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Synthetic Antibiofilm Agents: Design, Synthesis and Applications

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 24681

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Special Issue Editor

Prof. Dr. Mariana Chifiriuc

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Guest Editor

Faculty of Biology, Microbiology Department and the Research Institute of the University of Bucharest, ICUB, Bucharest, Romania
Interests: medical microbiology; antibiotic resistance–mechanisms, epidemiology, reservoirs, antimicrobial strategies; microbial virulence and pathogenicity

Special Issue Information

Dear Colleagues,

Microorganisms represent an important component of the planetary biomass, accounting for ≈70% of the total marine biomass and they mainly adhere to different surfaces, forming biofilms. Besides their essential ecological roles, microbial biofilms could also have negative impacts, such as biofouling, biocorrosion, and antibiotic resistance. Adhered bacteria exhibit phenotypic resistance to antimicrobial agents, being up to 1000 times more resistant than their planktonic counterparts and, thus, very difficult to eradicate with conventional strategies. Many important opportunistic and nosocomial pathogens adhere and develop biofilms on live tissues and implanted medical devices, consequently producing biofilm-associated infections accounting for ≈60–80% of total human infections. The antibiofilm strategies can involve the use of agents that either inhibit or kill microorganisms, or target the expression of adherence and biofilm-associated genes and/or of their regulators. Despite the huge body of research accumulated regarding the development of antibiofilm strategies, many challenges still remain to be addressed for their successful translation into practice. The purpose of the Special Issue “Synthetic Antibiofilm Agents: Design, Synthesis, and Applications” is to address the current progress and challenges for developing reliable antibiofilm strategies based on synthetic agents.

Prof. Dr. Mariana Chifiriuc
Guest Editor

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Keywords

Synthesis methodologies for antibiofilm agents
In vitro and in vivo biofilm models for assessing antibiofilm agents
Anti-virulence molecules
Synthetic antibiofilm peptides
Antibiofilm molecules’ targets
Drug repurposing
Anti-fouling agents
Cytotoxicity

Published Papers (9 papers)

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Research

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11 pages, 4317 KiB

Open AccessArticle

Sintered and 3D-Printed Bulks of MgB₂-Based Materials with Antimicrobial Properties

by Petre Badica, Nicolae Dan Batalu, Mariana Carmen Chifiriuc, Mihail Burdusel, Mihai Alexandru Grigoroscuta, Gheorghe Virgil Aldica, Iuliana Pasuk, Andrei Kuncser, Marcela Popa, Angelo Agostino, Lorenza Operti, Santanu Kumar Padhi, Valentina Bonino and Marco Truccato

Molecules 2021, 26(19), 6045; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26196045 - 06 Oct 2021

Cited by 4 | Viewed by 1758

Abstract

Pristine high-density bulk disks of MgB₂ with added hexagonal BN (10 wt.%) were prepared using spark plasma sintering. The BN-added samples are machinable by chipping them into desired geometries. Complex shapes of different sizes can also be obtained by the 3D printing of polylactic acid filaments embedded with MgB₂ powder particles (10 wt.%). Our present work aims to assess antimicrobial activity quantified as viable cells (CFU/mL) vs. time of sintered and 3D-printed materials. In vitro antimicrobial tests were performed against the bacterial strains Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923, Enterococcus faecium DSM 13590, and Enterococcus faecalis ATCC 29212; and the yeast strain Candida parapsilosis ATCC 22019. The antimicrobial effects were found to depend on the tested samples and microbes, with E. faecium being the most resistant and E. coli the most susceptible. Full article

(This article belongs to the Special Issue Synthetic Antibiofilm Agents: Design, Synthesis and Applications)

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21 pages, 2520 KiB

Open AccessArticle

Synthesis and Biological Evaluation of New N-Acyl-α-amino Ketones and 1,3-Oxazoles Derivatives

by Theodora-Venera Apostol, Luminita Gabriela Marutescu, Constantin Draghici, Laura-Ileana Socea, Octavian Tudorel Olaru, George Mihai Nitulescu, Elena Mihaela Pahontu, Gabriel Saramet, Cristian Enache-Preoteasa and Stefania-Felicia Barbuceanu

Molecules 2021, 26(16), 5019; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26165019 - 19 Aug 2021

Cited by 3 | Viewed by 2048

Abstract

In order to develop novel bioactive substances with potent activities, some new valine-derived compounds incorporating a 4-(phenylsulfonyl)phenyl fragment, namely, acyclic precursors from N-acyl-α-amino acids and N-acyl-α-amino ketones classes, and heterocycles from the large family of 1,3-oxazole-based compounds, were synthesized. The structures of the new compounds were established using elemental analysis and spectral (UV-Vis, FT-IR, MS, NMR) data, and their purity was checked by reversed-phase HPLC. The newly synthesized compounds were evaluated for their antimicrobial and antibiofilm activities, for toxicity on D. magna, and by in silico studies regarding their potential mechanism of action and toxicity. The 2-aza-3-isopropyl-1-[4-(phenylsulfonyl)phenyl]-1,4-butanedione 4b bearing a p-tolyl group in 4-position exhibited the best antibacterial activity against the planktonic growth of both Gram-positive and Gram-negative strains, while the N-acyl-α-amino acid 2 and 1,3-oxazol-5(4H)-one 3 inhibited the Enterococcus faecium biofilms. Despite not all newly synthesized compounds showing significant biological activity, the general scaffold allows several future optimizations for obtaining better novel antimicrobial agents by the introduction of various substituents on the phenyl moiety at position 5 of the 1,3-oxazole nucleus. Full article

(This article belongs to the Special Issue Synthetic Antibiofilm Agents: Design, Synthesis and Applications)

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15 pages, 2617 KiB

Open AccessArticle

Antimicrobial Activity of MgB₂ Powders Produced via Reactive Liquid Infiltration Method

by Santanu Kumar Padhi, Nicoletta Baglieri, Valentina Bonino, Angelo Agostino, Lorenza Operti, Nicolae Dan Batalu, Mariana Carmen Chifiriuc, Marcela Popa, Mihail Burdusel, Mihai Alexandru Grigoroscuta, Gheorghe Virgil Aldica, Dana Radu, Petre Badica and Marco Truccato

Molecules 2021, 26(16), 4966; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26164966 - 17 Aug 2021

Cited by 3 | Viewed by 2074

Abstract

We report for the first time on the antimicrobial activity of MgB₂ powders produced via the Reactive Liquid Infiltration (RLI) process. Samples with MgB₂ wt.% ranging from 2% to 99% were obtained and characterized, observing different levels of grain aggregation and of impurity phases. Their antimicrobial activity was tested against Staphylococcus aureus ATCC BAA 1026, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, and Candida albicans ATCC 10231. A general correlation is observed between the antibacterial activity and the MgB₂ wt.%, but the sample microstructure also appears to be very important. RLI-MgB₂ powders show better performances compared to commercial powders against microbial strains in the planktonic form, and their activity against biofilms is also very similar. Full article

(This article belongs to the Special Issue Synthetic Antibiofilm Agents: Design, Synthesis and Applications)

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16 pages, 4517 KiB

Open AccessArticle

Isoflavonoid-Antibiotic Thin Films Fabricated by MAPLE with Improved Resistance to Microbial Colonization

by Valentina Grumezescu, Irina Negut, Rodica Cristescu, Alexandru Mihai Grumezescu, Alina Maria Holban, Florin Iordache, Mariana Carmen Chifiriuc, Roger J. Narayan and Douglas B. Chrisey

Molecules 2021, 26(12), 3634; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26123634 - 14 Jun 2021

Cited by 4 | Viewed by 2190

Abstract

Staphylococcus aureus (Gram-positive) and Pseudomonas aeruginosa (Gram-negative) bacteria represent major infectious threats in the hospital environment due to their wide distribution, opportunistic behavior, and increasing antibiotic resistance. This study reports on the deposition of polyvinylpyrrolidone/antibiotic/isoflavonoid thin films by the matrix-assisted pulsed laser evaporation (MAPLE) method as anti-adhesion barrier coatings, on biomedical surfaces for improved resistance to microbial colonization. The thin films were characterized by Fourier transform infrared spectroscopy, infrared microscopy, and scanning electron microscopy. In vitro biological assay tests were performed to evaluate the influence of the thin films on the development of biofilms formed by Gram-positive and Gram-negative bacterial strains. In vitro biocompatibility tests were assessed on human endothelial cells examined for up to five days of incubation, via qualitative and quantitative methods. The results of this study revealed that the laser-fabricated coatings are biocompatible and resistant to microbial colonization and biofilm formation, making them successful candidates for biomedical devices and contact surfaces that would otherwise be amenable to contact transmission. Full article

(This article belongs to the Special Issue Synthetic Antibiofilm Agents: Design, Synthesis and Applications)

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18 pages, 4663 KiB

Open AccessArticle

New O-Aryl-Carbamoyl-Oxymino-Fluorene Derivatives with MI-Crobicidal and Antibiofilm Activity Enhanced by Combination with Iron Oxide Nanoparticles

by Ilinca Margareta Vlad, Diana Camelia Nuță, Robert Viorel Ancuceanu, Miron Teodor Caproiou, Florea Dumitrascu, Ioana Cristina Marinas, Mariana Carmen Chifiriuc, Luminita Gabriela Măruţescu, Irina Zarafu, Ioana Raluca Papacocea, Bogdan Ștefan Vasile, Adrian Ionuț Nicoară, Cornelia-Ioana Ilie, Anton Ficai and Carmen Limban

Molecules 2021, 26(10), 3002; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26103002 - 18 May 2021

Cited by 7 | Viewed by 2617

Abstract

Antimicrobial resistance is one of the major public health threats at the global level, urging the search for new antimicrobial molecules. The fluorene nucleus is a component of different bioactive compounds, exhibiting diverse pharmacological actions. The present work describes the synthesis, chemical structure elucidation, and bioactivity of new O-aryl-carbamoyl-oxymino-fluorene derivatives and the contribution of iron oxide nanoparticles to enhance the desired biological activity. The antimicrobial activity assessed against three bacterial and fungal strains, in suspension and biofilm growth state, using a quantitative assay, revealed that the nature of substituents on the aryl moiety are determinant for both the spectrum and intensity of the inhibitory effect. The electron-withdrawing inductive effect of chlorine atoms enhanced the activity against planktonic and adhered Staphylococcus aureus, while the +I effect of the methyl group enhanced the anti-fungal activity against Candida albicans strain. The magnetite nanoparticles have substantially improved the antimicrobial activity of the new compounds against planktonic microorganisms. The obtained compounds, as well as the magnetic core@shell nanostructures loaded with these compounds have a promising potential for the development of novel antimicrobial strategies. Full article

(This article belongs to the Special Issue Synthetic Antibiofilm Agents: Design, Synthesis and Applications)

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18 pages, 3326 KiB

Open AccessArticle

In Silico and In Vitro Experimental Studies of New Dibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)-oximes Designed as Potential Antimicrobial Agents

by Ilinca Margareta Vlad, Diana Camelia Nuta, Cornel Chirita, Miron Teodor Caproiu, Constantin Draghici, Florea Dumitrascu, Coralia Bleotu, Speranța Avram, Ana Maria Udrea, Alexandru Vasile Missir, Luminita Gabriela Marutescu and Carmen Limban

Molecules 2020, 25(2), 321; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25020321 - 13 Jan 2020

Cited by 16 | Viewed by 2676

Abstract

In a drug-repurposing-driven approach for speeding up the development of novel antimicrobial agents, this paper presents for the first time in the scientific literature the synthesis, physico-chemical characterization, in silico analysis, antimicrobial activity against bacterial and fungal strains in planktonic and biofilm growth state, as well as the in vitro cytotoxicity of some new 6,11-dihydrodibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)oximes. The structures of intermediary and final substances (compounds 7a–j) were confirmed by ¹H-NMR, ¹³C-NMR and IR spectra, as well as by elemental analysis. The in silico bioinformatic and cheminformatic studies evidenced an optimal pharmacokinetic profile for the synthesized compounds 7a–j, characterized by an average lipophilic character predicting good cell membrane permeability and intestinal absorption; low maximum tolerated dose for humans; potassium channels encoded by the hERG I and II genes as potential targets and no carcinogenic effects. The obtained compounds exhibited a higher antimicrobial activity against the planktonic Gram-positive Staphylococcus aureus and Bacillus subtilis strains and the Candida albicans fungal strain. The obtained compounds also inhibited the ability of S. aureus, B. subtilis, Escherichia coli and C. albicans strains to colonize the inert substratum, accounting for their possible use as antibiofilm agents. All the active compounds exhibited low or acceptable cytotoxicity levels on the HCT8 cells, ensuring the potential use of these compounds for the development of new antimicrobial drugs with minimal side effects on the human cells and tissues. Full article

(This article belongs to the Special Issue Synthetic Antibiofilm Agents: Design, Synthesis and Applications)

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18 pages, 2843 KiB

Open AccessArticle

Design, Synthesis and In Vitro Characterization of Novel Antimicrobial Agents Based on 6-Chloro-9H-carbazol Derivatives and 1,3,4-Oxadiazole Scaffolds

by Alexandra T. Bordei Telehoiu, Diana C. Nuță, Miron T. Căproiu, Florea Dumitrascu, Irina Zarafu, Petre Ioniță, Carmellina D. Bădiceanu, Speranța Avram, Mariana C. Chifiriuc, Coralia Bleotu and Carmen Limban

Molecules 2020, 25(2), 266; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25020266 - 09 Jan 2020

Cited by 24 | Viewed by 3572

Abstract

In this paper, we aimed to exploit and combine in the same molecule the carbazole and the 1,3,4-oxadiazole pharmacophores, to obtain novel carprofen derivatives, by using two synthesis pathways. For the first route, the following steps have been followed: (i) (RS)-2-(6-chloro-9H-carbazol-2-yl)propanonic acid (carprofen) treatment with methanol, yielding methyl (RS)-2-(6-chloro-9H-carbazol-2-yl)propanoate; (ii) the resulted methylic ester was converted to (RS)-2-(6-chloro-9H-carbazol-2-yl)propane hydrazide (carprofen hydrazide) by treatment with hydrazine hydrate; (iii) reaction of the hydrazide derivative with acyl chlorides led to N-[(2RS)-2-(6-chloro-9H-carbazol-2-yl)propanoil]-N′-R-substituted-benzoylhydrazine formation, which; (iv) in reaction with phosphorus oxychloride gave the (RS)-1-(6-chloro-9H-carbazol-2-yl)-1-(1,3,4-oxadiazol-2-yl)ethane derivatives. In the second synthesis pathway, new 1,3,4-oxadiazole ring compounds were obtained starting from carprofen which was reacted with isoniazid, in the presence of phosphorus oxychloride to form (RS)-1-(6-chloro-9H-carbazol-2-yl)-1-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]ethane. The synthesized compounds were characterized by IR, ¹H-NMR and ¹³C-NMR, screened for their drug-like properties and evaluated for in vitro cytotoxicity and antimicrobial activity. The obtained compounds exhibited a good antimicrobial activity, some of the compounds being particularly active on E. coli, while others on C. albicans. The most significant result is represented by their exceptional anti-biofilm activity, particularly against the P. aeruginosa biofilm. The cytotoxicity assay revealed that at concentrations lower than 100 μg/mL, the tested compounds do not induce cytotoxicity and do not alter the mammalian cell cycle. The new synthesized compounds show good drug-like properties. The ADME-Tox profiles indicate a good oral absorption and average permeability through the blood brain barrier. However, further research is needed to reduce the predicted mutagenic potential and the hepatotoxicity. Full article

(This article belongs to the Special Issue Synthetic Antibiofilm Agents: Design, Synthesis and Applications)

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18 pages, 4179 KiB

Open AccessFeature PaperArticle

The Analogs of Temporin-GHa Exhibit a Broader Spectrum of Antimicrobial Activity and a Stronger Antibiofilm Potential against Staphylococcus aureus

by Zhipeng Xie, Hanqi Wei, Jiahui Meng, Tong Cheng, Yanting Song, Manchuriga Wang and Yingxia Zhang

Molecules 2019, 24(22), 4173; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24224173 - 18 Nov 2019

Cited by 21 | Viewed by 3306

Abstract

The abuse of antibiotics has led to the emergence of multidrug-resistant bacteria, which is becoming a serious worldwide problem people have to face. In our previous study, temporin-GHa (GHa) cloned from Hylarana guentheri showed antimicrobial activity against Gram-positive bacteria. In order to improve its therapeutic potential, we used a template-based and a database-assisted design to obtain three derived peptides by replacing the histidine at both ends of GHa with lysine, which exhibited faster and stronger bactericidal activity and a broader spectrum than the parent peptide. GHaK and GHa4K targeted to the bacterial membrane to exert their antibacterial activities at a faster membrane damage rate. The derived peptides inhibited the initial adhesion and the formation of Staphylococcus aureus biofilms, and eradicated the mature biofilms, which indicated that the derived peptides effectively penetrated the biofilm and killed bacteria. The therapeutic index (TI) and cell selectivity index (CSI) of the derived peptides increased significantly, which means a broader therapeutic window of the derived peptides. The derived peptides with improved activity and cell selectivity have the potential to be the promising candidates for the treatment of S. aureus infections. Our research also provides new insights into the design and development of antimicrobial peptides. Full article

(This article belongs to the Special Issue Synthetic Antibiofilm Agents: Design, Synthesis and Applications)

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Review

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41 pages, 28741 KiB

Open AccessReview

Metal Complexes—A Promising Approach to Target Biofilm Associated Infections

by Rodica Olar, Mihaela Badea and Mariana Carmen Chifiriuc

Molecules 2022, 27(3), 758; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030758 - 24 Jan 2022

Cited by 19 | Viewed by 3454

Abstract

Microbial biofilms are represented by sessile microbial communities with modified gene expression and phenotype, adhered to a surface and embedded in a matrix of self-produced extracellular polymeric substances (EPS). Microbial biofilms can develop on both prosthetic devices and tissues, generating chronic and persistent infections that cannot be eradicated with classical organic-based antimicrobials, because of their increased tolerance to antimicrobials and the host immune system. Several complexes based mostly on 3D ions have shown promising potential for fighting biofilm-associated infections, due to their large spectrum antimicrobial and anti-biofilm activity. The literature usually reports species containing Mn(II), Ni(II), Co(II), Cu(II) or Zn(II) and a large variety of multidentate ligands with chelating properties such as antibiotics, Schiff bases, biguanides, N-based macrocyclic and fused rings derivatives. This review presents the progress in the development of such species and their anti-biofilm activity, as well as the contribution of biomaterials science to incorporate these complexes in composite platforms for reducing the negative impact of medical biofilms. Full article

(This article belongs to the Special Issue Synthetic Antibiofilm Agents: Design, Synthesis and Applications)

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