Novel Antibacterial Agents 2022

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

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 48580

Special Issue Editors

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
Special Issues, Collections and Topics in MDPI journals
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
* Retired
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Infectious diseases still account for a substantial proportion of deaths worldwide. The plague of antimicrobial resistance represents an alarming sign for both human and animal healthcare, which drives the search for novel classes of antibiotics to replenish our armamentarium against bacterial infections. In addition, the tremendous impact recently exerted by virus infections and related pathologies on our lives forced scientists to face the opportunities and challenges associated with tackling infectious diseases by developing effective antiviral agents endowed with new mechanisms of action. The discovery of new antimicrobials/antiviruses as well as the expansion of utility of existing drugs would be crucial to fight the ever-increasing resistance of “superbugs”, pathogenic fungi, viruses, and parasites.

Pharmaceuticals invites both reviews and original articles highlighting recent medicinal chemistry research on novel antibacterial/antivirus agents. Topics include natural product screening, identification and validation of new antibacterial/antivirus targets, and strategies for the discovery and optimization of the compounds.

Prof. Dr. Fiorella Meneghetti
Prof. Dr. Daniela Barlocco
Guest Editors

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Keywords

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

Published Papers (20 papers)

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23 pages, 3179 KiB  
Article
N-Derivatives of (Z)-Methyl 3-(4-Oxo-2-thioxothiazolidin-5-ylidene)methyl)-1H-indole-2-carboxylates as Antimicrobial Agents—In Silico and In Vitro Evaluation
Pharmaceuticals 2023, 16(1), 131; https://doi.org/10.3390/ph16010131 - 16 Jan 2023
Cited by 4 | Viewed by 1889
Abstract
Herein, we report the experimental evaluation of the antimicrobial activity of seventeen new (Z)-methyl 3-(4-oxo-2-thioxothiazolidin-5-ylidene)methyl)-1H-indole-2-carboxylate derivatives. All tested compounds exhibited antibacterial activity against eight Gram-positive and Gram-negative bacteria. Their activity exceeded those of ampicillin as well as streptomycin by [...] Read more.
Herein, we report the experimental evaluation of the antimicrobial activity of seventeen new (Z)-methyl 3-(4-oxo-2-thioxothiazolidin-5-ylidene)methyl)-1H-indole-2-carboxylate derivatives. All tested compounds exhibited antibacterial activity against eight Gram-positive and Gram-negative bacteria. Their activity exceeded those of ampicillin as well as streptomycin by 10–50 fold. The most sensitive bacterium was En. Cloacae, while E. coli was the most resistant one, followed by M. flavus. The most active compound appeared to be compound 8 with MIC at 0.004–0.03 mg/mL and MBC at 0.008–0.06 mg/mL. The antifungal activity of tested compounds was good to excellent with MIC in the range of 0.004–0.06 mg/mL, with compound 15 being the most potent. T. viride was the most sensitive fungal, while A. fumigatus was the most resistant one. Docking studies revealed that the inhibition of E. coli MurB is probably responsible for their antibacterial activity, while 14a–lanosterol demethylase of CYP51Ca is involved in the mechanism of antifungal activity. Furthermore, drug-likeness and ADMET profile prediction were performed. Finally, the cytotoxicity studies were performed for the most active compounds using MTT assay against normal MRC5 cells. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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15 pages, 2286 KiB  
Article
Exploration of Solanum xanthocarpum Schrad. & Wendl. against Mycobacterium avium Subspecies paratuberculosis and Assessment of Its Immunomodulatory and Anti-Inflammatory Potential
Pharmaceuticals 2022, 15(11), 1367; https://doi.org/10.3390/ph15111367 - 08 Nov 2022
Cited by 3 | Viewed by 1746
Abstract
Mycobacterium avium subspecies paratuberculosis (MAP), being a dairy-borne pathogen, resistant of pasteurization and other sterilization techniques, is a major cause for development of inflammatory bowel disorders such as Johne’s disease (JD) in dairy animals and Crohn’s Disease (CD) in humans, for which no [...] Read more.
Mycobacterium avium subspecies paratuberculosis (MAP), being a dairy-borne pathogen, resistant of pasteurization and other sterilization techniques, is a major cause for development of inflammatory bowel disorders such as Johne’s disease (JD) in dairy animals and Crohn’s Disease (CD) in humans, for which no therapy is available to date. In the absence of effective therapy or a vaccine, management of CD has been accomplished by removal of the affected intestines. However, usually, even after removal of 2/3 of the intestine, CD reoccurs. Hence, there exists a need to develop an alternative therapy for such infection. The potential of herbals remains unexplored against MAP and related infections. Therefore, the conducted study is a novel initiative for the evaluation of anti-mycobacterial activity of bioactive extracts of Solanum xanthocarpum Schrad. & Wendl. against MAP infection. The said plant was authenticated according to the Ayurvedic Pharmacopoeia of India. Qualitative and quantitative evaluation of the extracts were done using chromatographic and spectroscopic techniques. Preliminary in vitro pharmacological assessments revealed the immunomodulatory and anti-inflammatory potential of the extracts. REMA assay was conducted to determine their anti-MAP activity along with determination of the best active extract. The hydro-alcoholic extract showed the best inhibition of MAP, providing a potential ray of hope against this emerging major pathogen of animals, and associated with Crohn’s disease and other autoimmune disorders in human beings. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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17 pages, 882 KiB  
Article
The Antimicrobial Effects of Saudi Sumra Honey against Drug Resistant Pathogens: Phytochemical Analysis, Antibiofilm, Anti-Quorum Sensing, and Antioxidant Activities
Pharmaceuticals 2022, 15(10), 1212; https://doi.org/10.3390/ph15101212 - 30 Sep 2022
Cited by 10 | Viewed by 2670
Abstract
Honey exhibited potential antimicrobial activity against multidrug resistant (MDR) bacteria that continues to be a serious health problem. We reported the in-vitro activity of Saudi Sumra honey against clinical pathogenic bacteria and fungi, antibiofilm, anti-quorum-sensing (QS) and antioxidant activities in relation to its [...] Read more.
Honey exhibited potential antimicrobial activity against multidrug resistant (MDR) bacteria that continues to be a serious health problem. We reported the in-vitro activity of Saudi Sumra honey against clinical pathogenic bacteria and fungi, antibiofilm, anti-quorum-sensing (QS) and antioxidant activities in relation to its phytochemical composition assessed by gas chromatography-mass spectrometry (GC-MS). Broth dilution method and scavenging activities against 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and β-carotene bleaching assays were performed. The GC-MS analysis of Sumra honey showed that 2,4-dihydroxy-2,5-dimethyl-3(2H)-furan-3-one 1-methylcyclopropanemethanol were the major identified phytoconstituents. Sumra honey showed a minimum inhibitory concentration (MIC) to clinical isolates of Staphylococcus aureus including methicillin-resistant Staphylococcus aureus (MRSA) at 300 mg/mL, Pseudomonas aeruginosa (250 mg/mL), Escherichia coli (350 mg/mL) and Acinetobacter baumannii (250 mg/mL); clinical fungal isolates—Candida auris (600 mg/mL) and Cryptococcus neoformans (>1000 mg/mL); wild type fungal isolates—Candida krusei (>1000 mg/mL) and Candida albicans (700 mg/mL). In addition, Sumra honey demonstrated promising inhibition targeting biofilm formation by 59% for Bacillus subtilis, 48% for S. aureus, 38% for E. coli, and 33.63% for P. aeruginosa. The violacein production in Chromobacterium violaceum was reduced to 68%, whereas pyocyanin production in P. aeruginosa was reduced to 54.86% at ½ MIC. Furthermore, Sumra honey exhibited strong antioxidant activities (DPPH − IC50 = 7.7 mg/mL; ABTS − IC50 = 5.4 mg/mL; β-carotene − IC50 = >20 mg/mL). Overall, obtained data highlighted the promising potential therapeutic use of Sumra honey treating infections caused by MDR bacteria and fungi. Moreover, Sumra honey can be a good candidate as an inhibitor agent for bacterial cellular communication in strains of P. aeruginosa and C. violaceum. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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15 pages, 1404 KiB  
Communication
Novel Effective Fluorinated Benzothiophene-Indole Hybrid Antibacterials against S. aureus and MRSA Strains
Pharmaceuticals 2022, 15(9), 1138; https://doi.org/10.3390/ph15091138 - 13 Sep 2022
Cited by 4 | Viewed by 1361
Abstract
Increasing antibacterial drug resistance threatens global health, unfortunately, however, efforts to find novel antibacterial agents have been scaled back by the pharmaceutical industry due to concerns about a poor return on investment. Nevertheless, there is an urgent need to find novel antibacterial compounds [...] Read more.
Increasing antibacterial drug resistance threatens global health, unfortunately, however, efforts to find novel antibacterial agents have been scaled back by the pharmaceutical industry due to concerns about a poor return on investment. Nevertheless, there is an urgent need to find novel antibacterial compounds to combat antibacterial drug resistance. The synthesis of novel drugs from natural sources is mostly cost-intensive due to those drugs’ complicated structures. Therefore, it is necessary to find novel antibacterials by simple synthesis to become more attractive for industrial production. We succeeded in the discovery of four antibacterial compound (sub)classes accessible in a simple one-pot reaction based on fluorinated benzothiophene-indole hybrids. They have been evaluated against various S. aureus and MRSA strains. Structure- and substituent-dependent activities have been found within the (sub)classes and promising lead compounds have been identified. In addition, bacterial pyruvate kinase was found to be the molecular target of the active compounds. In conclusion, simple one-pot synthesis of benzothiophene-indoles represents a promising strategy for the search of novel antimicrobial compounds. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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25 pages, 4123 KiB  
Article
Antimicrobial Activity of Rhenium Di- and Tricarbonyl Diimine Complexes: Insights on Membrane-Bound S. aureus Protein Binding
Pharmaceuticals 2022, 15(9), 1107; https://doi.org/10.3390/ph15091107 - 05 Sep 2022
Cited by 6 | Viewed by 1866
Abstract
Antimicrobial resistance is one of the major human health threats, with significant impacts on the global economy. Antibiotics are becoming increasingly ineffective as drug-resistance spreads, imposing an urgent need for new and innovative antimicrobial agents. Metal complexes are an untapped source of antimicrobial [...] Read more.
Antimicrobial resistance is one of the major human health threats, with significant impacts on the global economy. Antibiotics are becoming increasingly ineffective as drug-resistance spreads, imposing an urgent need for new and innovative antimicrobial agents. Metal complexes are an untapped source of antimicrobial potential. Rhenium complexes, amongst others, are particularly attractive due to their low in vivo toxicity and high antimicrobial activity, but little is known about their targets and mechanism of action. In this study, a series of rhenium di- and tricarbonyl diimine complexes were prepared and evaluated for their antimicrobial potential against eight different microorganisms comprising Gram-negative and -positive bacteria. Our data showed that none of the Re dicarbonyl or neutral tricarbonyl species have either bactericidal or bacteriostatic potential. In order to identify possible targets of the molecules, and thus possibly understand the observed differences in the antimicrobial efficacy of the molecules, we computationally evaluated the binding affinity of active and inactive complexes against structurally characterized membrane-bound S. aureus proteins. The computational analysis indicates two possible major targets for this class of compounds, namely lipoteichoic acids flippase (LtaA) and lipoprotein signal peptidase II (LspA). Our results, consistent with the published in vitro studies, will be useful for the future design of rhenium tricarbonyl diimine-based antibiotics. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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11 pages, 1628 KiB  
Article
Efficacy Evaluation of 10-Hydroxy Chondrofoline and Tafenoquine against Leishmania tropica (HTD7)
Pharmaceuticals 2022, 15(8), 1005; https://doi.org/10.3390/ph15081005 - 15 Aug 2022
Cited by 3 | Viewed by 1308
Abstract
Leishmaniasis is affirmed as a category one disease (most emerging and unmanageable) by the World Health Organization (WHO), affecting 98 countries with an annual global incidence of ~1.2 million cases. Options for chemotherapeutic treatment are limited due to drug resistance and cytotoxicity. Thus, [...] Read more.
Leishmaniasis is affirmed as a category one disease (most emerging and unmanageable) by the World Health Organization (WHO), affecting 98 countries with an annual global incidence of ~1.2 million cases. Options for chemotherapeutic treatment are limited due to drug resistance and cytotoxicity. Thus, the search for new chemical compounds is instantly desirable. In this study, we used two compounds, i.e., 10-hydroxy chondrofoline and tafenoquine, for their antileishmanial activity against L. tropica (HTD7). First, the cytotoxicity assay of the test compounds against THP-1 cells was carried out, and these compounds were found safe. Intra-THP-1 amastigote activity (in vitro) was performed, which was then followed by the in vivo activity of 10-hydroxy chondrofoline in the murine cutaneous leishmaniasis (CL) model. A total of three concentrations were used, i.e., 25, 50, and 100 µM, to check the in vitro activity of the test compounds against the amastigotes. 10-hydroxy chondrofoline was found to be the most potent compound in vitro (and thus was selected for in vivo studies) with an LD50 value of 43.80 µM after 48 h incubation, whilst tafenoquine had an LD50 value of 53.57 µM. In vivo activity was conducted by injecting 10-hydroxy chondrofoline in the left hind foot of the infected BALB/c mice, where it caused a statistically significant 58.3% (F = 14.18; p = 0.002) reduction in lesion size (0.70 ± 0.03 mm) when compared with negative control (1.2 ± 0.3 mm). Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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22 pages, 6875 KiB  
Article
Synthesis and Assessment of the In Vitro and Ex Vivo Activity of Salicylate Synthase (Mbti) Inhibitors as New Candidates for the Treatment of Mycobacterial Infections
Pharmaceuticals 2022, 15(8), 992; https://doi.org/10.3390/ph15080992 - 11 Aug 2022
Cited by 12 | Viewed by 2028
Abstract
Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of M. tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently [...] Read more.
Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of M. 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 anti-TB agents is the salicylate synthase MbtI, the first enzyme of the mycobacterial siderophore biochemical machinery, absent in human cells. In this work, a set of analogues of 5-(3-cyanophenyl)furan-2-carboxylic acid (I), the most potent MbtI inhibitor identified to date, was synthesized, characterized, and tested to further elucidate the structural requirements for achieving an efficient MbtI inhibition and potent antitubercular activity. The structure–activity relationships (SAR) discussed herein evidenced the importance of the side chain linked to the phenyl moiety to improve the in vitro antimycobacterial activity. In detail, 1f emerged as the most effective analogue against the pathogen, acting without cytotoxicity issues. To deepen the understanding of its mechanism of action, we established a fluorescence-based screening test to quantify the pathogen infectivity within host cells, using MPI-2 murine cells, a robust surrogate for alveolar macrophages. The set-up of the new assay demonstrates significant potential to accelerate the discovery of new anti-TB drugs. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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19 pages, 3565 KiB  
Article
Hybrid Nanosystems Based on Nicotinate-Functionalized Mesoporous Silica and Silver Chloride Nanoparticles Loaded with Phenytoin for Preventing Pseudomonas aeruginosa Biofilm Development
Pharmaceuticals 2022, 15(7), 884; https://doi.org/10.3390/ph15070884 - 18 Jul 2022
Cited by 5 | Viewed by 1793
Abstract
Pseudomonas aeruginosa (PA) is one of the most common bacteria isolated from chronic wounds and burns. Its treatment is a challenge due to antimicrobial drug resistance and biofilm formation. In this context, this study aimed to perform the synthesis and full characterization of [...] Read more.
Pseudomonas aeruginosa (PA) is one of the most common bacteria isolated from chronic wounds and burns. Its treatment is a challenge due to antimicrobial drug resistance and biofilm formation. In this context, this study aimed to perform the synthesis and full characterization of hybrid nanosystems based on mesoporous silica nanoparticles (MSNs) functionalized with a nicotinic ligand and silver chloride nanoparticles, both phenytoin sodium (Ph)-loaded and unloaded, to evaluate the antibacterial properties against three different strains of PA (including two clinical strains) in a planktonic state and as biofilms. Ph is a well-known proliferative agent, which was incorporated into the hybrid nanomaterials to obtain an effective material for tissue healing and prevention of infection caused by PA. The Ph-loaded materials promoted a quasi-complete inhibition of bacterial growth in wound-like medium and biofilm development, with values of 99% and 96%, respectively, with selectivity indices above the requirements for drugs to become promising agents for the topic preventive treatment of chronic wounds and burns. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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13 pages, 3344 KiB  
Article
Synthesis of Quinolones and Zwitterionic Quinolonate Derivatives with Broad-Spectrum Antibiotic Activity
Pharmaceuticals 2022, 15(7), 818; https://doi.org/10.3390/ph15070818 - 01 Jul 2022
Viewed by 1363
Abstract
Quinolones are one of the most extensively used therapeutic families of antibiotics. However, the increase in antibiotic-resistant bacteria has rendered many of the available compounds useless. After applying our prediction model of activity against E. coli to a library of 1000 quinolones, two [...] Read more.
Quinolones are one of the most extensively used therapeutic families of antibiotics. However, the increase in antibiotic-resistant bacteria has rendered many of the available compounds useless. After applying our prediction model of activity against E. coli to a library of 1000 quinolones, two quinolones were selected to be synthesized. Additionally, a series of zwitterionic quinolonates were also synthesized. Quinolones and zwitterionic quinolonates were obtained by coupling the corresponding amine with reagent 1 in acetonitrile. Antibacterial activity was assessed using a microdilution method. All the compounds presented antibacterial activity, especially quinolones 2 and 3, selected by the prediction model, which had broad-spectrum activity. Furthermore, a new type of zwitterionic quinolonate with antibacterial activity was found. These compounds can lead to a new line of antimicrobials, as the structures, and, therefore, their properties, are easily adjustable in the amine in position 4 of the pyridine ring. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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19 pages, 10187 KiB  
Article
Design, Synthesis and Molecular Docking of Novel Acetophenone-1,2,3-Triazoles Containing Compounds as Potent Enoyl-Acyl Carrier Protein Reductase (InhA) Inhibitors
Pharmaceuticals 2022, 15(7), 799; https://doi.org/10.3390/ph15070799 - 27 Jun 2022
Cited by 6 | Viewed by 1587
Abstract
New medications are desperately needed to combat rising drug resistance among tuberculosis (TB) patients. New agents should ideally work through unique targets to avoid being hampered by preexisting clinical resistance to existing treatments. The enoyl-acyl carrier protein reductase InhA of M. tuberculosis is [...] Read more.
New medications are desperately needed to combat rising drug resistance among tuberculosis (TB) patients. New agents should ideally work through unique targets to avoid being hampered by preexisting clinical resistance to existing treatments. The enoyl-acyl carrier protein reductase InhA of M. tuberculosis is one of the most crucial targets since it is a promising target that has undergone extensive research for anti-tuberculosis drug development. A well-known scaffold for a variety of biological activities, including antitubercular activity, is the molecular linkage of a1,2,3-triazole with an acetamide group. As a result, in the current study, which was aided by ligand-based molecular modeling investigations, 1,2,3-triazolesweredesigned and synthesized adopting the CuAAC aided cycloaddition of 1-(4-(prop-2-yn-1-yloxy)phenyl)ethanone with appropriate acetamide azides. Standard spectroscopic methods were used to characterize the newly synthesized compounds. In vitro testing of the proposed compounds against the InhA enzyme was performed. All the synthesized inhibitors completely inhibited the InhA enzyme at a concentration of 10 µM that exceeded Rifampicin in terms of activity. Compounds 9, 10, and 14 were the most promising InhA inhibitors, with IC50 values of 0.005, 0.008, and 0.002 µM, respectively. To promote antitubercular action and investigate the binding manner of the screened compounds with the target InhA enzyme’s binding site, a molecular docking study was conducted. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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17 pages, 7655 KiB  
Article
Antioxidant and Antibacterial Activity of Helichrysum italicum (Roth) G. Don. from Central Europe
Pharmaceuticals 2022, 15(6), 735; https://doi.org/10.3390/ph15060735 - 10 Jun 2022
Cited by 15 | Viewed by 2542
Abstract
Helichrysum italicum (Roth) G. Don. is one of the most important cosmetic and medicinal plants originating from the Mediterranean region of Europe. The aim of this study was to assess the chemical profile as well as antioxidant and antibacterial potential of the species [...] Read more.
Helichrysum italicum (Roth) G. Don. is one of the most important cosmetic and medicinal plants originating from the Mediterranean region of Europe. The aim of this study was to assess the chemical profile as well as antioxidant and antibacterial potential of the species cultivated in the temperate climate of Central Europe. The analyses were carried out using herbs and inflorescences. The content of essential oil ranged from 0.25 g × 100 g−1 in the herb to 0.31 g × 100 g−1 in the inflorescences. Neryl acetate, accompanied by α-pinene in the herb (10.42%), and nerol in inflorescences (15.73%) were the dominants here. Rutoside, as well as rosmarinic, chlorogenic, neochlorogenic, isochlorogenic b and cichoric acids, were detected in both raw materials using HPLC-DAD. Within this group, cichoric acid was the dominant (2647.90 mg × 100 g−1 in the herb, 1381.06 mg × 100 g−1 in the inflorescences). The herb appeared to be more abundant in phenolics in comparison with the inflorescences. When given antioxidant activity (determined using DPPH and ABTS assays), both methanolic extract and essential oil obtained from the herb indicated higher potential than those originating from the inflorescences (74.72, 61.38 and 63.81, 58.59% in the case of DPPH, respectively). In turn, regarding antimicrobial activity, the essential oil from inflorescences was distinguished by stronger bacteriostatic power than the herb essential oil. Gram-positive bacteria were more sensitive to both essential oils in comparison with Gram-negative ones, with S. aureus ATCC 25923 as the most susceptible (MIC 1; MBC 16 mg × mL−1) among tested strains. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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8 pages, 2153 KiB  
Article
Impact of the Gram-Negative-Selective Inhibitor MAC13243 on In Vitro Simulated Gut Microbiota
Pharmaceuticals 2022, 15(6), 731; https://doi.org/10.3390/ph15060731 - 09 Jun 2022
Cited by 1 | Viewed by 1557
Abstract
New Gram-negative-selective antimicrobials are desirable to avoid perturbations in the gut microbiota leading to antibiotic-induced dysbiosis. We investigated the impact of a prototype drug (MAC13243) interfering with the Gram-negative outer membrane protein LolA on the faecal microbiota. Faecal suspensions from two healthy human [...] Read more.
New Gram-negative-selective antimicrobials are desirable to avoid perturbations in the gut microbiota leading to antibiotic-induced dysbiosis. We investigated the impact of a prototype drug (MAC13243) interfering with the Gram-negative outer membrane protein LolA on the faecal microbiota. Faecal suspensions from two healthy human donors were exposed to MAC13243 (16, 32, or 64 mg/L) using an in vitro gut model (CoMiniGut). Samples collected 0, 4, and 8 h after exposure were subjected to viable cell counts, 16S rRNA gene quantification and V3-V4 sequencing using the Illumina MiSeq platform. MAC13243 exhibited concentration-dependent killing of coliforms in both donors after 8 h. Concentrations of ≤32 mg/L reduced the growth of aerobic bacteria without influencing the microbiota composition and diversity. An expansion of Firmicutes at the expense of Bacteroidetes and Actinobacteria was observed in the faecal microbiota from one donor following exposure to 64 mg/L of MAC13242. At all concentrations tested, MAC13243 did not lead to the proliferation of Escherichia coli nor a reduced abundance of beneficial bacteria, which are typical changes observed in antibiotic-induced dysbiosis. These results support our hypothesis that a drug interfering with a specific target in Gram-negative bacteria has a low impact on the commensal gut microbiota and, therefore, a low risk of inducing dysbiosis. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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20 pages, 1601 KiB  
Article
Enhancing Colistin Activity against Colistin-Resistant Escherichia coli through Combination with Alginate Nanoparticles and Small Molecules
Pharmaceuticals 2022, 15(6), 682; https://doi.org/10.3390/ph15060682 - 28 May 2022
Cited by 1 | Viewed by 2071
Abstract
Bacterial resistance to antibiotics has become a major public health problem worldwide, with the yearly number of deaths exceeding 700,000. To face this well-acknowledged threat, new molecules and therapeutic methods are considered. In this context, the application of nanotechnology to fight bacterial infection [...] Read more.
Bacterial resistance to antibiotics has become a major public health problem worldwide, with the yearly number of deaths exceeding 700,000. To face this well-acknowledged threat, new molecules and therapeutic methods are considered. In this context, the application of nanotechnology to fight bacterial infection represents a viable approach and has experienced tremendous developments in the last decades. Escherichia coli (E. coli) is responsible for severe diarrhea, notably in the breeding sector, and especially in pig farming. The resulting infection (named colibacillosis) occurs in young piglets and could lead to important economic losses. Here, we report the design of several new formulations based on colistin loaded on alginate nanoparticles (Alg NPs) in the absence, but also in the presence, of small molecules, such as components of essential oils, polyamines, and lactic acid. These new formulations, which are made by concomitantly binding colistin and small molecules to Alg NPs, were successfully tested against E. coli 184, a strain resistant to colistin. When colistin was associated with Alg NPs, the minimal inhibition concentration (MIC) decreased from 8 to 1 µg/mL. It is notable that when menthol or lactic acid was co-loaded with colistin on Alg NPs, the MIC of colistin drastically decreased, reaching 0.31 or 0.62 µg/mL, respectively. These novel bactericidal formulations, whose innocuity towards eukaryotic HT-29 cells was established in vitro, are presumed to permeabilize the bacterial membrane and provoke the leakage of intracellular proteins. Our findings revealed the potentiating effect of the Alg NPs on colistin, but also of the small molecules mentioned above. Such ecological and economical formulations are easy to produce and could be proposed, after confirmation by in vivo and toxicology tests, as therapeutic strategies to replace fading antibiotics. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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23 pages, 1988 KiB  
Article
Synthesis, Antibacterial Evaluation, and Computational Studies of a Diverse Set of Linezolid Conjugates
Pharmaceuticals 2022, 15(2), 191; https://doi.org/10.3390/ph15020191 - 03 Feb 2022
Cited by 6 | Viewed by 2217
Abstract
The development of new antibiotics to treat multidrug-resistant (MDR) bacteria or possess broad-spectrum activity is one of the challenging tasks. Unfortunately, there are not many new antibiotics in clinical trials. So, the molecular hybridization approach could be an effective strategy to develop potential [...] Read more.
The development of new antibiotics to treat multidrug-resistant (MDR) bacteria or possess broad-spectrum activity is one of the challenging tasks. Unfortunately, there are not many new antibiotics in clinical trials. So, the molecular hybridization approach could be an effective strategy to develop potential drug candidates using the known scaffolds. We synthesized a total of 31 diverse linezolid conjugates 3, 5, 7, 9, 11, 13, and 15 using our established benzotriazole chemistry with good yield and purity. Some of the synthesized conjugates exhibited promising antibacterial properties against different strains of bacteria. Among all the synthesized compounds, 5d is the most promising antibacterial agent with MIC 4.5 µM against S. aureus and 2.25 µM against B. subtilis. Using our experimental data pool, we developed a robust QSAR (R2 = 0.926, 0.935; R2cvOO = 0.898, 0.915; R2cvMO = 0.903, 0.916 for the S. aureus and B. subtilis models, respectively) and 3D-pharmacophore models. We have also determined the drug-like properties of the synthesized conjugates using computational tools. Our findings provide valuable insight into the possible linezolid-based antibiotic drug candidates. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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19 pages, 866 KiB  
Article
Identification of Antibacterial Peptide Candidates Encrypted in Stress-Related and Metabolic Saccharomyces cerevisiae Proteins
Pharmaceuticals 2022, 15(2), 163; https://doi.org/10.3390/ph15020163 - 28 Jan 2022
Cited by 4 | Viewed by 2583
Abstract
The protein-rich nature of Saccharomyces cerevisiae has led this yeast to the spotlight concerning the search for antimicrobial peptides. Herein, a <10 kDa peptide-rich extract displaying antibacterial activity was obtained through the autolysis of yeast biomass under mild thermal treatment with self-proteolysis by [...] Read more.
The protein-rich nature of Saccharomyces cerevisiae has led this yeast to the spotlight concerning the search for antimicrobial peptides. Herein, a <10 kDa peptide-rich extract displaying antibacterial activity was obtained through the autolysis of yeast biomass under mild thermal treatment with self-proteolysis by endogenous peptidases. Estimated IC50 for the peptide pools obtained by FPLC gel filtration indicated improved antibacterial activities against foodborne bacteria and bacteria of clinical interest. Similarly, the estimated cytotoxicity concentrations against healthy human fibroblasts, alongside selective indices ≥10, indicates the fractions are safe, at least in a mixture format, for human tissues. Nano-LC-MS/MS analysis revealed that the peptides in FPLC fractions could be derived from both induced-proteolysis and proteasome activity in abundant proteins, up-regulated under stress conditions during S. cerevisiae biomass manufacturing, including those coded by TDH1/2/3, HSP12, SSA1/2, ADH1/2, CDC19, PGK1, PPI1, PDC1, and GMP1, as well as by other non-abundant proteins. Fifty-eight AMP candidate sequences were predicted following an in silico analysis using four independent algorithms, indicating their possible contribution to the bacterial inactivation observed in the peptides pool, which deserve special attention for further validation of individual functionality. S. cerevisiae-biomass peptides, an unconventional but abundant source of pharmaceuticals, may be promissory adjuvants to treat infectious diseases that are poorly sensitive to conventional antibiotics. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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13 pages, 3439 KiB  
Article
In Vitro and In Vivo Activity of AS101 against Carbapenem-Resistant Acinetobacter baumannii
Pharmaceuticals 2021, 14(8), 823; https://doi.org/10.3390/ph14080823 - 21 Aug 2021
Cited by 8 | Viewed by 2634
Abstract
The increasing trend of carbapenem-resistant Acinetobacter baumannii (CRAB) worldwide has become a concern, limiting therapeutic alternatives and increasing morbidity and mortality rates. The immunomodulation agent ammonium trichloro (dioxoethylene-O,O′-) tellurate (AS101) was repurposed as an antimicrobial agent against CRAB. Between 2016 and 2018, 27 [...] Read more.
The increasing trend of carbapenem-resistant Acinetobacter baumannii (CRAB) worldwide has become a concern, limiting therapeutic alternatives and increasing morbidity and mortality rates. The immunomodulation agent ammonium trichloro (dioxoethylene-O,O′-) tellurate (AS101) was repurposed as an antimicrobial agent against CRAB. Between 2016 and 2018, 27 CRAB clinical isolates were collected in Taiwan. The in vitro antibacterial activities of AS101 were evaluated using broth microdilution, time-kill assay, reactive oxygen species (ROS) detection and electron microscopy. In vivo effectiveness was assessed using a sepsis mouse infection model. The MIC range of AS101 for 27 CRAB isolates was from 0.5 to 32 µg/mL, which is below its 50% cytotoxicity (approximately 150 µg/mL). Bactericidal activity was confirmed using a time-kill assay. The antibacterial mechanism of AS101 was the accumulation of the ROS and the disruption of the cell membrane, which, in turn, results in cell death. The carbapenemase-producing A. baumannii mouse sepsis model showed that AS101 was a better therapeutic effect than colistin. The mice survival rate after 120 h was 33% (4/12) in the colistin-treated group and 58% (7/12) in the high-dose AS101 (3.33 mg/kg/day) group. Furthermore, high-dose AS101 significantly decreased bacterial population in the liver, kidney and spleen (all p < 0.001). These findings support the concept that AS101 is an ideal candidate for further testing in future studies. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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14 pages, 3265 KiB  
Article
Evaluation of the Organotellurium Compound AS101 for Treating Colistin- and Carbapenem-Resistant Klebsiella pneumoniae
Pharmaceuticals 2021, 14(8), 795; https://doi.org/10.3390/ph14080795 - 12 Aug 2021
Cited by 10 | Viewed by 3081
Abstract
Colistin- and carbapenem-resistant Enterobacteriaceae cases are increasing at alarming rates worldwide. Drug repurposing is receiving greater attention as an alternative approach in light of economic and technical barriers in antibiotics research. The immunomodulation agent ammonium trichloro(dioxoethylene-O,O’-)tellurate (AS101) was repurposed [...] Read more.
Colistin- and carbapenem-resistant Enterobacteriaceae cases are increasing at alarming rates worldwide. Drug repurposing is receiving greater attention as an alternative approach in light of economic and technical barriers in antibiotics research. The immunomodulation agent ammonium trichloro(dioxoethylene-O,O’-)tellurate (AS101) was repurposed as an antimicrobial agent against colistin- and carbapenem-resistant Klebsiella pneumoniae (CRKP). 134 CRKP isolates were collected between 2012 and 2015 in Taiwan. The in vitro antibacterial activities of AS101 was observed through broth microdilution, time-kill assay, and electron microscopy. Pharmaceutical manipulation and RNA microarray were applied to investigate these antimicrobial mechanisms. Caenorhabditis elegans, a nematode animal model, and the Institute for Cancer Research (ICR) mouse model was employed for the evaluation of in vivo efficacy. The in vitro antibacterial results were found for AS101 against colistin- and CRKP isolates, with minimum inhibitory concentration (MIC) values ranging from <0.5 to 32 μg/mL. ROS-mediated antibacterial activity eliminated 99.9% of bacteria within 2–4 h. AS101 also extended the median survival time in a C. elegans animal model infected with a colistin-resistant CRKP isolate and rescued lethally infected animals in a separate mouse model of mono-bacterial sepsis by eliminating bacterial organ loads. These findings support the use of AS101 as an antimicrobial agent for addressing the colistin and carbapenem resistance crisis. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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Review

Jump to: Research

23 pages, 2772 KiB  
Review
Recent Developments in Electrochemical Sensors for the Detection of Antibiotic-Resistant Bacteria
Pharmaceuticals 2022, 15(12), 1488; https://doi.org/10.3390/ph15121488 - 29 Nov 2022
Cited by 4 | Viewed by 2275
Abstract
The development of efficient point-of-care (POC) diagnostic tools for detecting infectious diseases caused by destructive pathogens plays an important role in clinical and environmental monitoring. Nevertheless, evolving complex and inconsistent antibiotic-resistant species mire their drug efficacy. In this regard, substantial effort has been [...] Read more.
The development of efficient point-of-care (POC) diagnostic tools for detecting infectious diseases caused by destructive pathogens plays an important role in clinical and environmental monitoring. Nevertheless, evolving complex and inconsistent antibiotic-resistant species mire their drug efficacy. In this regard, substantial effort has been expended to develop electrochemical sensors, which have gained significant interest for advancing POC testing with rapid and accurate detection of resistant bacteria at a low cost compared to conventional phenotype methods. This review concentrates on the recent developments in electrochemical sensing techniques that have been applied to assess the diverse latent antibiotic resistances of pathogenic bacteria. It deliberates the prominence of biorecognition probes and tailor-made nanomaterials used in electrochemical antibiotic susceptibility testing (AST). In addition, the bimodal functional efficacy of nanomaterials that can serve as potential transducer electrodes and the antimicrobial agent was investigated to meet the current requirements in designing sensor module development. In the final section, we discuss the challenges with contemporary AST sensor techniques and extend the key ideas to meet the demands of the next POC electrochemical sensors and antibiotic design modules in the healthcare sector. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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24 pages, 862 KiB  
Review
Overview on Strategies and Assays for Antibiotic Discovery
Pharmaceuticals 2022, 15(10), 1302; https://doi.org/10.3390/ph15101302 - 21 Oct 2022
Cited by 5 | Viewed by 4347
Abstract
The increase in antibiotic resistance poses a major threat to global health. Actinomycetes, the Gram-positive bacteria of the order Actinomycetales, are fertile producers of bioactive secondary metabolites, including antibiotics. Nearly two-thirds of antibiotics that are used for the treatment of bacterial infections [...] Read more.
The increase in antibiotic resistance poses a major threat to global health. Actinomycetes, the Gram-positive bacteria of the order Actinomycetales, are fertile producers of bioactive secondary metabolites, including antibiotics. Nearly two-thirds of antibiotics that are used for the treatment of bacterial infections were originally isolated from actinomycetes strains belonging to the genus Streptomyces. This emphasizes the importance of actinomycetes in antibiotic discovery. However, the identification of a new antimicrobial compound and the exploration of its mode of action are very challenging tasks. Therefore, different approaches that enable the “detection” of an antibiotic and the characterization of the mechanisms leading to the biological activity are indispensable. Beyond bioinformatics tools facilitating the identification of biosynthetic gene clusters (BGCs), whole cell-screenings—in which cells are exposed to actinomycete-derived compounds—are a common strategy applied at the very early stage in antibiotic drug development. More recently, target-based approaches have been established. In this case, the drug candidates were tested for interactions with usually validated targets. This review focuses on the bioactivity-based screening methods and provides the readers with an overview on the most relevant assays for the identification of antibiotic activity and investigation of mechanisms of action. Moreover, the article includes examples of the successful application of these methods and suggestions for improvement. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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25 pages, 1657 KiB  
Review
Microbiological, Clinical, and PK/PD Features of the New Anti-Gram-Negative Antibiotics: β-Lactam/β-Lactamase Inhibitors in Combination and Cefiderocol—An All-Inclusive Guide for Clinicians
Pharmaceuticals 2022, 15(4), 463; https://doi.org/10.3390/ph15040463 - 12 Apr 2022
Cited by 11 | Viewed by 4863
Abstract
Bacterial resistance mechanisms are continuously and rapidly evolving. This is particularly true for Gram-negative bacteria. Over the last decade, the strategy to develop new β-lactam/β-lactamase inhibitors (BLs/BLIs) combinations has paid off and results from phase 3 and real-world studies are becoming available for [...] Read more.
Bacterial resistance mechanisms are continuously and rapidly evolving. This is particularly true for Gram-negative bacteria. Over the last decade, the strategy to develop new β-lactam/β-lactamase inhibitors (BLs/BLIs) combinations has paid off and results from phase 3 and real-world studies are becoming available for several compounds. Cefiderocol warrants a separate discussion for its peculiar mechanism of action. Considering the complexity of summarizing and integrating the emerging literature data of clinical outcomes, microbiological mechanisms, and pharmacokinetic/pharmacodynamic properties of the new BL/BLI and cefiderocol, we aimed to provide an overview of data on the following compounds: aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, cefiderocol, ceftaroline/avibactam, ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam, meropenem/nacubactam and meropenem/vaborbactam. Each compound is described in a dedicated section by experts in infectious diseases, microbiology, and pharmacology, with tables providing at-a-glance information. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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