Novel Antibiotics and Novel Modes of Action to Fight Infectious Diseases in Antimicrobial Resistance Era

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 36051

Special Issue Editors

Laboratory of Hydrology and Geochemistry of Strasbourg (LHyGeS), University of Strasbourg –French National Centre for Scientific Research (CNRS), 67084 Strasbourg Cedex, France
Interests: antimicrobial resistance; environmental fate of pollutants and their health impacts; drug discovery from natural resources; green technology in agroindustry
Special Issues, Collections and Topics in MDPI journals
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90133 Palermo, Italy
Interests: antibiotic biosynthesis and Actinomycetes; antibiotic resistance; microbiome; resistome; glycopeptides; regulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Only a small percentage of novel discovered antibiotics are currently in the clinical trial phase, which is still insufficient to defeat the evolution of antimicrobial resistance in pathogens and to protect us from the emergence of new infectious diseases. For a long-term strategy, the discovery of novel antibiotics with mechanical and structural varieties from unexplored or rarely studied sources is still ongoing. Recently, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19) is spreading rapidly, leading to a global outbreak. This COVID-19 crisis would be an excellent example of what short-term strategy we need to overcome an emerging infectious disease. During this recent pandemic, there is no drug exhibiting a direct mode of action against SARS-CoV-2; however, some known medicines used for treatments of other relevant and/or occurring diseases have been tested for their activities to kill the virus or to treat COVID-19. Therefore, although antimicrobial resistance may result in the vitiation of several known drugs for treating their respective diseases, these drugs may have a hidden mode of action that is promising for the treatments of other or suddenly-emerging infectious diseases.

This Special Issue provides a platform for exchanging and updating our new insights into the discovery of novel antibiotics from various yet unexplored and underexplored sources to defeat infectious diseases in the antimicrobial resistance era and the hidden modes of action of currently available bioactive molecules using advanced in silico screening approaches and/or lab-based techniques. All types of articles falling within the scope of the above research areas are welcome.

Dr. Rungroch Sungthong
Dr. Rosa Alduina
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Antibiotics
  • Bioactive molecules
  • Antimicrobial resistance
  • Mode of action
  • Drug discovery
  • Infectious disease
  • Biosynthesis
  • In silico screening

Published Papers (10 papers)

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Research

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15 pages, 2195 KiB  
Article
Anti-Herpes Simplex Virus Efficacy of Silk Cocoon, Silkworm Pupa and Non-Sericin Extracts
Antibiotics 2021, 10(12), 1553; https://doi.org/10.3390/antibiotics10121553 - 19 Dec 2021
Cited by 2 | Viewed by 2039
Abstract
Herpes simplex virus (HSV) infections are prevalent worldwide and are the cause of life- threatening diseases. Standard treatment with antiviral drugs, such as acyclovir, could prevent serious complications; however, resistance has been reported specifically among immunocompromised patients. Therefore, the development of an alternative [...] Read more.
Herpes simplex virus (HSV) infections are prevalent worldwide and are the cause of life- threatening diseases. Standard treatment with antiviral drugs, such as acyclovir, could prevent serious complications; however, resistance has been reported specifically among immunocompromised patients. Therefore, the development of an alternative approach is needed. The silk cocoon derived from silkworm, Bombyx mori, has been recognized for its broad-spectrum biological activity, including antiviral activity; however, its effects against HSV infection are unknown. In this study, we investigated the inhibitory effects of silk extracts derived from the cocoon shell, silk cocoon, silkworm pupa and non-sericin extract, on blocking HSV-1 and HSV-2 binding to host cells, resulting in the inhibition of the virus infection in Vero cells. Non-sericin extract demonstrated the greatest effectiveness on inhibiting HSV-1 and HSV-2 binding activity. Moreover, the virucidal effect to inactivate HSV-1 and HSV-2 was determined and revealed that non-sericin extract also exerted the highest potential activity. Using the treatment of non-sericin extract in HSV-2-infected HeLa cells could significantly lower the HSV-induced cell death and prevent inflammation via lowering the inflammatory cytokine gene expression. The non-sericin extract was analyzed for its bioactive compounds in which gallic acid, flavonoid and xanthophyll were identified, and might have partially contributed to its antiviral activity. The finding in our study suggested the potential of silk extract as an alternative therapeutic treatment for HSV infection. Full article
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14 pages, 1485 KiB  
Article
Comparative Study of Antimicrobial Properties of Bee Venom Extracts and Melittins of Honey Bees
Antibiotics 2021, 10(12), 1503; https://doi.org/10.3390/antibiotics10121503 - 08 Dec 2021
Cited by 10 | Viewed by 3598
Abstract
Bee venom (BV), or apitoxin, is a complex substance produced by a gland in the abdominal cavity of bees. The main component of BV is melittin, which is a largely studied substance due to its biological properties. To date, the most well-known bee [...] Read more.
Bee venom (BV), or apitoxin, is a complex substance produced by a gland in the abdominal cavity of bees. The main component of BV is melittin, which is a largely studied substance due to its biological properties. To date, the most well-known bee venom and melittin are derived from domesticated honey bees, while venom and melittin derived from wild honey bees have been under-investigated. Hence, this study primarily reports the antimicrobial activities of bee venom and synthetic melittin derived from four different honey bee species (Apis mellifera, A. cerana, A. dorsata, and A. florea) in Thailand. All the bee venom extracts and melittins showed more robust antibacterial activities against Gram-positive (Bacillus subtilis, Micrococcus luteus, Staphylococcus aureus, S. aureus MRSA, and S. epidermidis) than Gram-negative bacteria (Escherichia coli, Klebsiella pneuminiae, and Salmonella typhimurium) or a fungus (Candida albicans), while the synthetic melittins also have antimicrobial activity at higher concentrations than the bee venom extract. Furthermore, the A. cerana venom extract showed the highest activity against the tested bacteria, followed by A. mellifera, A. florea, and A. dorsata. Therefore, A. cerana venom may be further developed for use in medical applications as a potential alternative agent against Gram-positive bacteria and antibiotic-resistant bacteria. Full article
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17 pages, 5392 KiB  
Article
In Vitro and In Silico Approaches for the Antileishmanial Activity Evaluations of Actinomycins Isolated from Novel Streptomyces smyrnaeus Strain UKAQ_23
Antibiotics 2021, 10(8), 887; https://doi.org/10.3390/antibiotics10080887 - 21 Jul 2021
Cited by 12 | Viewed by 3348
Abstract
Leishmaniasis, a Neglected Tropical Parasitic Disease (NTPD), is induced by several Leishmania species and is disseminated through sandfly (Lutzomyia longipalpis) bites. The parasite has developed resistance to currently prescribed antileishmanial drugs, and it has become pertinent to the search for new [...] Read more.
Leishmaniasis, a Neglected Tropical Parasitic Disease (NTPD), is induced by several Leishmania species and is disseminated through sandfly (Lutzomyia longipalpis) bites. The parasite has developed resistance to currently prescribed antileishmanial drugs, and it has become pertinent to the search for new antileishmanial agents. The current study aimed to investigate the in vitro and in silico antileishmanial activity of two newly sourced actinomycins, X2 and D, produced by the novel Streptomyces smyrnaeus strain UKAQ_23. The antileishmanial activity conducted on promastigotes and amastigotes of Leishmania major showed actinomycin X2 having half-maximal effective concentrations (EC50), at 2.10 ± 0.10 μg/mL and 0.10 ± 0.0 μg/mL, and selectivity index (SI) values of 0.048 and 1, respectively, while the actinomycin D exhibited EC50 at 1.90 ± 0.10 μg/mL and 0.10 ± 0.0 μg/mL, and SI values of 0.052 and 1. The molecular docking studies demonstrated squalene synthase as the most favorable antileishmanial target protein for both the actinomycins X2 and D, while the xanthine phosphoribosyltransferase was the least favorable target protein. The molecular dynamics simulations confirmed that both the actinomycins remained stable in the binding pocket during the simulations. Furthermore, the MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) binding energy calculations established that the actinomycin X2 is a better binder than the actinomycin D. In conclusion, both actinomycins X2 and D from Streptomyces smyrnaeus strain UKAQ_23 are promising antileishmanial drug candidates and have strong potential to be used for treating the currently drug-resistant leishmaniasis. Full article
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16 pages, 4179 KiB  
Article
Elucidation of Teicoplanin Interactions with Drug Targets Related to COVID-19
Antibiotics 2021, 10(7), 856; https://doi.org/10.3390/antibiotics10070856 - 15 Jul 2021
Cited by 23 | Viewed by 3536
Abstract
Teicoplanin is a glycopeptide antibiotic effective against several bacterial infections, has exhibited promising therapeutic efficiency against COVID-19 in vitro, and the rationale for its use in COVID-19 is yet to be recognized. Hence, in this study a number of molecular modeling techniques [...] Read more.
Teicoplanin is a glycopeptide antibiotic effective against several bacterial infections, has exhibited promising therapeutic efficiency against COVID-19 in vitro, and the rationale for its use in COVID-19 is yet to be recognized. Hence, in this study a number of molecular modeling techniques were employed to decrypt the mechanistic insight of teicoplanin interaction with several COVID-19 drug targets. Initially, molecular docking was employed to study the teicoplanin interaction with twenty-five SARS-CoV-2 structural and non-structural proteins which was followed by molecular mechanics/generalized Born surface area (MM/GBSA) computation for binding energy predictions of top ten models from each target. Amongst all macromolecular targets, the N-terminal domain of the nucleocapsid protein displayed the strongest affinity with teicoplanin showing binding energies of −7.4 and −102.13 kcal/mol, in docking and Prime MM/GBSA, respectively. Thermodynamic stability of the teicoplanin-nucleocapsid protein was further probed by molecular dynamics simulations of protein–ligand complex as well as unbounded protein in 100 ns trajectories. Post-simulation MM-GBSA computation of 50 frames extracted from simulated trajectories estimated an average binding energy of −62.52 ± 12.22 kcal/mol. In addition, conformational state of protein in complex with docked teicoplanin displayed stable root-mean-square deviation/fluctuation. In conclusion, computational investigation of the potential targets of COVID-19 and their interaction mechanism with teicoplanin can guide the design of novel therapeutic armamentarium for the treatment of SARS-CoV-2 infection. However, additional studies are warranted to establish the clinical use or relapses, if any, of teicoplanin in the therapeutic management of COVID-19 patients. Full article
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15 pages, 3794 KiB  
Article
A New Water-Soluble Bactericidal Agent for the Treatment of Infections Caused by Gram-Positive and Gram-Negative Bacterial Strains
Antibiotics 2020, 9(9), 586; https://doi.org/10.3390/antibiotics9090586 - 08 Sep 2020
Cited by 37 | Viewed by 5506
Abstract
Grapefruit and lemon pectin obtained from the respective waste citrus peels via hydrodynamic cavitation in water only are powerful, broad-scope antimicrobials against Gram-negative and -positive bacteria. Dubbed IntegroPectin, these pectic polymers functionalized with citrus flavonoids and terpenes show superior antimicrobial activity when compared [...] Read more.
Grapefruit and lemon pectin obtained from the respective waste citrus peels via hydrodynamic cavitation in water only are powerful, broad-scope antimicrobials against Gram-negative and -positive bacteria. Dubbed IntegroPectin, these pectic polymers functionalized with citrus flavonoids and terpenes show superior antimicrobial activity when compared to commercial citrus pectin. Similar to commercial pectin, lemon IntegroPectin determined ca. 3-log reduction in Staphylococcus aureus cells, while an enhanced activity of commercial citrus pectin was detected in the case of Pseudomonas aeruginosa cells with a minimal bactericidal concentration (MBC) of 15 mg mL−1. Although grapefruit and lemon IntegroPectin share equal MBC in the case of P. aeruginosa cells, grapefruit IntegroPectin shows boosted activity upon exposure of S. aureus cells with a 40 mg mL−1 biopolymer concentration affording complete killing of the bacterial cells. Insights into the mechanism of action of these biocompatible antimicrobials and their effect on bacterial cells, at the morphological level, were obtained indirectly through Fourier Transform Infrared spectroscopy and directly through scanning electron microscopy. In the era of antimicrobial resistance, these results are of great societal and sanitary relevance since citrus IntegroPectin biomaterials are also devoid of cytotoxic activity, as already shown for lemon IntegroPectin, opening the route to the development of new medical treatments of polymicrobial infections unlikely to develop drug resistance. Full article
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18 pages, 2974 KiB  
Article
Melittin from Apis florea Venom as a Promising Therapeutic Agent for Skin Cancer Treatment
Antibiotics 2020, 9(8), 517; https://doi.org/10.3390/antibiotics9080517 - 14 Aug 2020
Cited by 13 | Viewed by 4867
Abstract
Melittin, a major component found in bee venom, is produced by the Apis species of the honey bee. In this study, the effect of melittin derived from Apis florea (Mel-AF), which is a wild honey bee species that is indigenous to Thailand, was [...] Read more.
Melittin, a major component found in bee venom, is produced by the Apis species of the honey bee. In this study, the effect of melittin derived from Apis florea (Mel-AF), which is a wild honey bee species that is indigenous to Thailand, was investigated against human malignant melanoma (A375) cells. In this study, Mel-AF exhibited considerable potential in the anti-proliferative action of A375 cells. Subsequently, the cellular mechanism of Mel-AF that induced cell death was investigated in terms of apoptosis. As a result, gene and protein expression levels, which indicated the activation of cytochrome-c release and caspase-9 expression, eventually triggered the release of the caspase-3 executioner upon Mel-AF. We then determined that apoptosis-mediated cell death was carried out through the intrinsic mitochondrial pathway. Moreover, advanced abilities, including cell motility and invasion, were significantly suppressed. Mel-AF manipulated the actin arrangement via the trapping of stress fibers that were found underneath the membrane, which resulted in the defective actin cytoskeleton organization. Consequently, the expression of EGFR, a binding protein to F-actin, was also found to be suppressed. This outcome strongly supports the effects of Mel-AF in the inhibition of progressive malignant activity through the disruption of actin cytoskeleton-EGFR interaction and the EGFR signaling system. Thus, the findings of our current study indicate the potential usefulness of Mel-AF in cancer treatments as an apoptosis inducer and a potential actin-targeting agent. Full article
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13 pages, 1809 KiB  
Article
Antibiotic-Antiapoptotic Dual Function of Clinacanthus nutans (Burm. f.) Lindau Leaf Extracts against Bovine Mastitis
Antibiotics 2020, 9(7), 429; https://doi.org/10.3390/antibiotics9070429 - 21 Jul 2020
Cited by 9 | Viewed by 3079
Abstract
Mastitis caused by bacterial infection has negative impacts on milk quality and animal health, and ultimately causes economic losses to the dairy industry worldwide. Gram-negative bacteria and their component lipopolysaccharide (LPS) can trigger the inflammatory response of endothelial cells (ECs) and subsequently promote [...] Read more.
Mastitis caused by bacterial infection has negative impacts on milk quality and animal health, and ultimately causes economic losses to the dairy industry worldwide. Gram-negative bacteria and their component lipopolysaccharide (LPS) can trigger the inflammatory response of endothelial cells (ECs) and subsequently promote EC dysfunction or injury, which is a critical pathogenesis of mastitis-causing sepsis shock. To control the bacterial infection and to minimise the LPS negative effects on ECs, we thus aimed to identify the potential herb extracts that comprised antibacterial activity and protective ability to inhibit LPS-induced cell death. Extracts from seven types of herbs derived from antibacterial screening were investigated for their protective effects on LPS-stimulated bovine endothelial cell line. Clinacanthus nutans (Burm. f.) Lindau (C. nutans) extract appeared to be the most effective antiapoptotic extract against LPS stimulation. Treatment of C. nutans extract in LPS-stimulated cells significantly lowered apoptotic cell death through modulating pro-survival Bcl-2 and pro-apoptotic Bax expression. The investigation of bioactive compounds using solvent fractionation, HPLC, and LC-MS/MS analysis revealed glyceryl 1,3-disterate (C39H76O5), kaempferol 3-O-feruloyl-sophoroside 7-O-glucoside (C43H48O24), and hydroxypthioceranic acid (C46H92O3) as the candidate components. Our findings indicated that C. nutans extract has great potential to be further developed as an alternative therapeutic agent for mastitis treatment. Full article
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17 pages, 2890 KiB  
Article
Unveiling the Properties of Thai Stingless Bee Propolis via Diminishing Cell Wall-Associated Cryptococcal Melanin and Enhancing the Fungicidal Activity of Macrophages
Antibiotics 2020, 9(7), 420; https://doi.org/10.3390/antibiotics9070420 - 17 Jul 2020
Cited by 11 | Viewed by 2295
Abstract
Cryptococcus neoformans, a life-threatening human yeast pathogen, has the ability to produce melanin, which is one of the common virulence factors contributing to cryptococcal pathogenesis. This virulence factor is closely associated with the cryptococcal cell wall, specifically chitin and chitosan polysaccharides, a [...] Read more.
Cryptococcus neoformans, a life-threatening human yeast pathogen, has the ability to produce melanin, which is one of the common virulence factors contributing to cryptococcal pathogenesis. This virulence factor is closely associated with the cryptococcal cell wall, specifically chitin and chitosan polysaccharides, a complex structure that is essential for maintaining cellular structure and integrity. In this study, we aim to investigate the effects of two stingless bee (SLB) propolis from Tetragonula laeviceps and Tetrigona melanoleuca against cell wall-associated melanin in C. neoformans, and its immune response in RAW 264.7 macrophage. The ethanolic extract of SLB propolis (EEP) has strongly exhibited anti-cryptococcal activity. Moreover, EEP from both sources reduced chitin/chitosan and melanin production against C. neoformans in a dose-dependent manner. Likewise, the mRNA expression level of CDA1, IPC1-PKC1 and LAC1 genes involved in the cryptococcal melanization pathway was significantly decreased at 2 mg/mL in EEP treatment. Additionally, pretreatment with EEP prior to yeast infection dramatically reduced intracellular replication of C. neoformans in RAW 264.7 macrophages in a dose-dependent manner. This study might be a new insight to use a natural powerful source, not only acting to target cell wall-associated molecules, but also being capable to explore a novel strategy by which dysregulation of these molecules leads to promote immunomodulatory activity. Full article
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19 pages, 4144 KiB  
Article
New Synthetic Nitro-Pyrrolomycins as Promising Antibacterial and Anticancer Agents
Antibiotics 2020, 9(6), 292; https://doi.org/10.3390/antibiotics9060292 - 30 May 2020
Cited by 34 | Viewed by 3682
Abstract
Pyrrolomycins (PMs) are polyhalogenated antibiotics known as powerful biologically active compounds, yet featuring high cytotoxicity. The present study reports the antibacterial and antitumoral properties of new chemically synthesized PMs, where the three positions of the pyrrolic nucleus were replaced by nitro groups, aiming [...] Read more.
Pyrrolomycins (PMs) are polyhalogenated antibiotics known as powerful biologically active compounds, yet featuring high cytotoxicity. The present study reports the antibacterial and antitumoral properties of new chemically synthesized PMs, where the three positions of the pyrrolic nucleus were replaced by nitro groups, aiming to reduce their cytotoxicity while maintaining or even enhancing the biological activity. Indeed, the presence of the nitro substituent in diverse positions of the pyrrole determined an improvement of the minimal bactericidal concentration (MBC) against Gram-positive (i.e., Staphylococcus aureus) or -negative (i.e., Pseudomonas aeruginosa) pathogen strains as compared to the natural PM-C. Moreover, some new nitro-PMs were as active as or more than PM-C in inhibiting the proliferation of colon (HCT116) and breast (MCF 7) cancer cell lines and were less toxic towards normal epithelial (hTERT RPE-1) cells. Altogether, our findings contribute to increase the knowledge of the mode of action of these promising molecules and provide a basis for their rationale chemical or biological manipulation. Full article
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Review

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11 pages, 613 KiB  
Review
Efficiency of Diagnostic Testing for Helicobacter pylori Infections—A Systematic Review
Antibiotics 2021, 10(1), 55; https://doi.org/10.3390/antibiotics10010055 - 08 Jan 2021
Cited by 5 | Viewed by 2501
Abstract
Background: The most recommended treatment for a Helicobacter pylori infection is high doses of combined antibiotics. The objective of this article is to perform a systematic review of the economic evaluation studies applied to assess the efficiency of diagnostic testing for H. pylori [...] Read more.
Background: The most recommended treatment for a Helicobacter pylori infection is high doses of combined antibiotics. The objective of this article is to perform a systematic review of the economic evaluation studies applied to assess the efficiency of diagnostic testing for H. pylori infections, so that their main characteristics can be identified and to learn from the literature how the antimicrobial resistance (AMR) issue is incorporated into these economic evaluations. Methods: We conducted a systematic review to compare the costs and clinical effectiveness of diagnostic strategies for H. pylori infections. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and extracted the items from the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Results: We found thirteen articles that were of good quality according to CHEERS: six studies focused on diagnostics of Helicobacter pylori infections associated with dyspepsia and four on duodenal ulcers. Testing was found to be the most cost-effective strategy in eight articles. Four studies considered AMR. Conclusions: Testing was more cost-effective than empirical treatment, except in cases of high prevalence (as with developing countries) or when patients could be stratified according to their comorbidities. The introduction of AMR into the model may change the efficiency of the testing strategy. Full article
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