Nontraditional Antibiotics—Challenges and Triumphs, 2nd Volume

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

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 19520

Special Issue 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,

The first volume of the Special Issue “Nontraditional Antibiotics—Challenges and Triumphs” was published in 2019. It was a successful issue with nine published papers, encouraging us to open a second volume with the same topic.

This second volume aims to complement the 2019 Special Issue and invites submissions that highlight the current advances supporting the development and application of nontraditional antibiotic therapies. Topics may include but are not limited to:

  • Antibodies, including antibody/antibiotic conjugates;
  • Bacteriophages and lysins;
  • Microbiome modulation;
  • Narrow spectrum agents;
  • Antibiotic potentiators and inactivators;
  • Antimicrobial and immunomodulatory peptides;
  • Biofilm disruptors;
  • Virulence modulators;
  • Targeted degradation approaches.

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
  • antibodies
  • antimicrobial peptides
  • immunomodulatory peptides
  • antibiofilm
  • antivirulence
  • targeted protein degradation

Published Papers (7 papers)

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Research

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22 pages, 2035 KiB  
Article
Evaluation of a Conformationally Constrained Indole Carboxamide as a Potential Efflux Pump Inhibitor in Pseudomonas aeruginosa
Antibiotics 2022, 11(6), 716; https://doi.org/10.3390/antibiotics11060716 - 26 May 2022
Cited by 5 | Viewed by 2047
Abstract
Efflux pumps in Gram-negative bacteria such as Pseudomonas aeruginosa provide intrinsic antimicrobial resistance by facilitating the extrusion of a wide range of antimicrobials. Approaches for combating efflux-mediated multidrug resistance involve, in part, developing indirect antimicrobial agents capable of inhibiting efflux, thus rescuing the [...] Read more.
Efflux pumps in Gram-negative bacteria such as Pseudomonas aeruginosa provide intrinsic antimicrobial resistance by facilitating the extrusion of a wide range of antimicrobials. Approaches for combating efflux-mediated multidrug resistance involve, in part, developing indirect antimicrobial agents capable of inhibiting efflux, thus rescuing the activity of antimicrobials previously rendered inactive by efflux. Herein, TXA09155 is presented as a novel efflux pump inhibitor (EPI) formed by conformationally constraining our previously reported EPI TXA01182. TXA09155 demonstrates strong potentiation in combination with multiple antibiotics with efflux liabilities against wild-type and multidrug-resistant (MDR) P. aeruginosa. At 6.25 µg/mL, TXA09155, showed ≥8-fold potentiation of levofloxacin, moxifloxacin, doxycycline, minocycline, cefpirome, chloramphenicol, and cotrimoxazole. Several biophysical and genetic studies rule out membrane disruption and support efflux inhibition as the mechanism of action (MOA) of TXA09155. TXA09155 was determined to lower the frequency of resistance (FoR) to levofloxacin and enhance the killing kinetics of moxifloxacin. Most importantly, TXA09155 outperformed the levofloxacin-potentiation activity of EPIs TXA01182 and MC-04,124 against a CDC/FDA panel of MDR clinical isolates of P. aeruginosa. TXA09155 possesses favorable physiochemical and ADME properties that warrant its optimization and further development. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs, 2nd Volume)
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13 pages, 2045 KiB  
Article
Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria
Antibiotics 2022, 11(4), 449; https://doi.org/10.3390/antibiotics11040449 - 25 Mar 2022
Cited by 4 | Viewed by 2805
Abstract
Gram-positive bacteria do not produce lipopolysaccharide as a cell wall component. As such, the polymyxin class of antibiotics, which exert bactericidal activity against Gram-negative pathogens, are ineffective against Gram-positive bacteria. The safe-for-human-use hydroxyquinoline analog ionophore PBT2 has been previously shown to break polymyxin [...] Read more.
Gram-positive bacteria do not produce lipopolysaccharide as a cell wall component. As such, the polymyxin class of antibiotics, which exert bactericidal activity against Gram-negative pathogens, are ineffective against Gram-positive bacteria. The safe-for-human-use hydroxyquinoline analog ionophore PBT2 has been previously shown to break polymyxin resistance in Gram-negative bacteria, independent of the lipopolysaccharide modification pathways that confer polymyxin resistance. Here, in combination with zinc, PBT2 was shown to break intrinsic polymyxin resistance in Streptococcus pyogenes (Group A Streptococcus; GAS), Staphylococcus aureus (including methicillin-resistant S. aureus), and vancomycin-resistant Enterococcus faecium. Using the globally disseminated M1T1 GAS strain 5448 as a proof of principle model, colistin in the presence of PBT2 + zinc was shown to be bactericidal in activity. Any resistance that did arise imposed a substantial fitness cost. PBT2 + zinc dysregulated GAS metal ion homeostasis, notably decreasing the cellular manganese content. Using a murine model of wound infection, PBT2 in combination with zinc and colistin proved an efficacious treatment against streptococcal skin infection. These findings provide a foundation from which to investigate the utility of PBT2 and next-generation polymyxin antibiotics for the treatment of Gram-positive bacterial infections. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs, 2nd Volume)
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16 pages, 3558 KiB  
Article
Evaluation of Heterocyclic Carboxamides as Potential Efflux Pump Inhibitors in Pseudomonas aeruginosa
Antibiotics 2022, 11(1), 30; https://doi.org/10.3390/antibiotics11010030 - 28 Dec 2021
Cited by 6 | Viewed by 2129
Abstract
The ability to rescue the activity of antimicrobials that are no longer effective against bacterial pathogens such as Pseudomonas aeruginosa is an attractive strategy to combat antimicrobial drug resistance. Herein, novel efflux pump inhibitors (EPIs) demonstrating strong potentiation in combination with levofloxacin against [...] Read more.
The ability to rescue the activity of antimicrobials that are no longer effective against bacterial pathogens such as Pseudomonas aeruginosa is an attractive strategy to combat antimicrobial drug resistance. Herein, novel efflux pump inhibitors (EPIs) demonstrating strong potentiation in combination with levofloxacin against wild-type P. aeruginosa ATCC 27853 are presented. A structure activity relationship of aryl substituted heterocyclic carboxamides containing a pentane diamine side chain is described. Out of several classes of fused heterocyclic carboxamides, aryl indole carboxamide compound 6j (TXA01182) at 6.25 µg/mL showed 8-fold potentiation of levofloxacin. TXA01182 was found to have equally synergistic activities with other antimicrobial classes (monobactam, fluoroquinolones, sulfonamide and tetracyclines) against P. aeruginosa. Several biophysical and genetic studies rule out membrane disruption and support efflux inhibition as the mechanism of action (MOA) of TXA01182. TXA01182 was determined to lower the frequency of resistance (FoR) of the partner antimicrobials and enhance the killing kinetics of levofloxacin. Furthermore, TXA01182 demonstrated a synergistic effect with levofloxacin against several multidrug resistant P. aeruginosa clinical isolates. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs, 2nd Volume)
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Review

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15 pages, 6720 KiB  
Review
The Structures and Binding Modes of Small-Molecule Inhibitors of Pseudomonas aeruginosa Elastase LasB
Antibiotics 2022, 11(8), 1060; https://doi.org/10.3390/antibiotics11081060 - 04 Aug 2022
Cited by 3 | Viewed by 2450
Abstract
Elastase B (LasB) is a zinc metalloprotease and a crucial virulence factor of Pseudomonas aeruginosa. As the need for new strategies to fight antimicrobial resistance (AMR) constantly rises, this protein has become a key target in the development of novel antivirulence agents. [...] Read more.
Elastase B (LasB) is a zinc metalloprotease and a crucial virulence factor of Pseudomonas aeruginosa. As the need for new strategies to fight antimicrobial resistance (AMR) constantly rises, this protein has become a key target in the development of novel antivirulence agents. The extensive knowledge of the structure of its active site, containing two subpockets and a zinc atom, led to various structure-based medicinal chemistry programs and the optimization of several chemical classes of inhibitors. This review provides a brief reminder of the structure of the active site and a summary of the disclosed P. aeruginosa LasB inhibitors. We specifically focused on the analysis of their binding modes with a detailed representation of them, hence giving an overview of the strategies aiming at targeting LasB by small molecules. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs, 2nd Volume)
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25 pages, 1277 KiB  
Review
Microbiome Modulation as a Novel Strategy to Treat and Prevent Respiratory Infections
Antibiotics 2022, 11(4), 474; https://doi.org/10.3390/antibiotics11040474 - 01 Apr 2022
Cited by 13 | Viewed by 4099
Abstract
Acute and chronic lower airway disease still represent a major cause of morbidity and mortality on a global scale. With the steady rise of multidrug-resistant respiratory pathogens, such as Pseudomonas aeruginosa and Klebsiella pneumoniae, we are rapidly approaching the advent of a [...] Read more.
Acute and chronic lower airway disease still represent a major cause of morbidity and mortality on a global scale. With the steady rise of multidrug-resistant respiratory pathogens, such as Pseudomonas aeruginosa and Klebsiella pneumoniae, we are rapidly approaching the advent of a post-antibiotic era. In addition, potentially detrimental novel variants of respiratory viruses continuously emerge with the most prominent recent example being severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To this end, alternative preventive and therapeutic intervention strategies will be critical to combat airway infections in the future. Chronic respiratory diseases are associated with alterations in the lung and gut microbiome, which is thought to contribute to disease progression and increased susceptibility to infection with respiratory pathogens. In this review we will focus on how modulating and harnessing the microbiome may pose a novel strategy to prevent and treat pulmonary infections as well as chronic respiratory disease. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs, 2nd Volume)
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12 pages, 975 KiB  
Review
The Engineered Antibiotic Peptide PLG0206 Eliminates Biofilms and Is a Potential Treatment for Periprosthetic Joint Infections
Antibiotics 2022, 11(1), 41; https://doi.org/10.3390/antibiotics11010041 - 30 Dec 2021
Cited by 5 | Viewed by 2397
Abstract
Antimicrobial peptides (AMPs) have recently gained attention for their potential to treat diseases related to bacterial and viral infections, as many traditional antimicrobial drugs have reduced efficacy in treating these infections due to the increased prevalence of drug-resistant pathogens. PLG0206, an engineered cationic [...] Read more.
Antimicrobial peptides (AMPs) have recently gained attention for their potential to treat diseases related to bacterial and viral infections, as many traditional antimicrobial drugs have reduced efficacy in treating these infections due to the increased prevalence of drug-resistant pathogens. PLG0206, an engineered cationic antibiotic peptide that is 24 residues long, has been designed to address some limitations of other natural AMPs, such as toxicity and limited activity due to pH and ion concentrations. Nonclinical studies have shown that PLG0206 is highly selective for targeting bacterial cells and is not toxic to human blood cells. Antibiofilm experiments demonstrated that PLG0206 is effective at reducing both biotic and abiotic biofilm burdens following direct biofilm contact. PLG0206 has rapid and broad-spectrum activity against both Gram-positive and Gram-negative bacteria that are implicated as etiologic agents in periprosthetic joint infections, including multidrug-resistant ESKAPE pathogens and colistin-resistant isolates. A recent first-in-human study demonstrated that PLG0206 is well tolerated and safe as an intravenous infusion in healthy volunteers. Studies are planned to determine the efficacy of PLG0206 in patients for the treatment of periprosthetic joint infections. This review summarizes the chemistry, pharmacology, and microbiology of PLG0206 and explores its current preclinical, clinical, and regulatory status. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs, 2nd Volume)
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Other

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13 pages, 1760 KiB  
Perspective
Crumbling the Castle: Targeting DNABII Proteins for Collapsing Bacterial Biofilms as a Therapeutic Approach to Treat Disease and Combat Antimicrobial Resistance
Antibiotics 2022, 11(1), 104; https://doi.org/10.3390/antibiotics11010104 - 14 Jan 2022
Cited by 9 | Viewed by 2546
Abstract
Antimicrobial resistance (AMR) is a concerning global threat that, if not addressed, could lead to increases in morbidity and mortality, coupled with societal and financial burdens. The emergence of AMR bacteria can be attributed, in part, to the decreased development of new antibiotics, [...] Read more.
Antimicrobial resistance (AMR) is a concerning global threat that, if not addressed, could lead to increases in morbidity and mortality, coupled with societal and financial burdens. The emergence of AMR bacteria can be attributed, in part, to the decreased development of new antibiotics, increased misuse and overuse of existing antibiotics, and inadequate treatment options for biofilms formed during bacterial infections. Biofilms are complex microbiomes enshrouded in a self-produced extracellular polymeric substance (EPS) that is a primary defense mechanism of the resident microorganisms against antimicrobial agents and the host immune system. In addition to the physical protective EPS barrier, biofilm-resident bacteria exhibit tolerance mechanisms enabling persistence and the establishment of recurrent infections. As current antibiotics and therapeutics are becoming less effective in combating AMR, new innovative technologies are needed to address the growing AMR threat. This perspective article highlights such a product, CMTX-101, a humanized monoclonal antibody that targets a universal component of bacterial biofilms, leading to pathogen-agnostic rapid biofilm collapse and engaging three modes of action—the sensitization of bacteria to antibiotics, host immune enablement, and the suppression of site-specific tissue inflammation. CMTX-101 is a new tool used to enhance the effectiveness of existing, relatively inexpensive first-line antibiotics to fight infections while promoting antimicrobial stewardship. Full article
(This article belongs to the Special Issue Nontraditional Antibiotics—Challenges and Triumphs, 2nd Volume)
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