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Antibiotics
Special Issues
Nontraditional Antibiotics—Challenges and Triumphs
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Nontraditional Antibiotics—Challenges and Triumphs

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

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 62136

Special Issue Editor

Dr. Karl Hansford

E-Mail Website
Guest Editor
Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia
Interests: antibiotics; antimicrobial resistance; polymyxins; peptide chemistry; peptide mimicry; drug discovery; organic synthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In this Special Issue of Antibiotics, we invite submissions describing the latest developments in the design and preclinical evaluation of nontraditional antibiotics. Contemporary antibiotic discovery has hit a fork in the road—in one direction, we face major scientific obstacles preventing reinvigoration of the antibiotic pipeline using traditional approaches. Encouragingly, a paradigm shift is in motion to suggest that the alternative direction, involving nontraditional approaches, may assist in filling the void as we wait for new breakthroughs.

For example, phage lysins, antibodies and probiotics, amongst others, have been found to be of merit on the basis of technical feasibility, and the potential for high clinical impact. An estimated 30 nontraditional products are currently in clinical development. Indeed, the recent FDA approval of the first US clinical trial for bacteriophage-based therapy and the recent positive Phase II results of the lysin Exebacase provide much-needed optimism for the development of nontraditional therapies. The flipside is that the development of such products may face a host of new challenges associated with clinical trial design and regulation.

Therefore, this Special Issue aims to deliver an invaluable compendium of the latest approaches and challenges associated with the development of nontraditional antibiotics. Topics may include but are not limited to:

  • Antibodies;
  • Bacteriophages;
  • Lysins;
  • Probiotics;
  • Antibody/antibiotic conjugates;
  • Narrow spectrum agents;
  • Antibiotic inactivators;
  • Vaccines;
  • Antimicrobial peptides;
  • Biofilm inhibitors;
  • Virulence modulators.

Dr. Karl Hansford
Guest Editor

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

  • Nontraditional antibiotics
  • bacteriophages
  • lysins
  • probiotics
  • narrow spectrum agents
  • antibiotic inactivators
  • vaccines
  • antibodies
  • antimicrobial peptides
  • biofilm inhibitors
  • virulence modulators

Published Papers (9 papers)

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Editorial

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2 pages, 163 KiB  
Editorial
Nontraditional Antibiotics—Challenges and Triumphs
by Karl A. Hansford
Antibiotics 2020, 9(4), 169; https://doi.org/10.3390/antibiotics9040169 - 09 Apr 2020
Viewed by 1962
Abstract
The pursuit of nontraditional antibiotics is becoming an increasingly important means to tackle seemingly insurmountable challenges faced by contemporary antibiotic researchers as they overcome the shifting landscape of bacterial pathogenesis, particularly for Gram-negative bacteria [...] Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs)

Research

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10 pages, 541 KiB  
Article
Antimicrobial and Antifungal Activities of Terpene-Derived Palladium Complexes
by Olga Zalevskaya, Yana Gur’eva, Aleksandr Kutchin and Karl A. Hansford
Antibiotics 2020, 9(5), 277; https://doi.org/10.3390/antibiotics9050277 - 25 May 2020
Cited by 22 | Viewed by 3707
Abstract
In an era of multidrug-resistant bacterial infections overshadowed by a lack of innovation in the antimicrobial drug development pipeline, there has been a resurgence in multidisciplinary approaches aimed at tackling this global health problem. One such approach is to use metal complexes as [...] Read more.
In an era of multidrug-resistant bacterial infections overshadowed by a lack of innovation in the antimicrobial drug development pipeline, there has been a resurgence in multidisciplinary approaches aimed at tackling this global health problem. One such approach is to use metal complexes as a framework for new antimicrobials. Indeed, in this context, bismuth-, silver- and gold-derived compounds in particular have displayed demonstrable antimicrobial activity. In this work, we discuss the antimicrobial and antifungal activities of terpene-derived chiral palladium complexes against Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, Escherichia coli, Candida albicans, and Cryptococcus neoformans. It was established that all studied coordination compounds of palladium were highly active antifungal drugs. In contrast, the subset of palladacycles possessing a palladium–carbon bond were only active against the Gram-positive bacterium Staphylococcus aureus. All compounds were inactive against the Gram-negative bacteria tested. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs)
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18 pages, 1648 KiB  
Communication
The Role of Drug Repurposing in the Development of Novel Antimicrobial Drugs: Non-Antibiotic Pharmacological Agents as Quorum Sensing-Inhibitors
by Márió Gajdács and Gabriella Spengler
Antibiotics 2019, 8(4), 270; https://doi.org/10.3390/antibiotics8040270 - 17 Dec 2019
Cited by 42 | Viewed by 6147
Abstract
Background: The emergence of multidrug-resistant organisms (MDROs) is a global public health issue, severely hindering clinicians in administering appropriate antimicrobial therapy. Drug repurposing is a drug development strategy, during which new pharmacological applications are identified for already approved drugs. From the viewpoint of [...] Read more.
Background: The emergence of multidrug-resistant organisms (MDROs) is a global public health issue, severely hindering clinicians in administering appropriate antimicrobial therapy. Drug repurposing is a drug development strategy, during which new pharmacological applications are identified for already approved drugs. From the viewpoint of the development of virulence inhibitors, inhibition of quorum sensing (QS) is a promising route because various important features in bacterial physiology and virulence are mediated by QS-dependent gene expression. Methods: Forty-five pharmacological agents, encompassing a wide variety of different chemical structures and mechanisms of action, were tested during our experiments. The antibacterial activity of the compounds was tested using the broth microdilution method. Screening and semi-quantitative assessment of QS-inhibition by the compounds was performed using QS-signal molecule-producing and indicator strains. Results: Fourteen pharmaceutical agents showed antibacterial activity in the tested concentration range, while eight drugs (namely 5-fluorouracil, metamizole-sodium, cisplatin, methotrexate, bleomycin, promethazine, chlorpromazine, and thioridazine) showed dose-dependent QS-inhibitory activity in the in vitro model systems applied during the experiments. Conclusions: Virulence inhibitors represent an attractive alternative strategy to combat bacterial pathogens more efficiently. Some of the tested compounds could be considered potential QS-inhibitory agents, warranting further experiments involving additional model systems to establish the extent of their efficacy. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs)
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Review

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12 pages, 548 KiB  
Review
Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens
by Daniel V. Zurawski and Molly K. McLendon
Antibiotics 2020, 9(4), 155; https://doi.org/10.3390/antibiotics9040155 - 01 Apr 2020
Cited by 84 | Viewed by 8604
Abstract
In the beginning of the 21st century, the frequency of antimicrobial resistance (AMR) has reached an apex, where even 4th and 5th generation antibiotics are becoming useless in clinical settings. In turn, patients are suffering from once-curable infections, with increases in morbidity and [...] Read more.
In the beginning of the 21st century, the frequency of antimicrobial resistance (AMR) has reached an apex, where even 4th and 5th generation antibiotics are becoming useless in clinical settings. In turn, patients are suffering from once-curable infections, with increases in morbidity and mortality. The root cause of many of these infections are the ESKAPEE pathogens (Enterococcus species, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli), which thrive in the nosocomial environment and are the bacterial species that have seen the largest rise in the acquisition of antibiotic resistance genes. While traditional small-molecule development still dominates the antibacterial landscape for solutions to AMR, some researchers are now turning to biological approaches as potential game changers. Monoclonal antibodies (mAbs)—more specifically, human monoclonal antibodies (Hu-mAbs)—have been highly pursued in the anti-cancer, autoimmune, and antiviral fields with many success stories, but antibody development for bacterial infection is still just scratching the surface. The untapped potential for Hu-mAbs to be used as a prophylactic or therapeutic treatment for bacterial infection is exciting, as these biologics do not have the same toxicity hurdles of small molecules, could have less resistance as they often target virulence proteins rather than proteins required for survival, and are narrow spectrum (targeting just one pathogenic species), therefore avoiding the disruption of the microbiome. This mini-review will highlight the current antibacterial mAbs approved for patient use, the success stories for mAb development, and new Hu-mAb products in the antibacterial pipeline. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs)
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13 pages, 291 KiB  
Review
Bacteriophage Therapy: Developments and Directions
by Mikeljon P. Nikolich and Andrey A. Filippov
Antibiotics 2020, 9(3), 135; https://doi.org/10.3390/antibiotics9030135 - 24 Mar 2020
Cited by 77 | Viewed by 13474
Abstract
In an era of proliferating multidrug resistant bacterial infections that are exhausting the capacity of existing chemical antibiotics and in which the development of new antibiotics is significantly rarer, Western medicine must seek additional therapeutic options that can be employed to treat these [...] Read more.
In an era of proliferating multidrug resistant bacterial infections that are exhausting the capacity of existing chemical antibiotics and in which the development of new antibiotics is significantly rarer, Western medicine must seek additional therapeutic options that can be employed to treat these infections. Among the potential antibacterial solutions are bacteriophage therapeutics, which possess very different properties from broad spectrum antibiotics that are currently the standard of care, and which can be used in combination with them and often provide synergies. In this review we summarize the state of the development of bacteriophage therapeutics and discuss potential paths to the implementation of phage therapies in contemporary medicine, focused on fixed phage cocktail therapeutics since these are likely to be the first bacteriophage products licensed for broad use in Western countries. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs)
13 pages, 511 KiB  
Review
Gram-Negative Bacterial Lysins
by Chandrabali Ghose and Chad W. Euler
Antibiotics 2020, 9(2), 74; https://doi.org/10.3390/antibiotics9020074 - 11 Feb 2020
Cited by 69 | Viewed by 8422
Abstract
Antibiotics have had a profound impact on human society by enabling the eradication of otherwise deadly infections. Unfortunately, antibiotic use and overuse has led to the rapid spread of acquired antibiotic resistance, creating a major threat to public health. Novel therapeutic agents called [...] Read more.
Antibiotics have had a profound impact on human society by enabling the eradication of otherwise deadly infections. Unfortunately, antibiotic use and overuse has led to the rapid spread of acquired antibiotic resistance, creating a major threat to public health. Novel therapeutic agents called bacteriophage endolysins (lysins) provide a solution to the worldwide epidemic of antibiotic resistance. Lysins are a class of enzymes produced by bacteriophages during the lytic cycle, which are capable of cleaving bonds in the bacterial cell wall, resulting in the death of the bacteria within seconds after contact. Through evolutionary selection of the phage progeny to be released and spread, these lysins target different critical components in the cell wall, making resistance to these molecules orders of magnitude less likely than conventional antibiotics. Such properties make lysins uniquely suitable for the treatment of multidrug resistant bacterial pathogens. Lysins, either naturally occurring or engineered, have the potential of being developed into fast-acting, narrow-spectrum, biofilm-disrupting antimicrobials that act synergistically with standard of care antibiotics. This review focuses on newly discovered classes of Gram-negative lysins with emphasis on prototypical enzymes that have been evaluated for efficacy against the major antibiotic resistant organisms causing nosocomial infections. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs)
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Other

9 pages, 239 KiB  
Commentary
Prevalence and Therapeutic Challenges of Fungal Drug Resistance: Role for Plants in Drug Discovery
by Lewis Marquez and Cassandra L. Quave
Antibiotics 2020, 9(4), 150; https://doi.org/10.3390/antibiotics9040150 - 31 Mar 2020
Cited by 25 | Viewed by 4156
Abstract
Antimicrobial resistance is a global issue that threatens the effective practice of modern medicine and global health. The emergence of multidrug-resistant (MDR) fungal strains of Candida auris and azole-resistant Aspergillus fumigatus were highlighted in the Centers for Disease Control and Prevention’s (CDC) 2019 [...] Read more.
Antimicrobial resistance is a global issue that threatens the effective practice of modern medicine and global health. The emergence of multidrug-resistant (MDR) fungal strains of Candida auris and azole-resistant Aspergillus fumigatus were highlighted in the Centers for Disease Control and Prevention’s (CDC) 2019 report, Antibiotic Resistance Threats in the United States. Conventional antifungals used to treat fungal infections are no longer as effective, leading to increased mortality. Compounding this issue, there are very few new antifungals currently in development. Plants from traditional medicine represent one possible research path to addressing the issue of MDR fungal pathogens. In this commentary piece, we discuss how medical ethnobotany—the study of how people use plants in medicine—can be used as a guide to identify plant species for the discovery and development of novel antifungal therapies. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs)
13 pages, 1271 KiB  
Concept Paper
Critical Parameters for the Development of Novel Therapies for Severe and Resistant Infections—A Case Study on CAL02, a Non-Traditional Broad-Spectrum Anti-Virulence Drug
by Samareh Azeredo da Silveira and Andrew F. Shorr
Antibiotics 2020, 9(2), 94; https://doi.org/10.3390/antibiotics9020094 - 21 Feb 2020
Cited by 5 | Viewed by 4180
Abstract
Background: Poor outcomes in severe and resistant infections, together with the economic struggles of companies active in the field of anti-infective development, call for new solutions and front runners with novel approaches. Among “non-traditional” approaches, blocking virulence could be a game changer. Objectives: [...] Read more.
Background: Poor outcomes in severe and resistant infections, together with the economic struggles of companies active in the field of anti-infective development, call for new solutions and front runners with novel approaches. Among “non-traditional” approaches, blocking virulence could be a game changer. Objectives: This review offers a perspective on parameters that have determined the development path of CAL02, a novel anti-virulence agent, with a view to steering clear of the obstacles and limitations that impede market sustainability for new anti-infective drugs. Conclusions and implications of key findings: This case study highlights four pillars that may support the development of other non-traditional drugs and, concurrently, provide a new model that could reshape the field. Therapeutic triggers, study designs, and economic parameters are discussed. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs)
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24 pages, 1829 KiB  
Perspective
Metal Complexes, an Untapped Source of Antibiotic Potential?
by Angelo Frei
Antibiotics 2020, 9(2), 90; https://doi.org/10.3390/antibiotics9020090 - 18 Feb 2020
Cited by 119 | Viewed by 10602
Abstract
With the widespread rise of antimicrobial resistance, most traditional sources for new drug compounds have been explored intensively for new classes of antibiotics. Meanwhile, metal complexes have long had only a niche presence in the medicinal chemistry landscape, despite some compounds, such as [...] Read more.
With the widespread rise of antimicrobial resistance, most traditional sources for new drug compounds have been explored intensively for new classes of antibiotics. Meanwhile, metal complexes have long had only a niche presence in the medicinal chemistry landscape, despite some compounds, such as the anticancer drug cisplatin, having had a profound impact and still being used extensively in cancer treatments today. Indeed, metal complexes have been largely ignored for antibiotic development. This is surprising as metal compounds have access to unique modes of action and exist in a wider range of three-dimensional geometries than purely organic compounds. These properties make them interesting starting points for the development of new drugs. In this perspective article, the encouraging work that has been done on antimicrobial metal complexes, mainly over the last decade, is highlighted. Promising metal complexes, their activity profiles, and possible modes of action are discussed and issues that remain to be addressed are emphasized. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs)
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