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Special Issue "Novel Antibacterial Agents"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 64945

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Dr. Fiorella Meneghetti

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Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, Italy
Interests: diffraction techniques; structure elucidation; conformation of bioactive compounds; antitubercular and anticancer agents; metal complexes, protein–protein interaction inhibitors; enzymatic inhibitors; multi-target drugs
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Prof. Dr. Daniela Barlocco

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Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy
Interests: protein–protein interaction inhibitors; enzyme inhibitors; multi-target drugs; anticancer agents
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Infectious diseases still account for a substantial proportion of deaths worldwide. The plague of antimicrobial resistance represents an alarming signal for both human and animal healthcare, which drives the search for novel classes of antibiotics to replenish our armamentarium against bacterial infections.There is a great interest in the opportunities and challenges associated with tackling infectious diseases for developing effective and possibly cheap antimicrobial agents endowed with new mechanisms of action. The discovery of new antimicrobials as well as the expansion of utility of existing antibiotics would be crucial to fight the ever-increasing antimicrobial resistance of “superbugs”, pathogenic fungi, viruses, and parasites. Pharmaceuticals invites both reviews and original articles highlighting the recent medicinal chemistry research on novel antibacterial agents. Topics include natural product screening, identification and validation of new antibacterial targets and strategies for the discovery and optimization of antibacterial compounds.

The collection of manuscripts will be published as a Special Issue of the journal.

Dr. Fiorella Meneghetti
Prof. Daniela Barlocco
Guest Editors

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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. Pharmaceuticals 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 2200 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

small molecules
peptides
peptidomimetics
bacterial infections
fungi
virus
parasites
drug design
computational tools
biology assays
resistance mechanisms.

Related Special Issues

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Antibiotics in Pharmaceuticals (10 articles)
Antimicrobial Agents in Pharmaceuticals (6 articles)
Bacterial Drug Persisters: Basis, Regulatory Events, and Role in Pathogenesis in Pharmaceuticals (1 article)

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Editorial

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Open AccessEditorial

Special Issue “Novel Antibacterial Agents”

Fiorella Meneghetti

and

Daniela Barlocco

Pharmaceuticals 2021, 14(4), 382; https://doi.org/10.3390/ph14040382 - 19 Apr 2021

Cited by 2 | Viewed by 1460

Abstract

This Special Issue of Pharmaceuticals is devoted to significant advances achieved in the field of antibacterial agents [...] Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

Research

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Open AccessArticle

Synthesis, Characterization, and Biological Evaluation of New Derivatives Targeting MbtI as Antitubercular Agents

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Pharmaceuticals 2021, 14(2), 155; https://doi.org/10.3390/ph14020155 - 13 Feb 2021

Cited by 16 | Viewed by 2543

Abstract

Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of Mycobacterium tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new antitubercular agents is the salicylate synthase MbtI, an essential enzyme for the mycobacterial siderophore biochemical machinery, absent in human cells. A set of analogues of I and II, two of the most potent MbtI inhibitors identified to date, was synthesized, characterized, and tested to elucidate the structural requirements for achieving an efficient MbtI inhibition and a potent antitubercular activity with this class of compounds. The structure-activity relationships (SAR) here discussed evidenced the importance of the furan as part of the pharmacophore and led to the preparation of six new compounds (IV–IX), which gave us the opportunity to examine a hitherto unexplored position of the phenyl ring. Among them emerged 5-(3-cyano-5-(trifluoromethyl)phenyl)furan-2-carboxylic acid (IV), endowed with comparable inhibitory properties to the previous leads, but a better antitubercular activity, which is a key issue in MbtI inhibitor research. Therefore, compound IV offers promising prospects for future studies on the development of novel agents against mycobacterial infections. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Open AccessArticle

Liquid and Vapor Phase of Four Conifer-Derived Essential Oils: Comparison of Chemical Compositions and Antimicrobial and Antioxidant Properties

Stefania Garzoli

Valentina Laghezza Masci

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Pharmaceuticals 2021, 14(2), 134; https://doi.org/10.3390/ph14020134 - 08 Feb 2021

Cited by 18 | Viewed by 2297

Abstract

In this study, the chemical composition of the vapor and liquid phase of Pinus cembra L., Pinus mugo Turra, Picea abies L., and Abies Alba M. needles essential oils (EOs) was investigated by Headspace-Gas Chromatography/Mass Spectrometry (HS-GC/MS). In the examined EOs, a total of twenty-eight components were identified, most of which belong to the monoterpenes family. α-Pinene (16.6–44.0%), β-pinene (7.5–44.7%), limonene (9.5–32.5%), and γ-terpinene (0.3–19.7%) were the most abundant components of the liquid phase. Such major compounds were also detected in the vapor phase of all EOs, and α-pinene reached higher relative percentages than in the liquid phase. Then, both the liquid and vapor phases were evaluated in terms of antibacterial activity against three Gram-negative bacteria (Escherichia coli, Pseudomonas fluorescens, and Acinetobacter bohemicus) and two Gram-positive bacteria (Kocuria marina and Bacillus cereus) using a microwell dilution assay, disc diffusion assay, and vapor phase test. The lowest Minimum Inhibitory Concentration (MIC) (13.28 mg/mL) and Minimal Bactericidal Concentration (MBC) (26.56 mg/mL) values, which correspond to the highest antibacterial activities, were reported for P. abies EO against A. bohemicus and for A. alba EO against A. bohemicus and B. cereus. The vapor phase of all the tested EOs was more active than liquid phase, showing the inhibition halos from 41.00 ± 10.15 mm to 80.00 ± 0.00 mm for three bacterial strains (A. bohemicus, K. marina, and B. cereus). Furthermore, antioxidant activities were also investigated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azinobis (3- ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) assays, and a concentration-dependent antioxidant capacity for all EOs was found. P. mugo EO showed the best antioxidant activity than the other Pinaceae EOs. The four Pinaceae EOs could be further investigated for their promising antibacterial and antioxidant properties, and, in particular, α-pinene seems to have interesting possibilities for use as a novel natural antibacterial agent. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Open AccessArticle

Antimicrobial Peptide K11 Selectively Recognizes Bacterial Biomimetic Membranes and Acts by Twisting Their Bilayers

Francisco Ramos-Martín

and

Pharmaceuticals 2021, 14(1), 1; https://doi.org/10.3390/ph14010001 - 22 Dec 2020

Cited by 18 | Viewed by 2778

Abstract

K11 is a synthetic peptide originating from the introduction of a lysine residue in position 11 within the sequence of a rationally designed antibacterial scaffold. Despite its remarkable antibacterial properties towards many ESKAPE bacteria and its optimal therapeutic index (320), a detailed description of its mechanism of action is missing. As most antimicrobial peptides act by destabilizing the membranes of the target organisms, we investigated the interaction of K11 with biomimetic membranes of various phospholipid compositions by liquid and solid-state NMR. Our data show that K11 can selectively destabilize bacterial biomimetic membranes and torque the surface of their bilayers. The same is observed for membranes containing other negatively charged phospholipids which might suggest additional biological activities. Molecular dynamic simulations reveal that K11 can penetrate the membrane in four steps: after binding to phosphate groups by means of the lysine residue at the N-terminus (anchoring), three couples of lysine residues act subsequently to exert a torque in the membrane (twisting) which allows the insertion of aromatic side chains at both termini (insertion) eventually leading to the flip of the amphipathic helix inside the bilayer core (helix flip and internalization). Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Imidazole and Imidazolium Antibacterial Drugs Derived from Amino Acids

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Pharmaceuticals 2020, 13(12), 482; https://doi.org/10.3390/ph13120482 - 21 Dec 2020

Cited by 18 | Viewed by 3248

Abstract

The antibacterial activity of imidazole and imidazolium salts is highly dependent upon their lipophilicity, which can be tuned through the introduction of different hydrophobic substituents on the nitrogen atoms of the imidazole or imidazolium ring of the molecule. Taking this into consideration, we have synthesized and characterized a series of imidazole and imidazolium salts derived from L-valine and L-phenylalanine containing different hydrophobic groups and tested their antibacterial activity against two model bacterial strains, Gram-negative E. coli and Gram-positive B. subtilis. Importantly, the results demonstrate that the minimum bactericidal concentration (MBC) of these derivatives can be tuned to fall close to the cytotoxicity values in eukaryotic cell lines. The MBC value of one of these compounds toward B. subtilis was found to be lower than the IC₅₀ cytotoxicity value for the control cell line, HEK-293. Furthermore, the aggregation behavior of these compounds has been studied in pure water, in cell culture media, and in mixtures thereof, in order to determine if the compounds formed self-assembled aggregates at their bioactive concentrations with the aim of determining whether the monomeric species were in fact responsible for the observed antibacterial activity. Overall, these results indicate that imidazole and imidazolium compounds derived from L-valine and L-phenylalanine—with different alkyl lengths in the amide substitution—can serve as potent antibacterial agents with low cytotoxicity to human cell lines. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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N-(Hydroxyalkyl) Derivatives of tris(1H-indol-3-yl)methylium Salts as Promising Antibacterial Agents: Synthesis and Biological Evaluation

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Pharmaceuticals 2020, 13(12), 469; https://doi.org/10.3390/ph13120469 - 16 Dec 2020

Cited by 3 | Viewed by 1423

Abstract

The wide spread of pathogens resistance requires the development of new antimicrobial agents capable of overcoming drug resistance. The main objective of the study is to elucidate the effect of substitutions in tris(1H-indol-3-yl)methylium derivatives on their antibacterial activity and toxicity to human cells. A series of new compounds were synthesized and tested. Their antibacterial activity in vitro was performed on 12 bacterial strains, including drug resistant strains, that were clinical isolates or collection strains. The cytotoxic effect of the compounds was determined using an test with HPF-hTERT (human postnatal fibroblasts, immortalized with hTERT) cells. The activity of the obtained compounds depended on the carbon chain length. Derivatives with C5–C6 chains were more active. The minimum inhibitory concentration (MIC) of the most active compound on Gram-positive bacteria, including MRSA, was 0.5 μg/mL. Compounds with C5–C6 chains also revealed high activity against Staphylococcus epidermidis (1.0 and 0.5 μg/mL, respectively) and moderate activity against Gram-negative bacteria Escherichia coli (8 μg/mL) and Klebsiella pneumonia (2 and 8 μg/mL, respectively). However, they have no activity against Salmonella cholerasuis and Pseudomonas aeruginosa. The most active compounds revealed higher antibacterial activity on MRSA than the reference drug levofloxacin, and their ratio between antibacterial and cytotoxic activity exceeded 10 times. The data obtained provide a basis for further study of this promising group of substances. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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3-Pentylcatechol, a Non-Allergenic Urushiol Derivative, Displays Anti-Helicobacter pylori Activity In Vivo

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Pharmaceuticals 2020, 13(11), 384; https://doi.org/10.3390/ph13110384 - 13 Nov 2020

Cited by 5 | Viewed by 1681

Abstract

We previously reported that 3-pentylcatechol (PC), a synthetic non-allergenic urushiol derivative, inhibited the growth of Helicobacter pylori in an in vitro assay using nutrient agar and broth. In this study, we aimed to investigate the in vivo antimicrobial activity of PC against H. pylori growing in the stomach mucous membrane. Four-week-old male C57BL/6 mice (n = 4) were orally inoculated with H. pylori Sydney Strain-1 (SS-1) for 8 weeks. Thereafter, the mice received PC (1, 5, and 15 mg/kg) and triple therapy (omeprazole, 0.7 mg/kg; metronidazole, 16.7 mg/kg; clarithromycin, 16.7 mg/kg, reference groups) once daily for 10 days. Infiltration of inflammatory cells in gastric tissue was greater in the H. pylori-infected group compared with the control group and lower in both the triple therapy- and PC-treated groups. In addition, upregulation of cytokine mRNA was reversed after infection, upon administration of triple therapy and PC. Interestingly, PC was more effective than triple therapy at all doses, even at 1/15th the dose of triple therapy. In addition, PC demonstrated synergism with triple therapy, even at low concentrations. The results suggest that PC may be more effective against H. pylori than established antibiotics. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Open AccessArticle

Biofilm Inhibition and Eradication Properties of Medicinal Plant Essential Oils against Methicillin-Resistant Staphylococcus aureus Clinical Isolates

Fethi Ben Abdallah

Rihab Lagha

and

Ahmed Gaber

Pharmaceuticals 2020, 13(11), 369; https://doi.org/10.3390/ph13110369 - 06 Nov 2020

Cited by 16 | Viewed by 2105

Abstract

Methicillin-resistant Staphylococcus aureus is a major human pathogen that poses a high risk to patients due to the development of biofilm. Biofilms, are complex biological systems difficult to treat by conventional antibiotic therapy, which contributes to >80% of humans infections. In this report, we examined the antibacterial activity of Origanum majorana, Rosmarinus officinalis, and Thymus zygis medicinal plant essential oils against MRSA clinical isolates using disc diffusion and MIC methods. Moreover, biofilm inhibition and eradication activities of oils were evaluated by crystal violet. Gas chromatography–mass spectrometry analysis revealed variations between oils in terms of component numbers in addition to their percentages. Antibacterial activity testing showed a strong effect of these oils against MRSA isolates, and T. zygis had the highest activity succeeded by O. majorana and R. officinalis. Investigated oils demonstrated high biofilm inhibition and eradication actions, with the percentage of inhibition ranging from 10.20 to 95.91%, and the percentage of eradication ranging from 12.65 to 98.01%. O. majorana oil had the highest biofilm inhibition and eradication activities. Accordingly, oils revealed powerful antibacterial and antibiofilm activities against MRSA isolates and could be a good alternative for antibiotics substitution. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Open AccessCommunication

Bromo-Cyclobutenaminones as New Covalent UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) Inhibitors

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Pharmaceuticals 2020, 13(11), 362; https://doi.org/10.3390/ph13110362 - 03 Nov 2020

Cited by 4 | Viewed by 2690

Abstract

Drug discovery programs against the antibacterial target UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) have already resulted in covalent inhibitors having small three- and five-membered heterocyclic rings. In the current study, the reactivity of four-membered rings was carefully modulated to obtain a novel family of covalent MurA inhibitors. Screening a small library of cyclobutenone derivatives led to the identification of bromo-cyclobutenaminones as new electrophilic warheads. The electrophilic reactivity and cysteine specificity have been determined in a glutathione (GSH) and an oligopeptide assay, respectively. Investigating the structure-activity relationship for MurA suggests a crucial role for the bromine atom in the ligand. In addition, MS/MS experiments have proven the covalent labelling of MurA at Cys115 and the observed loss of the bromine atom suggests a net nucleophilic substitution as the covalent reaction. This new set of compounds might be considered as a viable chemical starting point for the discovery of new MurA inhibitors. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Quinolizidine-Derived Lucanthone and Amitriptyline Analogues Endowed with Potent Antileishmanial Activity

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Pharmaceuticals 2020, 13(11), 339; https://doi.org/10.3390/ph13110339 - 25 Oct 2020

Cited by 6 | Viewed by 1739

Abstract

Leishmaniases are neglected diseases that are endemic in many tropical and sub-tropical Countries. Therapy is based on different classes of drugs which are burdened by severe side effects, occurrence of resistance and high costs, thereby creating the need for more efficacious, safer and inexpensive drugs. Herein, sixteen 9-thioxanthenone derivatives (lucanthone analogues) and four compounds embodying the diarylethene substructure of amitriptyline (amitriptyline analogues) were tested in vitro for activity against Leishmania tropica and L. infantum promastigotes. All compounds were characterized by the presence of a bulky quinolizidinylalkyl moiety. All compounds displayed activity against both species of Leishmania with IC₅₀ values in the low micromolar range, resulting in several fold more potency than miltefosine, comparable to that of lucanthone, and endowed with substantially lower cytotoxicity to Vero-76 cells, for the best of them. Thus, 4-amino-1-(quinolizidinylethyl)aminothioxanthen-9-one (14) and 9-(quinolizidinylmethylidene)fluorene (17), with selectivity index (SI) in the range 16–24, represent promising leads for the development of improved antileishmanial agents. These two compounds also exhibited comparable activity against intramacrophagic amastigotes of L. infantum. Docking studies have suggested that the inhibition of trypanothione reductase (TryR) may be at the basis (eventually besides other mechanisms) of the observed antileishmanial activity. Therefore, these investigated derivatives may deserve further structural improvements and more in-depth biological studies of their mechanisms of action in order to develop more efficient antiparasitic agents. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Open AccessArticle

Antibacterial Drug-Release Polydimethylsiloxane Coating for 3D-Printing Dental Polymer: Surface Alterations and Antimicrobial Effects

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Pharmaceuticals 2020, 13(10), 304; https://doi.org/10.3390/ph13100304 - 12 Oct 2020

Cited by 15 | Viewed by 2974

Abstract

Polymers are the most commonly used material for three-dimensional (3D) printing in dentistry; however, the high porosity and water absorptiveness of the material adversely influence biofilm formation on the surface of the 3D-printed dental prostheses. This study evaluated the effects of a newly developed chlorhexidine (CHX)-loaded polydimethylsiloxane (PDMS)-based coating material on the surface microstructure, surface wettability and antibacterial activity of 3D-printing dental polymer. First, mesoporous silica nanoparticles (MSN) were used to encapsulate CHX, and the combination was added to PDMS to synthesize the antibacterial agent-releasing coating substance. Then, a thin coating film was formed on the 3D-printing polymer specimens using oxygen plasma and thermal treatment. The results show that using the coating substance significantly reduced the surface irregularity and increased the hydrophobicity of the specimens. Remarkably, the culture media containing coated specimens had a significantly lower number of bacterial colony formation units than the noncoated specimens, thereby indicating the effective antibacterial activity of the coating. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Cytotoxicity Effects of Water-Soluble Multi-Walled Carbon Nanotubes Decorated with Quaternized Hyperbranched Poly(ethyleneimine) Derivatives on Autotrophic and Heterotrophic Gram-Negative Bacteria

Nikolaos S. Heliopoulos

Georgia Kythreoti

Kyriaki Marina Lyra

Katerina N. Panagiotaki

Aggeliki Papavasiliou

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Pharmaceuticals 2020, 13(10), 293; https://doi.org/10.3390/ph13100293 - 06 Oct 2020

Cited by 4 | Viewed by 1925

Abstract

Oxidized multi-walled carbon nanotubes (oxCNTs) were functionalized by a simple non-covalent modification procedure using quaternized hyperbranched poly(ethyleneimine) derivatives (QPEIs), with various quaternization degrees. Structural characterization of these hybrids using a variety of techniques, revealed the successful and homogenous anchoring of QPEIs on the oxCNTs’ surface. Moreover, these hybrids efficiently dispersed in aqueous media, forming dispersions with excellent aqueous stability for over 12 months. Their cytotoxicity effect was investigated on two types of gram(−) bacteria, an autotrophic (cyanobacterium Synechococcus sp. PCC 7942) and a heterotrophic (bacterium Escherichia coli). An enhanced, dose-dependent antibacterial and anti-cyanobacterial activity against both tested organisms was observed, increasing with the quaternization degree. Remarkably, in the photosynthetic bacteria it was shown that the hybrid materials affect their photosynthetic apparatus by selective inhibition of the Photosystem-I electron transport activity. Cytotoxicity studies on a human prostate carcinoma DU145 cell line and 3T3 mouse fibroblasts revealed that all hybrids exhibit high cytocompatibility in the concentration range, in which they also exhibit both high antibacterial and anti-cyanobacterial activity. Thus, QPEI-functionalized oxCNTs can be very attractive candidates as antibacterial and anti-cyanobacterial agents that can be used for potential applications in the disinfection industry, as well as for the control of harmful cyanobacterial blooms. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Open AccessArticle

Potential of Cell-Free Supernatant from Lactobacillus plantarum NIBR97, Including Novel Bacteriocins, as a Natural Alternative to Chemical Disinfectants

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Pharmaceuticals 2020, 13(10), 266; https://doi.org/10.3390/ph13100266 - 23 Sep 2020

Cited by 17 | Viewed by 3053

Abstract

The recent pandemic of coronavirus disease 2019 (COVID-19) has increased demand for chemical disinfectants, which can be potentially hazardous to users. Here, we suggest that the cell-free supernatant from Lactobacillus plantarum NIBR97, including novel bacteriocins, has potential as a natural alternative to chemical disinfectants. It exhibits significant antibacterial activities against a broad range of pathogens, and was observed by scanning electron microscopy (SEM) to cause cellular lysis through pore formation in bacterial membranes, implying that its antibacterial activity may be mediated by peptides or proteins and supported by proteinase K treatment. It also showed significant antiviral activities against HIV-based lentivirus and influenza A/H3N2, causing lentiviral lysis through envelope collapse. Furthermore, whole-genome sequencing revealed that NIBR97 has diverse antimicrobial peptides, and among them are five novel bacteriocins, designated as plantaricin 1 to 5. Plantaricin 3 and 5 in particular showed both antibacterial and antiviral activities. SEM revealed that plantaricin 3 causes direct damage to both bacterial membranes and viral envelopes, while plantaricin 5 damaged only bacterial membranes, implying different antiviral mechanisms. Our data suggest that the cell-free supernatant from L. plantarum NIBR97, including novel bacteriocins, is potentially useful as a natural alternative to chemical disinfectants. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Screening of Bacterial Quorum Sensing Inhibitors in a Vibrio fischeri LuxR-Based Synthetic Fluorescent E. coli Biosensor

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Francisco M. Goycoolea

Pharmaceuticals 2020, 13(9), 263; https://doi.org/10.3390/ph13090263 - 22 Sep 2020

Cited by 4 | Viewed by 3264

Abstract

A library of 23 pure compounds of varying structural and chemical characteristics was screened for their quorum sensing (QS) inhibition activity using a synthetic fluorescent Escherichia coli biosensor that incorporates a modified version of lux regulon of Vibrio fischeri. Four such compounds exhibited QS inhibition activity without compromising bacterial growth, namely, phenazine carboxylic acid (PCA), 2-heptyl-3-hydroxy-4-quinolone (PQS), 1H-2-methyl-4-quinolone (MOQ) and genipin. When applied at 50 µM, these compounds reduced the QS response of the biosensor to 33.7% ± 2.6%, 43.1% ± 2.7%, 62.2% ± 6.3% and 43.3% ± 1.2%, respectively. A series of compounds only showed activity when tested at higher concentrations. This was the case of caffeine, which, when applied at 1 mM, reduced the QS to 47% ± 4.2%. In turn, capsaicin, caffeic acid phenethyl ester (CAPE), furanone and polygodial exhibited antibacterial activity when applied at 1mM, and reduced the bacterial growth by 12.8% ± 10.1%, 24.4% ± 7.0%, 91.4% ± 7.4% and 97.5% ± 3.8%, respectively. Similarly, we confirmed that trans-cinnamaldehyde and vanillin, when tested at 1 mM, reduced the QS response to 68.3% ± 4.9% and 27.1% ± 7.4%, respectively, though at the expense of concomitantly reducing cell growth by 18.6% ± 2.5% and 16% ± 2.2%, respectively. Two QS natural compounds of Pseudomonas aeruginosa, namely PQS and PCA, and the related, synthetic compounds MOQ, 1H-3-hydroxyl-4-quinolone (HOQ) and 1H-2-methyl-3-hydroxyl-4-quinolone (MHOQ) were used in molecular docking studies with the binding domain of the QS receptor TraR as a target. We offer here a general interpretation of structure-function relationships in this class of compounds that underpins their potential application as alternatives to antibiotics in controlling bacterial virulence. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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In Vitro Selective Growth-Inhibitory Activities of Phytochemicals, Synthetic Phytochemical Analogs, and Antibiotics against Diarrheagenic/Probiotic Bacteria and Cancer/Normal Intestinal Cells

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Pharmaceuticals 2020, 13(9), 233; https://doi.org/10.3390/ph13090233 - 03 Sep 2020

Cited by 12 | Viewed by 3383

Abstract

A desirable attribute of novel antimicrobial agents for bacterial diarrhea is decreased toxicity toward host intestinal microbiota. In addition, gut dysbiosis is associated with an increased risk of developing intestinal cancer. In this study, the selective growth-inhibitory activities of ten phytochemicals and their synthetic analogs (berberine, bismuth subsalicylate, ferron, 8-hydroxyquinoline, chloroxine, nitroxoline, salicylic acid, sanguinarine, tannic acid, and zinc pyrithione), as well as those of six commercial antibiotics (ceftriaxone, ciprofloxacin, chloramphenicol, metronidazole, tetracycline, and vancomycin) against 21 intestinal pathogenic/probiotic (e.g., Salmonella spp. and bifidobacteria) bacterial strains and three intestinal cancer/normal (Caco-2, HT29, and FHs 74 Int) cell lines were examined in vitro using the broth microdilution method and thiazolyl blue tetrazolium bromide assay. Chloroxine, ciprofloxacin, nitroxoline, tetracycline, and zinc pyrithione exhibited the most potent selective growth-inhibitory activity against pathogens, whereas 8-hydroxyquinoline, chloroxine, nitroxoline, sanguinarine, and zinc pyrithione exhibited the highest cytotoxic activity against cancer cells. None of the tested antibiotics were cytotoxic to normal cells, whereas 8-hydroxyquinoline and sanguinarine exhibited selective antiproliferative activity against cancer cells. These findings indicate that 8-hydroxyquinoline alkaloids and metal-pyridine derivative complexes are chemical structures derived from plants with potential bioactive properties in terms of selective antibacterial and anticancer activities against diarrheagenic bacteria and intestinal cancer cells. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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3-Amino-5-(indol-3-yl)methylene-4-oxo-2-thioxothiazolidine Derivatives as Antimicrobial Agents: Synthesis, Computational and Biological Evaluation

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Pharmaceuticals 2020, 13(9), 229; https://doi.org/10.3390/ph13090229 - 01 Sep 2020

Cited by 15 | Viewed by 2922

Abstract

Herein we report the design, synthesis, computational, and experimental evaluation of the antimicrobial activity of fourteen new 3-amino-5-(indol-3-yl) methylene-4-oxo-2-thioxothiazolidine derivatives. The structures were designed, and their antimicrobial activity and toxicity were predicted in silico. All synthesized compounds exhibited antibacterial activity against eight Gram-positive and Gram-negative bacteria. Their activity exceeded those of ampicillin and (for the majority of compounds) streptomycin. The most sensitive bacterium was S. aureus (American Type Culture Collection ATCC 6538), while L. monocytogenes (NCTC 7973) was the most resistant. The best antibacterial activity was observed for compound 5d (Z)-N-(5-((1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-4-hydroxybenzamide (Minimal inhibitory concentration, MIC at 37.9–113.8 μM, and Minimal bactericidal concentration MBC at 57.8–118.3 μM). Three most active compounds 5d, 5g, and 5k being evaluated against three resistant strains, Methicillin resistant Staphilococcus aureus (MRSA), P. aeruginosa, and E. coli, were more potent against MRSA than ampicillin (MIC at 248–372 μM, MBC at 372–1240 μM). At the same time, streptomycin (MIC at 43–172 μM, MBC at 86–344 μM) did not show bactericidal activity at all. The compound 5d was also more active than ampicillin towards resistant P. aeruginosa strain. Antifungal activity of all compounds exceeded those of the reference antifungal agents bifonazole (MIC at 480–640 μM, and MFC at 640–800 μM) and ketoconazole (MIC 285–475 μM and MFC 380–950 μM). The best activity was exhibited by compound 5g. The most sensitive fungal was T. viride (IAM 5061), while A. fumigatus (human isolate) was the most resistant. Low cytotoxicity against HEK-293 human embryonic kidney cell line and reasonable selectivity indices were shown for the most active compounds 5d, 5g, 5k, 7c using thiazolyl blue tetrazolium bromide MTT assay. The docking studies indicated a probable involvement of E. coli Mur B inhibition in the antibacterial action, while CYP51 inhibition is likely responsible for the antifungal activity of the tested compounds. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Open AccessCommunication

A Fluorinated Analogue of Marine Bisindole Alkaloid 2,2-Bis(6-bromo-1H-indol-3-yl)ethanamine as Potential Anti-Biofilm Agent and Antibiotic Adjuvant Against Staphylococcus aureus

Raffaella Campana

Gianmarco Mangiaterra

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Pharmaceuticals 2020, 13(9), 210; https://doi.org/10.3390/ph13090210 - 26 Aug 2020

Cited by 7 | Viewed by 2470

Abstract

Methicillin resistant Staphylococcus aureus (MRSA) infections represent a major global healthcare problem. Therapeutic options are often limited by the ability of MRSA strains to grow as biofilms on medical devices, where antibiotic persistence and resistance is positively selected, leading to recurrent and chronic implant-associated infections. One strategy to circumvent these problems is the co-administration of adjuvants, which may prolong the efficacy of antibiotic treatments, by broadening their spectrum and lowering the required dosage. The marine bisindole alkaloid 2,2-bis(6-bromo-1H-indol-3-yl)ethanamine (1) and its fluorinated analogue (2) were tested for their potential use as antibiotic adjuvants and antibiofilm agents against S. aureus CH 10850 (MRSA) and S. aureus ATCC 29213 (MSSA). Both compounds showed antimicrobial activity and bisindole 2 enabled 256-fold reduction (ΣFICs = 0.5) in the minimum inhibitory concentration (MIC) of oxacillin for the clinical MRSA strain. In addition, these molecules inhibited biofilm formation of S. aureus strains, and compound 2 showed greater eradicating activity on preformed biofilm compared to 1. None of the tested molecules exerted a viable but non-culturable cells (VBNC) inducing effect at their MIC values. Moreover, both compounds exhibited no hemolytic activity and a good stability in plasma, indicating a non-toxic profile, hence, in particular compound 2, a potential for in vivo applications to restore antibiotic treatment against MRSA infections. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Open AccessArticle

Bactericidal and In Vitro Cytotoxicity of Moringa oleifera Seed Extract and Its Elemental Analysis Using Laser-Induced Breakdown Spectroscopy

Reem K. Aldakheel

Suriya Rehman

Munirah A. Almessiere

and

Pharmaceuticals 2020, 13(8), 193; https://doi.org/10.3390/ph13080193 - 13 Aug 2020

Cited by 30 | Viewed by 3519

Abstract

In the current study, we present the correlation between the capability of laser-induced breakdown spectroscopy (LIBS) to monitor the elemental compositions of plants and their biological effects. The selected plant, Moringa oleifera, is known to harbor various minerals and vitamins useful for human health and is a potential source for pharmaceutical interventions. From this standpoint, we assessed the antibacterial and in vitro cytotoxicity of the bioactive components present in Moringa oleifera seed (MOS) extract. Detailed elemental analyses of pellets of MOSs were performed via LIBS. Furthermore, the LIBS outcome was validated using gas chromatography–mass spectrometry (GC-MS). The LIBS signal was recorded, and the presence of the essential elements (Na, Ca, Se, K, Mg, Zn, P, S, Fe and Mn) in the MOSs were examined. The bactericidal efficacy of the alcoholic MOS extract was examined against Escherichia coli (E. coli) and Staphylococcus aureus(S. aureus) by agar well diffusion (AWD) assays and scanning electron microscopy (SEM), which depicted greater inhibition against Gram-positive bacteria. The validity and DNA nuclear morphology of human colorectal carcinoma cells (HCT-116) cells were evaluated via an MTT assay and DAPI staining. The MTT assay results manifested a profoundly inhibitory action of MOS extract on HCT116 cell growth. Additionally, MOS extracts produced inhibitory action in colon cancer cells (HCT-116), whereas no inhibitory action was seen using the same concentrations of MOS extract on HEK-293 cells (non-cancerous cells), suggesting that MOS extracts could be non-cytotoxic to normal cells. The antibacterial and anticancer potency of these MOS extracts could be due to the presence of various bioactive chemical complexes, such as ethyl ester and D-allose and hexadecenoic, oleic and palmitic acids, making them an ideal candidate for pharmaceutical research and applications. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Open AccessArticle

Products Derived from Buchenavia tetraphylla Leaves Have In Vitro Antioxidant Activity and Protect Tenebrio molitor Larvae against Escherichia coli-Induced Injury

Tiago Fonseca Silva

José Robson Neves Cavalcanti Filho

Mariana Mirelle Lima Barreto Fonsêca

Natalia Medeiros dos Santos

Ana Carolina Barbosa da Silva

Adrielle Zagmignan

Afonso Gomes Abreu

Ana Paula Sant’Anna da Silva

Vera Lúcia de Menezes Lima

Nicácio Henrique da Silva

Lívia Macedo Dutra

Jackson Roberto Guedes da Silva Almeida

Márcia Vanusa da Silva

Maria Tereza dos Santos Correia

and

Luís Cláudio Nascimento da Silva

Pharmaceuticals 2020, 13(3), 46; https://doi.org/10.3390/ph13030046 - 16 Mar 2020

Cited by 9 | Viewed by 2674

Abstract

The relevance of oxidative stress in the pathogenesis of several diseases (including inflammatory disorders) has traditionally led to the search for new sources of antioxidant compounds. In this work, we report the selection of fractions with high antioxidant action from B. tetraphylla (BT) leaf extracts. In vitro methods (DPPH and ABTS assays; determination of phenolic and flavonoid contents) were used to select products derived from B. tetraphylla with high antioxidant action. Then, the samples with the highest potentials were evaluated in a model of injury based on the inoculation of a lethal dose of heat-inactivated Escherichia coli in Tenebrio molitor larvae. Due to its higher antioxidant properties, the methanolic extract (BTME) was chosen to be fractionated using Sephadex LH-20 column-based chromatography. Two fractions from BTME (BTFC and BTFD) were the most active fractions. Pre-treatment with these fractions protected larvae of T. molitor from the stress induced by inoculation of heat-inactivated E. coli. Similarly, BTFC and BTFD increased the lifespan of larvae infected with a lethal dose of enteroaggregative E. coli 042. NMR data indicated the presence of aliphatic compounds (terpenes, fatty acids, carbohydrates) and aromatic compounds (phenolic compounds). These findings suggested that products derived from B. tetraphylla leaves are promising candidates for the development of antioxidant and anti-infective agents able to treat oxidative-related dysfunctions. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Open AccessArticle

In Vitro Assessment of Antimicrobial, Antioxidant, and Cytotoxic Properties of Saccharin–Tetrazolyl and –Thiadiazolyl Derivatives: The Simple Dependence of the pH Value on Antimicrobial Activity

M. Lurdes S. Cristiano

Patrícia Rijo

and

Armando J. L. Pombeiro

Pharmaceuticals 2019, 12(4), 167; https://doi.org/10.3390/ph12040167 - 12 Nov 2019

Cited by 11 | Viewed by 3046

Abstract

The antimicrobial, antioxidant, and cytotoxic activities of a series of saccharin–tetrazolyl and –thiadiazolyl analogs were examined. The assessment of the antimicrobial properties of the referred-to molecules was completed through an evaluation of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values against Gram-positive and Gram-negative bacteria and yeasts. Scrutiny of the MIC and MBC values of the compounds at pH 4.0, 7.0, and 9.0 against four Gram-positive strains revealed high values for both the MIC and MBC at pH 4.0 (ranging from 0.98 to 125 µg/mL) and moderate values at pH 7.0 and 9.0, exposing strong antimicrobial activities in an acidic medium. An antioxidant activity analysis of the molecules was performed by using the DPPH (2,2-diphenyl-1-picrylhydrazyl) method, which showed high activity for the TSMT (N-(1-methyl-2H-tetrazol-5-yl)-N-(1,1-dioxo-1,2-benzisothiazol-3-yl) amine, 7) derivative (90.29% compared to a butylated hydroxytoluene positive control of 61.96%). Besides, the general toxicity of the saccharin analogs was evaluated in an Artemia salina model, which displayed insignificant toxicity values. In turn, upon an assessment of cell viability, all of the compounds were found to be nontoxic in range concentrations of 0–100 µg/mL in H7PX glioma cells. The tested molecules have inspiring antimicrobial and antioxidant properties that represent potential core structures in the design of new drugs for the treatment of infectious diseases. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Open AccessReview

Bacteriophage Therapy of Bacterial Infections: The Rediscovered Frontier

Nejat Düzgüneş

Melike Sessevmez

and

Metin Yildirim

Pharmaceuticals 2021, 14(1), 34; https://doi.org/10.3390/ph14010034 - 05 Jan 2021

Cited by 23 | Viewed by 6601

Abstract

Antibiotic-resistant infections present a serious health concern worldwide. It is estimated that there are 2.8 million antibiotic-resistant infections and 35,000 deaths in the United States every year. Such microorganisms include Acinetobacter, Enterobacterioceae, Pseudomonas, Staphylococcus and Mycobacterium. Alternative treatment methods are, thus, necessary to treat such infections. Bacteriophages are viruses of bacteria. In a lytic infection, the newly formed phage particles lyse the bacterium and continue to infect other bacteria. In the early 20th century, d’Herelle, Bruynoghe and Maisin used bacterium-specific phages to treat bacterial infections. Bacteriophages are being identified, purified and developed as pharmaceutically acceptable macromolecular “drugs,” undergoing strict quality control. Phages can be applied topically or delivered by inhalation, orally or parenterally. Some of the major drug-resistant infections that are potential targets of pharmaceutically prepared phages are Pseudomonas aeruginosa, Mycobacterium tuberculosis and Acinetobacter baumannii. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Thymus mastichina: Composition and Biological Properties with a Focus on Antimicrobial Activity

and

André R. T. S. Araujo

Pharmaceuticals 2020, 13(12), 479; https://doi.org/10.3390/ph13120479 - 19 Dec 2020

Cited by 9 | Viewed by 3191

Abstract

Thymus mastichina has the appearance of a semishrub and can be found in jungles and rocky lands of the Iberian Peninsula. This work aimed to review and gather available scientific information on the composition and biological properties of T. mastichina. The main constituents of T. mastichina essential oil are 1,8-cineole (or eucalyptol) and linalool, while the extracts are characterized by the presence of flavonoids, phenolic acids, and terpenes. The essential oil and extracts of T. mastichina have demonstrated a wide diversity of biological activities. They showed antibacterial activity against several bacteria such as Escherichia coli, Proteus mirabilis, Salmonella subsp., methicillin-resistant and methicillin-sensitive Staphylococcus aureus, Listeria monocytogenes EGD, Bacillus cereus, and Pseudomonas, among others, and antifungal activity against Candida spp. and Fusarium spp. Additionally, it has antioxidant activity, which has been evaluated through different methods. Furthermore, other activities have also been studied, such as anticancer, antiviral, insecticidal, repellent, anti-Alzheimer, and anti-inflammatory activity. In conclusion, considering the biological activities reported for the essential oil and extracts of T. mastichina, its potential as a preservative agent could be explored to be used in the food, cosmetic, or pharmaceutical industries. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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Atopic Dermatitis as a Multifactorial Skin Disorder. Can the Analysis of Pathophysiological Targets Represent the Winning Therapeutic Strategy?

Irene Magnifico

Giulio Petronio Petronio

and

Pharmaceuticals 2020, 13(11), 411; https://doi.org/10.3390/ph13110411 - 22 Nov 2020

Cited by 15 | Viewed by 2685

Abstract

Atopic dermatitis (AD) is a pathological skin condition with complex aetiological mechanisms that are difficult to fully understand. Scientific evidence suggests that of all the causes, the impairment of the skin barrier and cutaneous dysbiosis together with immunological dysfunction can be considered as the two main factors involved in this pathological skin condition. The loss of the skin barrier function is often linked to dysbiosis and immunological dysfunction, with an imbalance in the ratio between the pathogen Staphylococcus aureus and/or other microorganisms residing in the skin. The bibliographic research was conducted on PubMed, using the following keywords: ‘atopic dermatitis’, ‘bacterial therapy’, ‘drug delivery system’ and ‘alternative therapy’. The main studies concerning microbial therapy, such as the use of bacteria and/or part thereof with microbiota transplantation, and drug delivery systems to recover skin barrier function have been summarized. The studies examined show great potential in the development of effective therapeutic strategies for AD and AD-like symptoms. Despite this promise, however, future investigative efforts should focus both on the replication of some of these studies on a larger scale, with clinical and demographic characteristics that reflect the general AD population, and on the process of standardisation, in order to produce reliable data. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents)

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