of microorganisms. Simple C-22-substituted amino esters or diamines 16, 17, 18, [...] Read more.
In an effort to expand the spectrum of the antibacterial activity of pleuromutilin, a series of amine- and polyamine-linked analogues were prepared and evaluated for activities against a panel of microorganisms. Simple C-22-substituted amino esters or diamines 16, 17, 18, and 22, as well as two unusual amine-linked bis-pleuromutilin examples 20 and 23, displayed variable levels of activity towards Staphylococcus aureus ATCC 25923 and methicillin-resistant S. aureus, but with no detectable activities towards Gram-negative bacteria. Fortunately, the incorporation of a longer-chain triamine or polyamine (spermine) at C-22 did afford analogues (30, 31) that exhibited activity towards both S. aureus ATCC 25923 and Escherichia coli ATCC 25922 with MIC 6.1–13.4 µM. Spermine–pleuromutilin analogue 31 was also able to enhance the action of doxycycline towards Pseudomonas aeruginosa ATCC 27853 by eight-fold, highlighting it as a useful scaffold for the development of new antibacterial pleuromutilin analogues that exhibit a broader spectrum of activity. Full article
(This article belongs to the Special Issue Multitalented Synthetic Antimicrobial Compounds: From Design to Effect)
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