Design, Synthesis and Biological Assessment of Novel Antimicrobial Compounds

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

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 8270

Special Issue Editors


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Guest Editor
Department of Chemistry, Faculty of Science, University of Zagreb, HR-10001 Zagreb, Croatia
Interests: Bioactive compounds; design; synthesis; antibacterial activity; oxime antidotes for OP poisoning; PCA analysis; molecular modeling studies

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Guest Editor
Department of Chemistry, Faculty of Science, University of Split, HR-21000 Split, Croatia
Interests: design and synthesis of heterocyclic compounds; antimicrobial agents; antidotes for toxic OP compounds
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Chemistry, Faculty of Science, University of Split, HR-21000 Split, Croatia
Interests: protein drug target; antimicrobial agents; mode of antibacterial action; cytotoxicity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since 2019, the novel human coronavirus SARS CoV-2 became a major health, sanitary and economic threat worldwide. It is presumed that the COVID-19 pandemic will significantly increase bacterial resistance due to the intensified consumption of antimicrobial agents. Furthermore, there is a greater need for efficient disinfectants. Thus, it is imperative to develop new antimicrobial scaffolds as a basis for the design of new potential leads.

This Special Issue invites research papers covering the most recent developments in new antimicrobial compounds by rational design, synthesis, biological assessment and/or in silico determination of relationships between structure and bioactivity. Manuscripts describing new comprehensive libraries of synthetic or natural-product-based bioactive compounds as well as optimized procedures for their synthesis, antimicrobial evaluations, and mode of action studies are also appreciated.

Prof. Dr. Ines Primožič
Prof. Dr. Renata Odžak
Prof. Dr. Matilda Šprung
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

  • antibacterials
  • antifungals
  • synthetic methods
  • drug discovery
  • antimicrobial targets and mechanisms
  • bacterial resistance

Published Papers (4 papers)

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Research

21 pages, 8087 KiB  
Article
Further Study of the Polar Group’s Influence on the Antibacterial Activity of the 3-Substituted Quinuclidine Salts with Long Alkyl Chains
by Renata Odžak, Doris Crnčević, Antonio Sabljić, Lucija Krce, Antonela Paladin, Ines Primožič and Matilda Šprung
Antibiotics 2023, 12(8), 1231; https://doi.org/10.3390/antibiotics12081231 - 25 Jul 2023
Cited by 1 | Viewed by 1022
Abstract
Quaternary ammonium compounds (QACs) are among the most potent antimicrobial agents increasingly used by humans as disinfectants, antiseptics, surfactants, and biological dyes. As reports of bacterial co- and cross-resistance to QACs and their toxicity have emerged in recent years, new attempts are being [...] Read more.
Quaternary ammonium compounds (QACs) are among the most potent antimicrobial agents increasingly used by humans as disinfectants, antiseptics, surfactants, and biological dyes. As reports of bacterial co- and cross-resistance to QACs and their toxicity have emerged in recent years, new attempts are being made to develop soft QACs by introducing hydrolyzable groups that allow their controlled degradation. However, the development of such compounds has been hindered by the structural features that affect the bioactivity of QACs, one of them being polarity of the substituent near the quaternary center. To further investigate the influence of the polar group on the bioactivity of QACs, we synthesized 3-aminoquinuclidine salts for comparison with their structural analogues, 3-acetamidoquinuclidines. We found that the less polar amino-substituted compounds exhibited improved antibacterial activity over their more polar amide analogues. In addition to their better minimum inhibitory concentrations, the candidates were excellent at suppressing Staphylococcus aureus biofilm formation and killing bacteria almost immediately, as shown by the flow cytometry measurements. In addition, two candidates, namely QNH2-C14 and QNH2-C16, effectively suppressed bacterial growth even at concentrations below the MIC. QNH2-C14 was particularly effective at subinhibitory concentrations, inhibiting bacterial growth for up to 6 h. In addition, we found that the compounds targeted the bacterial membrane, leading to its perforation and subsequent cell death. Their low toxicity to human cells and low potential to develop bacterial resistance suggest that these compounds could serve as a basis for the development of new QACs. Full article
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20 pages, 2366 KiB  
Article
Semisynthetic Amides of Amphotericin B and Nystatin A1: A Comparative Study of In Vitro Activity/Toxicity Ratio in Relation to Selectivity to Ergosterol Membranes
by Anna Tevyashova, Svetlana Efimova, Alexander Alexandrov, Olga Omelchuk, Eslam Ghazy, Elena Bychkova, Georgy Zatonsky, Natalia Grammatikova, Lyubov Dezhenkova, Svetlana Solovieva, Olga Ostroumova and Andrey Shchekotikhin
Antibiotics 2023, 12(1), 151; https://doi.org/10.3390/antibiotics12010151 - 11 Jan 2023
Cited by 10 | Viewed by 2715
Abstract
Polyene antifungal amphotericin B (AmB) has been used for over 60 years, and remains a valuable clinical treatment for systemic mycoses, due to its broad antifungal activity and low rate of emerging resistance. There is no consensus on how exactly it kills fungal [...] Read more.
Polyene antifungal amphotericin B (AmB) has been used for over 60 years, and remains a valuable clinical treatment for systemic mycoses, due to its broad antifungal activity and low rate of emerging resistance. There is no consensus on how exactly it kills fungal cells but it is certain that AmB and the closely-related nystatin (Nys) can form pores in membranes and have a higher affinity towards ergosterol than cholesterol. Notably, the high nephro- and hemolytic toxicity of polyenes and their low solubility in water have led to efforts to improve their properties. We present the synthesis of new amphotericin and nystatin amides and a comparative study of the effects of identical modifications of AmB and Nys on the relationship between their structure and properties. Generally, increases in the activity/toxicity ratio were in good agreement with increasing ratios of selective permeabilization of ergosterol- vs. cholesterol-containing membranes. We also show that the introduced modifications had an effect on the sensitivity of mutant yeast strains with alterations in ergosterol biosynthesis to the studied polyenes, suggesting a varying affinity towards intermediate ergosterol precursors. Three new water-soluble nystatin derivatives showed a prominent improvement in safety and were selected as promising candidates for drug development. Full article
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18 pages, 4111 KiB  
Article
The Design, Synthesis, and Evaluation of Diaminopimelic Acid Derivatives as Potential dapF Inhibitors Preventing Lysine Biosynthesis for Antibacterial Activity
by Mohd Sayeed Shaikh, Mayura A. Kale, V. Muralidharan, T. Venkatachalam, Syed Sarfaraz Ali, Fahadul Islam, Sharuk L. Khan, Falak A. Siddiqui, Humaira Urmee, Ganesh G. Tapadiya, Sachin A. Dhawale, Long Chiau Ming, Ibrahim Abdel Aziz Ibrahim, Abdullah R. Alzahrani, Md. Moklesur Rahman Sarker and Mohd Fahami Nur Azlina
Antibiotics 2023, 12(1), 47; https://doi.org/10.3390/antibiotics12010047 - 28 Dec 2022
Cited by 1 | Viewed by 2744
Abstract
We created thiazole and oxazole analogues of diaminopimelic acid (DAP) by replacing its carboxyl groups and substituting sulphur for the central carbon atom. Toxicity, ADME, molecular docking, and in vitro antimicrobial studies of the synthesized compounds were carried out. These compounds displayed significant [...] Read more.
We created thiazole and oxazole analogues of diaminopimelic acid (DAP) by replacing its carboxyl groups and substituting sulphur for the central carbon atom. Toxicity, ADME, molecular docking, and in vitro antimicrobial studies of the synthesized compounds were carried out. These compounds displayed significant antibacterial efficacy, with MICs of 70–80 µg/mL against all tested bacteria. Comparative values of the MIC, MBC, and ZOI of the synthesized compound were noticed when compared with ciprofloxacin. At 200 µg/mL, thio-DAP (1) had a ZOI of 22.67 ± 0.58, while ciprofloxacin had a ZOI of 23.67 ± 0.58. To synthesize thio-DAP (1) and oxa-DAP (2), l-cysteine was used as a precursor for the L-stereocenter (l-cysteine), which is recognized by the dapF enzyme’s active site and selectively binds to the ligand’s L-stereocenter. Docking studies of these compounds were carried out using the programme version 11.5 Schrodinger to reveal the hydrophobic and hydrophilic properties of these complexes. The docking scores of compounds one and two were −9.823 and −10.098 kcal/mol, respectively, as compared with LL-DAP (−9.426 kcal/mol.). This suggests that compounds one and two interact more precisely with dapF than LL-DAP. Chemicals one and two were synthesized via the SBDD (structure-based drug design) approach and these act as inhibitors of the dapF in the lysine pathway of bacterial cell wall synthesis. Full article
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15 pages, 4275 KiB  
Article
Screening of Novel Antimicrobial Diastereomers of Azithromycin–Thiosemicarbazone Conjugates: A Combined LC-SPE/Cryo NMR, MS/MS and Molecular Modeling Approach
by Iva Habinovec, Ivana Mikulandra, Paula Pranjić, Saša Kazazić, Hana Čipčić Paljetak, Antun Barišić, Branimir Bertoša, Mirjana Bukvić and Predrag Novak
Antibiotics 2022, 11(12), 1738; https://doi.org/10.3390/antibiotics11121738 - 2 Dec 2022
Viewed by 1242
Abstract
A well-known class of antibacterials, 14- and 15-membered macrolides are widely prescribed to treat upper and lower respiratory tract infections. Azithromycin is a 15-membered macrolide antibiotic possessing a broad spectrum of antibacterial potency and favorable pharmacokinetics. Bacterial resistance to marketed antibiotics is growing [...] Read more.
A well-known class of antibacterials, 14- and 15-membered macrolides are widely prescribed to treat upper and lower respiratory tract infections. Azithromycin is a 15-membered macrolide antibiotic possessing a broad spectrum of antibacterial potency and favorable pharmacokinetics. Bacterial resistance to marketed antibiotics is growing rapidly and represents one of the major global hazards to human health. Today, there is a high need for discovery of new anti-infective agents to combat resistance. Recently discovered conjugates of azithromycin and thiosemicarbazones, the macrozones, represent one such class that exhibits promising activities against resistant pathogens. In this paper, we employed an approach which combined LC-SPE/cryo NMR, MS/MS and molecular modeling for rapid separation, identification and characterization of bioactive macrozones and their diastereomers. Multitrapping of the chromatographic peaks on SPE cartridges enabled sufficient sample quantities for structure elucidation and biological testing. Furthermore, two-dimensional NOESY NMR data and molecular dynamics simulations revealed stereogenic centers with inversion of chirality. Differences in biological activities among diastereomers were detected. These results should be considered in the process of designing new macrolide compounds with bioactivity. We have shown that this methodology can be used for a fast screening and identification of the macrolide reaction components, including stereoisomers, which can serve as a source of new antibacterials. Full article
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