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Discovery and Development of the Novel Antimicrobial Agent

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

Deadline for manuscript submissions: closed (20 January 2024) | Viewed by 18616

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Special Issue Editors

Dr. Zeinab Khalil

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Guest Editor

Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia
Interests: biosynthesis; microbial; natural product biodiscovery; gene clusters; multi-drug resistant pathogens
Special Issues, Collections and Topics in MDPI journals

Dr. Marcelo Marucci Pereira Tangerina

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Guest Editor

Department of Botany, Institute of Biosciences, University of São Paulo, São Paulo 05508-090, SP, Brazil
Interests: natural products; metabolomics; secondary metabolites; bioprospecting
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Secondary metabolites, also known as natural products, are produced by a range of species, including bacteria, fungi, and plants. Many medical agents with divergent chemical structures and biological activities such as antibiotic, immunosuppressive, and anti-inflammatory properties have been developed as treatments with potential therapeutic applications for many human diseases. The discovery of penicillin in 1928 contributed to a significant shift in the bio-discovery of antibiotics, emphasizing the crucial role of microbes in the discovery of new antibiotics. Modern healthcare is increasingly confronted with multidrug resistant (MDR) pathogens that are immune to most, if not all, existing antibiotics. Confronted by the loss of the efficacy of existing antibiotic treatments and the rising incidences of intractable infections and morbidity, there is an urgent need to discover new antibiotic classes that have not been compromised by existing resistance mechanisms. Microorganisms produce a wealth of structurally diverse, specialized metabolites with a remarkable range of biological activities and a wide variety of applications in antibiotic biodiscovery. Microbes are a rich source of new drug leads and include polyketides, non-ribosomal peptides, and aminoglycosides. One of the famous microbial polyketides is erythromycin, which was originally isolated from Streptomyces erythraea. This antibiotic is prescribed for many human diseases such as syphilis, acne, and whooping cough. Therefore, microbe-derived biologically active natural products (i.e., antibiotics) and their analogues will continue to inspire the development of new chemical entities (i.e., medicines). This Special Issue seeks manuscript submissions that focus on the discovery of new antibiotics from microbial/plant resources.

Dr. Zeinab Khalil
Dr. Marcelo Marucci Pereira Tangerina
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

antibiotics
bacteria
fungi
plants
multidrug-resistant pathogens
natural products
mode of action
mechanism of action
drug target
drug development

Published Papers (10 papers)

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Research

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25 pages, 1321 KiB

Open AccessArticle

Synthesis of 3-((4-Hydroxyphenyl)amino)propanoic Acid Derivatives as Promising Scaffolds for the Development of Antimicrobial Candidates Targeting Multidrug-Resistant Bacterial and Fungal Pathogens

by Povilas Kavaliauskas, Birutė Grybaitė, Birutė Sapijanskaitė-Banevič, Rita Vaickelionienė, Vidmantas Petraitis, Rūta Petraitienė, Ethan Naing, Andrew Garcia, Ramunė Grigalevičiūtė and Vytautas Mickevičius

Antibiotics 2024, 13(2), 193; https://doi.org/10.3390/antibiotics13020193 - 17 Feb 2024

Viewed by 1082

Abstract

Infections caused by multidrug-resistant bacterial and fungal pathogens represent a significant global health concern, contributing to increased morbidity and mortality rates. Therefore, it is crucial to develop novel compounds targeting drug-resistant microbial strains. Herein, we report the synthesis of amino acid derivatives bearing an incorporated 4-hydroxyphenyl moiety with various substitutions. The resultant novel 3-((4-hydroxyphenyl)amino)propanoic acid derivatives 2–37 exhibited structure-dependent antimicrobial activity against both ESKAPE group bacteria and drug-resistant Candida species. Furthermore, these derivatives demonstrated substantial activity against Candida auris, with minimum inhibitory concentrations ranging from 0.5 to 64 µg/mL. Hydrazones 14–16, containing heterocyclic substituents, showed the most potent and broad-spectrum antimicrobial activity. This activity extended to methicillin-resistant Staphylococcus aureus (MRSA) with MIC values ranging from 1 to 8 µg/mL, vancomycin-resistant Enterococcus faecalis (0.5–2 µg/mL), Gram-negative pathogens (MIC 8–64 µg/mL), and drug-resistant Candida species (MIC 8–64 µg/mL), including Candida auris. Collectively, these findings underscore the potential utility of the novel 3-((4-hydroxyphenyl)amino)propanoic acid scaffold for further development as a foundational platform for novel antimicrobial agents targeting emerging and drug-resistant bacterial and fungal pathogens. Full article

(This article belongs to the Special Issue Discovery and Development of the Novel Antimicrobial Agent)

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12 pages, 1095 KiB

Open AccessFeature PaperArticle

Jugiones A–D: Antibacterial Xanthone–Anthraquinone Heterodimers from Australian Soil-Derived Penicillium shearii CMB-STF067

by Thulasi Sritharan, Angela A. Salim, Zeinab G. Khalil and Robert J. Capon

Antibiotics 2024, 13(1), 97; https://doi.org/10.3390/antibiotics13010097 - 18 Jan 2024

Viewed by 1186

Abstract

The Australian roadside soil-derived fungus Penicillium shearii CMB-STF067 was prioritized for chemical investigation based on an SDA cultivation extract exhibiting both antibacterial properties and natural products with unprecedented molecular formulae (GNPS). Subsequent miniaturized 24-well plate cultivation profiling (MATRIX) identified red rice as optimal for the production of the target chemistry, with scaled-up cultivation, extraction and fractionation yielding four new xanthone–anthraquinone heterodimers, jugiones A–D (1–4), whose structures were assigned by detailed spectroscopic analysis and biosynthetic considerations. Of note, where 1–2 and 4 were active against the Gram-positive bacteria vancomycin-resistant Enterococcus faecalis (IC₅₀ 2.6–3.9 μM) and multiple-drug-resistant clinical isolates of Staphylococcus aureus (IC₅₀ 1.8–6.4 μM), and inactive against the Gram-negative bacteria Escherichia coli (IC₅₀ > 30 μM), the closely related analog 3 exhibited no antibacterial properties (IC₅₀ > 30 μM). Furthermore, where 1 was cytotoxic to human carcinoma (IC₅₀ 9.0–9.8 μM) and fungal (IC₅₀ 4.1 μM) cells, 2 and 4 displayed no such cytotoxicity (IC₅₀ > 30 μM), revealing an informative structure activity relationship (SAR). We also extended the SAR study to other known compounds of this heterodimer class, which showed that the modification of ring G can reduce or eliminate the cytotoxicity while retaining the antibacterial activity. Full article

(This article belongs to the Special Issue Discovery and Development of the Novel Antimicrobial Agent)

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17 pages, 4932 KiB

Open AccessArticle

Hydroquinine Enhances the Efficacy of Contact Lens Solutions for Inhibiting Pseudomonas aeruginosa Adhesion and Biofilm Formation

by Sattaporn Weawsiangsang, Nontaporn Rattanachak, Sukunya Ross, Gareth M. Ross, Robert A. Baldock, Touchkanin Jongjitvimol and Jirapas Jongjitwimol

Antibiotics 2024, 13(1), 56; https://doi.org/10.3390/antibiotics13010056 - 05 Jan 2024

Viewed by 2114

Abstract

P. aeruginosa is one of the most common bacteria causing contact lens-related microbial keratitis (CLMK). Previous studies report that disinfecting solutions were ineffective in preventing biofilm formation. Solutions containing novel natural agents may be an excellent alternative for reducing the risk of CLMK. Here, we investigate the disinfecting properties of hydroquinine in combination with multipurpose solutions (MPSs) to prevent P. aeruginosa adhesion and biofilm formation. We examined the antibacterial, anti-adhesion, and anti-biofilm properties of hydroquinine-formulated MPSs compared to MPSs alone. Using RT-qPCR, hydroquinine directly affected the expression levels of adhesion-related genes, namely, cgrC, cheY, cheZ, fimU, and pilV, resulting in reduced adhesion and anti-biofilm formation. Using ISO 14729 stand-alone testing, hydroquinine met the criteria (>99.9% killing at disinfection time) against both P. aeruginosa reference and clinical strains. Using the crystal violet retention assay and FE-SEM, MPSs combined with hydroquinine were effective in inhibiting P. aeruginosa adhesion and destroying preexisting biofilms. This report is the first to highlight the potential utility of hydroquinine-containing formulations as a disinfecting solution for contact lenses, specifically for inhibiting adhesion and destroying biofilm. These findings may aid in the development of novel disinfectants aimed at combating P. aeruginosa, thereby potentially reducing the incidence of CLMK. Full article

(This article belongs to the Special Issue Discovery and Development of the Novel Antimicrobial Agent)

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16 pages, 4566 KiB

Open AccessArticle

Diflunisal and Analogue Pharmacophores Mediating Suppression of Virulence Phenotypes in Staphylococcus aureus

by Liana C. Chan, Hong K. Lee, Ling Wang, Siyang Chaili, Yan Q. Xiong, Arnold S. Bayer, Richard A. Proctor and Michael R. Yeaman

Antibiotics 2023, 12(7), 1180; https://doi.org/10.3390/antibiotics12071180 - 12 Jul 2023

Viewed by 970

Abstract

Invasive methicillin-resistant Staphylococcus aureus (MRSA) infections are leading causes of morbidity and mortality that are complicated by increasing resistance to conventional antibiotics. Thus, minimizing virulence and enhancing antibiotic efficacy against MRSA is a public health imperative. We originally demonstrated that diflunisal (DIF; [2-hydroxy-5-(2,4-difluorophenyl) benzoic acid]) inhibits S. aureus virulence factor expression. To investigate pharmacophores that are active in this function, we evaluated a library of structural analogues for their efficacy to modulate virulence phenotypes in a panel of clinically relevant S. aureus isolates in vitro. Overall, the positions of the phenyl, hydroxyl, and carboxylic moieties and the presence or type of halogen (F vs. Cl) influenced the efficacy of compounds in suppressing hemolysis, proteolysis, and biofilm virulence phenotypes. Analogues lacking halogens inhibited proteolysis to an extent similar to DIF but were ineffective at reducing hemolysis or biofilm production. In contrast, most analogues lacking the hydroxyl or carboxylic acid groups did not suppress proteolysis but did mitigate hemolysis and biofilm production to an extent similar to DIF. Interestingly, chirality and the substitution of fluorine with chlorine resulted in a differential reduction in virulence phenotypes. Together, this pattern of data suggests virulence-suppressing pharmacophores of DIF and structural analogues integrate halogen, hydroxyl, and carboxylic acid moiety stereochemistry. The anti-virulence effects of DIF were achieved using concentrations that are safe in humans, do not impair platelet antimicrobial functions, do not affect S. aureus growth, and do not alter the efficacy of conventional antibiotics. These results offer proof of concept for using novel anti-virulence strategies as adjuvants to antibiotic therapy to address the challenge of MRSA infection. Full article

(This article belongs to the Special Issue Discovery and Development of the Novel Antimicrobial Agent)

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18 pages, 1712 KiB

Open AccessEditor’s ChoiceArticle

Investigation of α,ω-Disubstituted Polyamine-Cholic Acid Conjugates Identifies Hyodeoxycholic and Chenodeoxycholic Scaffolds as Non-Toxic, Potent Antimicrobials

by Kenneth Sue, Melissa M. Cadelis, Thomas Troia, Florent Rouvier, Marie-Lise Bourguet-Kondracki, Jean Michel Brunel and Brent R. Copp

Antibiotics 2023, 12(2), 404; https://doi.org/10.3390/antibiotics12020404 - 17 Feb 2023

Cited by 1 | Viewed by 1276

Abstract

With the increased incidence of antibiotic resistance, the discovery and development of new antibacterials is of increasing importance and urgency. The report of the natural product antibiotic squalamine in 1993 has stimulated a lot of interest in the study of structurally simplified cholic acid-polyamine derivatives. We report the synthesis of a focused set of deoxycholic acid-polyamine conjugates and the identification of hyodeoxycholic acid derivatives as being potently active towards S. aureus MRSA and some fungal strains, but with no attendant cytotoxicity or hemolytic properties. Analogue 7e exhibited bactericidal activity towards a range of Gram-positive bacteria, while preliminary investigation of its mechanism of action ruled out the bacterial membrane as being a primary cellular target as determined using an ATP-release bioluminescence assay. Full article

(This article belongs to the Special Issue Discovery and Development of the Novel Antimicrobial Agent)

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11 pages, 5294 KiB

Open AccessArticle

In Vitro and In Vivo Studies of Heraclenol as a Novel Bacterial Histidine Biosynthesis Inhibitor against Invasive and Biofilm-Forming Uropathogenic Escherichia coli

by Harpreet Kaur, Naveen Chaudhary, Vinay Modgil, Manmohit Kalia, Vishal Kant, Balvinder Mohan, Alka Bhatia and Neelam Taneja

Antibiotics 2023, 12(1), 110; https://doi.org/10.3390/antibiotics12010110 - 06 Jan 2023

Viewed by 1791

Abstract

Globally, urinary tract infections (UTIs) are one of the most frequent bacterial infections. Uropathogenic Escherichia coli (UPEC) are the predominant etiological agents causing community and healthcare-associated UTIs. Biofilm formation is an important pathogenetic mechanism of UPEC responsible for chronic and recurrent infections. The development of high levels of antimicrobial resistance (AMR) among UPEC has complicated therapeutic management. Newer antimicrobial agents are needed to tackle the increasing trend of AMR and inhibit biofilms. Heraclenol is a natural furocoumarin compound that inhibits histidine biosynthesis selectively. In this study, for the first time, we have demonstrated the antimicrobial and antibiofilm activity of heraclenol against UPEC. The drug reduced the bacterial load in the murine catheter UTI model by ≥4 logs. The drug effectively reduced bacterial loads in kidney, bladder, and urine samples. On histopathological examination, heraclenol treatment showed a reversal of inflammatory changes in the bladder and kidney tissues. It reduced the biofilm formation by 70%. The MIC value of heraclenol was observed to be high (1024 µg/mL), though the drug at MIC concentration did not have significant cytotoxicity on the Vero cell line. Further molecular docking revealed that heraclenol binds to the active site of the HisC, thereby preventing its activation by native substrate, which might be responsible for its antibacterial and antibiofilm activity. Since the high MIC of heraclenol is not achievable clinically in human tissues, further chemical modifications will be required to lower the drug’s MIC value and increase its potency. Alternatively, its synergistic action with other antimicrobials may also be studied. Full article

(This article belongs to the Special Issue Discovery and Development of the Novel Antimicrobial Agent)

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10 pages, 1546 KiB

Open AccessArticle

Expression Profiles of Zebrafish (Danio rerio) Lysozymes and Preparation of c-Type Lysozyme with High Bacteriolytic Activity against Vibrio vulnificus

by Hua Chen, Xi Chen, Tie-Ying Song and Jun-Qing Ge

Antibiotics 2022, 11(12), 1803; https://doi.org/10.3390/antibiotics11121803 - 12 Dec 2022

Cited by 1 | Viewed by 1180

Abstract

Lysozyme is a crucial component of the host’s innate immune system. Due to its natural non-toxic and harmless characteristics, lysozyme is considered to be an ideal antibiotic substitute. In this study, we analyzed the expression profiles of lysozymes from zebrafish (Danio rerio) in uninfected or V. vulnificus-infected tissues using real-time quantitative PCR (qPCR). Furthermore, lysozymes that might be involved in the defense against V. vulnificus were selected for over-expression, and the antibacterial activity of over-expressed lysozyme proteins were evaluated using V. vulnificus. The results showed that three types of zebrafish lysozyme, i.e., c-type lysozyme (DrLysC), g1-type lysozyme (DrLysG1), and g2-type lysozyme (DrLysG2), were identified, and V. vulnificus infection significantly changed the expression levels of DrLysC and DrLysG1. Then, DrLysC and DrLysG1 were over-expressed in E. coli, and the purified recombinant DrLysC (rDrLysC) showed more potent antibacterial activity against V. vulnificus. This finding lays the foundation for further application of rDrLysC to treat V. vulnificus infection. Full article

(This article belongs to the Special Issue Discovery and Development of the Novel Antimicrobial Agent)

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16 pages, 4339 KiB

Open AccessArticle

Synthesis of Fully Deacetylated Quaternized Chitosan with Enhanced Antimicrobial Activity and Low Cytotoxicity

by Yeon Ho Kim, Ki Sun Yoon, Sung-Jae Lee, Eun-Jung Park and Jong-Whan Rhim

Antibiotics 2022, 11(11), 1644; https://doi.org/10.3390/antibiotics11111644 - 17 Nov 2022

Cited by 4 | Viewed by 1530

Abstract

Fully deacetylated quaternary chitosan (DQCTS) was prepared by replacing the carboxyl group of chitosan with a quaternary ammonium salt. The DQCTS was characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), and nuclear magnetic resonance (NMR). The antimicrobial activity of DQCTS was evaluated using the minimum inhibitory concentrations (MIC) methods and time-kill assay. DQCTS exhibited strong antibacterial and antifungal activity against Staphylococcus aureus, Escherichia coli O157: H7, Candida albicans, and Aspergillus flavus. Especially, the antifungal activity against C. albicans of DQCTS was greatly improved at 15.6 µg/mL of MIC and 31.3 µg/mL of minimum fungicidal concentration (MFC). Expression levels of virulence genes of microorganisms were also significantly decreased by DQCTS treatment, and the risk of virulence of microorganisms might be decreased. The result of the cytotoxic effect of DQCTS on human skin cells (HaCaT cells) indicated that the cytotoxicity of DQCTS on HaCaT cells was nearly non-toxic at 50 μg/mL. The DQCTS, with strong antimicrobial and low toxicity, has a high potential for use in functional food packaging and biomedical applications. Full article

(This article belongs to the Special Issue Discovery and Development of the Novel Antimicrobial Agent)

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17 pages, 2395 KiB

Open AccessArticle

New Hygrocins K–U and Streptophenylpropanamide A and Bioactive Compounds from the Marine-Associated Streptomyces sp. ZZ1956

by Wenwen Yi, Asif Wares Newaz, Kuo Yong, Mingzhu Ma, Xiao-Yuan Lian and Zhizhen Zhang

Antibiotics 2022, 11(11), 1455; https://doi.org/10.3390/antibiotics11111455 - 22 Oct 2022

Cited by 3 | Viewed by 1410

Abstract

Marine-derived Streptomyces actinomycetes are one of the most important sources for the discovery of novel bioactive natural products. This study characterized the isolation, structural elucidation and biological activity evaluation of thirty compounds, including twelve previously undescribed compounds, namely hygrocins K–U (5–13, 17 and 18) and streptophenylpropanamide A (23), from the marine-associated actinomycete Streptomyces sp. ZZ1956. Structures of the isolated compounds were determined by a combination of extensive NMR spectroscopic analyses, HRESIMS data, the Mosher’s method, ECD calculations, single crystal X-ray diffraction and comparison with reported data. Hygrocins C (1), D (2), F (4), N (8), Q (11) and R (12), 2-acetamide-6-hydroxy-7-methyl-1,4-naphthoquinone (22), echoside C (27), echoside A (28) and 11,11′-O-dimethylelaiophylin (30) had antiproliferative activity (IC₅₀: 0.16–19.39 μM) against both human glioma U87MG and U251 cells with hygrocin C as the strongest active compound (IC₅₀: 0.16 and 0.35 μM, respectively). The analysis of the structure–activity relationship indicated that a small change in the structures of the naphthalenic ansamycins had significant influence on their antiglioma activities. Hygrocins N (8), O (9), R (12), T (17) and U (18), 2-amino-6-hydroxy-7-methyl-1,4-naphthoquinone (21), 2-acetamide-6-hydroxy-7-methyl-1,4-naphthoquinone (22), 3′-methoxy(1,1′,4′,1″-terphenyl)-2′,6′-diol (26), echoside C (27) and echoside A (28) showed antibacterial activity against methicillin-resistant Staphylococcus aureus and Escherichia coli with MIC values of 3–48 μg/mL. Full article

(This article belongs to the Special Issue Discovery and Development of the Novel Antimicrobial Agent)

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Review

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18 pages, 2224 KiB

Open AccessReview

Combating Bacterial Biofilms: Current and Emerging Antibiofilm Strategies for Treating Persistent Infections

by Ahmed G. Abdelhamid and Ahmed E. Yousef

Antibiotics 2023, 12(6), 1005; https://doi.org/10.3390/antibiotics12061005 - 03 Jun 2023

Cited by 12 | Viewed by 5111

Abstract

Biofilms are intricate multicellular structures created by microorganisms on living (biotic) or nonliving (abiotic) surfaces. Medically, biofilms often lead to persistent infections, increased antibiotic resistance, and recurrence of infections. In this review, we highlighted the clinical problem associated with biofilm infections and focused on current and emerging antibiofilm strategies. These strategies are often directed at disrupting quorum sensing, which is crucial for biofilm formation, preventing bacterial adhesion to surfaces, impeding bacterial aggregation in viscous mucus layers, degrading the extracellular polymeric matrix, and developing nanoparticle-based antimicrobial drug complexes which target persistent cells within the biofilm core. It is important to acknowledge, however, that the use of antibiofilm agents faces obstacles, such as limited effectiveness in vivo, potential cytotoxicity to host cells, and propensity to elicit resistance in targeted biofilm-forming microbes. Emerging next generation antibiofilm strategies, which rely on multipronged approaches, were highlighted, and these benefit from current advances in nanotechnology, synthetic biology, and antimicrobial drug discovery. The assessment of current antibiofilm mitigation approaches, as presented here, could guide future initiatives toward innovative antibiofilm therapeutic strategies. Enhancing the efficacy and specificity of some emerging antibiofilm strategies via careful investigations, under conditions that closely mimic biofilm characteristics within the human body, could bridge the gap between laboratory research and practical application. Full article

(This article belongs to the Special Issue Discovery and Development of the Novel Antimicrobial Agent)

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