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Antibiotics
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Multidrug Resistance as Trigger for the Development of Novel Antimicrobials
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Multidrug Resistance as Trigger for the Development of Novel Antimicrobials

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 8838

Special Issue Editors

Dr. Luis G. Alves

E-Mail Website
Guest Editor
Centro de Química Estrutural, Associação do Instituto Superior Técnico para a Investigação e Desenvolvimento, Lisbon, Portugal
Interests: azamacrocyles; antimicrobials; antitumorals; metallodrugs
Special Issues, Collections and Topics in MDPI journals
Dr. Jorge H. Leitão

E-Mail Website
Guest Editor
Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
Interests: molecular microbiology; biology and biochemistry of Gram-negative bacteria; bacterial small non-coding regulatory RNAs; mechanisms of resistance to antimicrobials; development of new antimicrobials; vaccine research
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The incidence of human pathogens that are resistant to multiple antimicrobials has been increasing over recent decades. Infections caused by pathogens that are resistant to multiple antimicrobials are relatively difficult to eradicate and are associated with a worst outcome than those caused by the respective susceptible strains, being directly associated with an increased risk of morbidity, mortality and cost. While the emergence of multidrug resistance has been associated with the misuse and abuse of antimicrobials, the number of available effective drugs is decreasing and the arrival of novel compounds on the market is scarce.

This Special Issue aims to gather papers describing novel antimicrobials, originating from chemical synthesis, repurposing of existing drugs or from natural sources. Papers providing descriptions of novel structures, discovery of novel targets and mechanisms of action, as well as pertaining to the use of omics approaches in the field of novel antimicrobials discovery and characterization are also welcome.

Dr. Luis G. Alves
Dr. Jorge H. Leitão
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

  • novel antimicrobials
  • multidrug resistance
  • target identification
  • ESKAPE bacteria
  • drug design
  • mechanisms of action

Published Papers (4 papers)

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Research

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39 pages, 9412 KiB  
Article
Antibiofilm and Anti-Quorum-Sensing Activities of Novel Pyrazole and Pyrazolo[1,5-a]pyrimidine Derivatives as Carbonic Anhydrase I and II Inhibitors: Design, Synthesis, Radiosterilization, and Molecular Docking Studies
by Ahmed Ragab, Sawsan A. Fouad, Yousry A. Ammar, Dina S. Aboul-Magd and Moustafa S. Abusaif
Antibiotics 2023, 12(1), 128; https://doi.org/10.3390/antibiotics12010128 - 09 Jan 2023
Cited by 15 | Viewed by 2512
Abstract
Nowadays, searching for new anti-infective agents with diverse mechanisms of action has become necessary. In this study, 16 pyrazole and pyrazolo[1,5-a]pyrimidine derivatives were synthesized and assessed for their preliminary antibacterial and antibiofilm activities. All these derivatives were initially screened for their [...] Read more.
Nowadays, searching for new anti-infective agents with diverse mechanisms of action has become necessary. In this study, 16 pyrazole and pyrazolo[1,5-a]pyrimidine derivatives were synthesized and assessed for their preliminary antibacterial and antibiofilm activities. All these derivatives were initially screened for their antibacterial activity against six clinically isolated multidrug resistance by agar well-diffusion and broth microdilution methods. The initial screening presented significant antibacterial activity with a bactericidal effect for five compounds, namely 3a, 5a, 6, 9a, and 10a, compared with Erythromycin and Amikacin. These five derivatives were further evaluated for their antibiofilm activity against both S. aureus and P. aeruginosa, which showed strong biofilm-forming activity at their MICs by >60%. The SEM analysis confirmed the biofilm disruption in the presence of these derivatives. Furthermore, anti-QS activity was observed for the five hybrids at their sub-MICs, as indicated by the visible halo zone. In addition, the presence of the most active derivatives reduces the violacein production by CV026, confirming that these compounds yielded anti-QS activity. Furthermore, these compounds showed strong inhibitory action against human carbonic anhydrase (hCA-I and hCA-II) isoforms with IC50 values ranging between 92.34 and 168.84 nM and between 73.2 and 161.22 nM, respectively. Finally, radiosterilization, ADMET, and a docking simulation were performed. Full article
(This article belongs to the Special Issue Multidrug Resistance as Trigger for the Development of Novel Antimicrobials)
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14 pages, 1377 KiB  
Article
Octenidine’s Efficacy: A Matter of Interpretation or the Influence of Experimental Setups?
by Djenana Vejzovic, Azra Iftic, Ayse Ön, Enrico F. Semeraro and Nermina Malanovic
Antibiotics 2022, 11(11), 1665; https://doi.org/10.3390/antibiotics11111665 - 19 Nov 2022
Cited by 1 | Viewed by 1646
Abstract
With its broad antimicrobial spectrum and non-specific mode of action via membrane disruption, any resistance to octenidine (OCT) seems unlikely and has not been observed in clinical settings so far. In this study, we aimed to investigate the efficacy of OCT against Escherichia [...] Read more.
With its broad antimicrobial spectrum and non-specific mode of action via membrane disruption, any resistance to octenidine (OCT) seems unlikely and has not been observed in clinical settings so far. In this study, we aimed to investigate the efficacy of OCT against Escherichia coli and mutants lacking specific lipid head groups which, due to altered membrane properties, might be the root cause for resistance development of membrane-active compounds. Furthermore, we aimed to test its efficacy under different experimental conditions including different solvents for OCT, bacterial concentration and methods for analysis. Our primary goal was to estimate how many OCT molecules are needed to kill one bacterium. We performed susceptibility assays by observing bacterial growth behavior, using a Bioscreen in an analogous manner for every condition. The growth curves were recorded for 20 h at 420–580 nm in presence of different OCT concentrations and were used to assess the inhibitory concentrations (IC100%) for OCT. Bacterial concentrations given in cell numbers were determined, followed by Bioscreen measurement by manual colony counting on agar plates and QUANTOMTM cell staining. This indicated a significant variance between both methods, which influenced IC100% of OCT, especially when used at low doses. The binding capacity of OCT to E. coli was investigated by measuring UV-absorbance of OCT exposed to bacteria and a common thermodynamic framework based on Bioscreen measurements. Results showed that OCT’s antimicrobial activity in E. coli is not affected by changes at the membrane level but strongly dependent on experimental settings in respect to solvents and applied bacterial counts. More OCT was required when the active was dissolved in phosphate or Hepes buffers instead of water and when higher bacterial concentration was used. Furthermore, binding studies revealed that 107–108 OCT molecules bind to bacteria, which is necessary for the saturation of the bacterial surface to initiate the killing cascade. Our results clearly demonstrate that in vitro data, depending on the applied materials and the methods for determination of IC100%, can easily be misinterpreted as reduced bacterial susceptibility towards OCT. Full article
(This article belongs to the Special Issue Multidrug Resistance as Trigger for the Development of Novel Antimicrobials)
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20 pages, 3055 KiB  
Article
Antifungal Activity of a Library of Aminothioxanthones
by Joana Cardoso, Joana Freitas-Silva, Fernando Durães, Diogo Teixeira Carvalho, Luís Gales, Madalena Pinto, Emília Sousa and Eugénia Pinto
Antibiotics 2022, 11(11), 1488; https://doi.org/10.3390/antibiotics11111488 - 27 Oct 2022
Cited by 2 | Viewed by 1731
Abstract
Fungal infections are one of the main causes of mortality and morbidity worldwide and taking into account the increasing incidence of strains resistant to classical antifungal drugs, the development of new agents has become an urgent clinical need. Considering that thioxanthones are bioisosteres [...] Read more.
Fungal infections are one of the main causes of mortality and morbidity worldwide and taking into account the increasing incidence of strains resistant to classical antifungal drugs, the development of new agents has become an urgent clinical need. Considering that thioxanthones are bioisosteres of xanthones with known anti-infective actions, their scaffolds were selected for this study. A small library of synthesized aminothioxanthones (1–10) was evaluated for in vitro antifungal activity against Candida albicans, Aspergillus fumigatus, and Trichophyton rubrum; for the active compounds, the spectrum was further extended to other clinically relevant pathogenic fungi. The results showed that only compounds 1, 8, and 9 exhibited inhibitory and broad-spectrum antifungal effects. Given the greater antifungal potential presented, compound 1 was the subject of further investigations to study its anti-virulence activity and in an attempt to elucidate its mechanism of action; compound 1 seems to act predominantly on the cellular membrane of C. albicans ATCC 10231, altering its structural integrity, without binding to ergosterol, while inhibiting two important virulence factors—dimorphic transition and biofilm formation—frequently associated with C. albicans pathogenicity and resistance. In conclusion, the present work proved the usefulness of thioxanthones in antifungal therapy as new models for antifungal agents. Full article
(This article belongs to the Special Issue Multidrug Resistance as Trigger for the Development of Novel Antimicrobials)
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Review

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18 pages, 3680 KiB  
Review
Synthetic Imidazopyridine-Based Derivatives as Potential Inhibitors against Multi-Drug Resistant Bacterial Infections: A Review
by Bharat Kumar Reddy Sanapalli, Akram Ashames, Dilep Kumar Sigalapalli, Afzal B. Shaik, Richie R. Bhandare and Vidyasrilekha Yele
Antibiotics 2022, 11(12), 1680; https://doi.org/10.3390/antibiotics11121680 - 22 Nov 2022
Cited by 6 | Viewed by 2260
Abstract
Fused pyridines are reported to display various pharmacological activities, such as antipyretic, analgesic, antiprotozoal, antibacterial, antitumor, antifungal, anti-inflammatory, and antiapoptotic. They are widely used in the field of medicinal chemistry. Imidazopyridines (IZPs) are crucial classes of fused heterocycles that are expansively reported on [...] Read more.
Fused pyridines are reported to display various pharmacological activities, such as antipyretic, analgesic, antiprotozoal, antibacterial, antitumor, antifungal, anti-inflammatory, and antiapoptotic. They are widely used in the field of medicinal chemistry. Imidazopyridines (IZPs) are crucial classes of fused heterocycles that are expansively reported on in the literature. Evidence suggests that IZPs, as fused scaffolds, possess more diverse profiles than individual imidazole and pyridine moieties. Bacterial infections and antibacterial resistance are ever-growing risks in the 21st century. Only one IZP, i.e., rifaximin, is available on the market as an antibiotic. In this review, the authors highlight strategies for preparing other IZPs. A particular focus is on the antibacterial profile and structure–activity relationship (SAR) of various synthesized IZP derivatives. This research provides a foundation for the tuning of available compounds to create novel, potent antibacterial agents with fewer side effects. Full article
(This article belongs to the Special Issue Multidrug Resistance as Trigger for the Development of Novel Antimicrobials)
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