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Antibiotics
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Development of Effective Antibacterial Treatment: Lessons from the Past and...
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Development of Effective Antibacterial Treatment: Lessons from the Past and Novel Approaches

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

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 35476

Special Issue Editors

Dr. Tiziano Marzo

E-Mail Website1 Website2
Guest Editor
Department of Pharmacy, University of Pisa, Pisa, Italy
Interests: inorganic medicinal chemistry; bioinorganic chemistry; protein metalation; metal-based drugs; metal-based anticancer agents; metal-based antimicrobial agents; gold; platinum; ruthenium; targeting and delivery strategies; DNA interactions; drug repurposing
Special Issues, Collections and Topics in MDPI journals
Dr. Mariagrazia Di Luca

E-Mail Website
Guest Editor
Department of Biology, University of Pisa, Via San Zeno 37, 56127 Pisa, Italy
Interests: medical biofilms; persister cells; implant-associated infections; antimicrobial resistance; antimicrobial tolerance; bacteriophages; phage therapy; antimicrobials
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the last three decades, the appearance and rapid diffusion of antibiotic-resistant bacterial strains, due to inappropriate prescription and extensively use of antibiotics in agriculture and veterinary practice, have been observed. Contextually, the discovery rate of novel antibacterial agents has declined steeply. Therefore, overuse/misuse of antimicrobials and the lack of development of new effective molecules led to the so called “antibiotic resistance crisis”, making infections one of the leading causes of death worldwide. In this frame, active substances and alternative strategies to fight this global threat to the public health, are urgently needed. The development of novel active molecules is extensively pursed, but at the same time this approach might be time-consuming and very expensive. Thus, testing novel associations of already approved drugs and drug repositioning may represent valuable tools to answer the problem. As an example, Auranofin a gold-based drug approved for the treatment of rheumatoid arthritis, also exhibited an antimicrobial activity against Gram-positive bacteria. Moreover, rediscovering older antimicrobial therapies, such as treatment based on bacteriophages, which are active against multi-drug resistant bacteria, could be a promising approach for the therapy of difficult to treat infections. Also, innovative strategies for drug delivery has been successfully applied in some case, revealing that this may represent an additional weapon, worthy of further investigation. For instance, combination of either different antibiotics or antibiotics together with bacteriophages or other molecules has been successfully exploited to eradicate resistant chronic infections. Finally, several promising targeted and responsive drug delivery platforms aiming to enhance the antibacterial properties have been recently tested.

This Special Issue aims to collect original contributions (articles, reports and reviews) describing and reporting recent advances and developments in the field of antibacterial agents both laboratory studies and clinical applications.

Potential topics include, but are not limited to:

  • Design and synthesis of novel antibacterial drugs
  • Drug repositioning
  • Metal-complexes with antimicrobial properties
  • Lytic bacteriophages
  • Antimicrobial peptides
  • Innovative drug associations to overcome resistance
  • Innovative strategies for antibacterial-agents delivery
  • Study of mechanistic aspects involved in resistance phenomena
  • New targets for antibiotics action
  • Anti-persister drugs

Dr. Tiziano Marzo

Dr. Mariagrazia Di Luca
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

  • Design and synthesis of novel antibacterial drugs
  • Drug repositioning
  • Metal-complexes with antimicrobial properties
  • Lytic bacteriophages
  • Antimicrobial peptides
  • Innovative drug associations to overcome resistance
  • Innovative strategies for antibacterial-agents delivery
  • Study of mechanistic aspects involved in resistance phenomena
  • New targets for antibiotics action
  • Anti-persister drugs

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Published Papers (9 papers)

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Editorial

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3 pages, 162 KiB  
Editorial
Development of Effective Antibacterial Treatment: Lessons from the Past and Novel Approaches
by Mariagrazia Di Luca and Tiziano Marzo
Antibiotics 2021, 10(3), 230; https://doi.org/10.3390/antibiotics10030230 - 25 Feb 2021
Cited by 8 | Viewed by 1788
Abstract
In the last three decades, the appearance and rapid diffusion of antibiotic-resistant bacterial strains have been observed [...] Full article
(This article belongs to the Special Issue Development of Effective Antibacterial Treatment: Lessons from the Past and Novel Approaches)

Research

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13 pages, 1386 KiB  
Article
Enhanced Antimicrobial and Antibiofilm Effect of New Colistin-Loaded Human Albumin Nanoparticles
by Sara Scutera, Monica Argenziano, Rosaria Sparti, Federica Bessone, Gabriele Bianco, Chiara Bastiancich, Carlotta Castagnoli, Maurizio Stella, Tiziana Musso and Roberta Cavalli
Antibiotics 2021, 10(1), 57; https://doi.org/10.3390/antibiotics10010057 - 8 Jan 2021
Cited by 35 | Viewed by 3718
Abstract
Multidrug-resistant (MDR) Gram-negative bacteria (GNB), such as Acinetobacter and Klebsiella, are responsible for severe hospital-acquired infections. Colistin, despite its toxicity and low tissue penetration, is considered the last resort antibiotic against these microorganisms. Of concern, the use of Colistin has recently been [...] Read more.
Multidrug-resistant (MDR) Gram-negative bacteria (GNB), such as Acinetobacter and Klebsiella, are responsible for severe hospital-acquired infections. Colistin, despite its toxicity and low tissue penetration, is considered the last resort antibiotic against these microorganisms. Of concern, the use of Colistin has recently been compromised by the emergence of Colistin resistance. Herein, we developed a new formulation consisting of multifunctional chitosan-coated human albumin nanoparticles for the delivery of Colistin (Col/haNPs). Col/haNPs were in vitro characterized for encapsulation efficiency, drug release, stability and cytotoxicity and were evaluated for antibacterial activity against MDR GNB (Acinetobacter baumannii and Klebsiella pneumoniae). Col/haNPs showed sizes lower than 200 nm, high encapsulation efficiency (98.65%) and prolonged in vitro release of Colistin. The safety of the nanoformulation was demonstrated by a negligible cytotoxicity on human fibroblasts and hemolytic activity. Col/haNPs evidenced a high antibacterial effect with a significant decrease in MIC values compared to free Colistin, in particular against Col-resistant strains with a pronounced decline of bacterial growth over time. Moreover, Col/haNPs exhibited an inhibitory effect on biofilm formation that was 4 and 60 fold higher compared to free Colistin, respectively for Colistin susceptible and resistant A. baumannii. Our findings suggest that Col/haNPs could represent a promising Colistin nanocarrier with high antimicrobial activity on MDR GNB. Full article
(This article belongs to the Special Issue Development of Effective Antibacterial Treatment: Lessons from the Past and Novel Approaches)
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12 pages, 1763 KiB  
Article
Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)
by Philip Storck, Florian Umstätter, Sabrina Wohlfart, Cornelius Domhan, Christian Kleist, Julia Werner, Klaus Brandenburg, Stefan Zimmermann, Uwe Haberkorn, Walter Mier and Philipp Uhl
Antibiotics 2020, 9(12), 844; https://doi.org/10.3390/antibiotics9120844 - 26 Nov 2020
Cited by 16 | Viewed by 3416
Abstract
The increasing number of infections caused by multidrug-resistant bacteria requires an intensified search for new antibiotics. Pep19-4LF is a synthetic antimicrobial peptide (GKKYRRFRWKFKGKLFLFG) that was previously designed with the main focus on high antimicrobial activity. The hydrophobic motif, LFLFG, was found to be [...] Read more.
The increasing number of infections caused by multidrug-resistant bacteria requires an intensified search for new antibiotics. Pep19-4LF is a synthetic antimicrobial peptide (GKKYRRFRWKFKGKLFLFG) that was previously designed with the main focus on high antimicrobial activity. The hydrophobic motif, LFLFG, was found to be essential for antimicrobial activity. However, this motif shows several limitations such as aggregation in biological media, low solubility, and small yields in peptide synthesis. In order to obtain more appropriate peptide characteristics, the hydrophobic motif was replaced with fatty acids. For this purpose, a shortened variant of Pep19-4LF (Pep19-short; GKKYRRFRWKFKGK) was synthesized and covalently linked to saturated fatty acids of different chain lengths. The peptide conjugates were tested with respect to their antibacterial activity by microdilution experiments on different bacterial strains. The length of the fatty acid was found to be directly correlated to the antimicrobial activity up to an ideal chain length (undecanoic acid, C11:0). This conjugate showed high antimicrobial activity in absence of toxicity. Time–kill studies revealed a fast and bactericidal mode of action. Furthermore, the first in vivo experiments of the conjugate in rodents demonstrated pharmacokinetics appropriate for application as a drug. These results clearly indicate that the hydrophobic motif of the peptide can be replaced by a single fatty acid of medium length, simplifying the design of this antimicrobial peptide while retaining high antimicrobial activity in the absence of toxicity. Full article
(This article belongs to the Special Issue Development of Effective Antibacterial Treatment: Lessons from the Past and Novel Approaches)
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Graphical abstract

12 pages, 1636 KiB  
Article
Adjunctive Use of Phage Sb-1 in Antibiotics Enhances Inhibitory Biofilm Growth Activity versus Rifampin-Resistant Staphylococcus aureus Strains
by Lei Wang, Tamta Tkhilaishvili and Andrej Trampuz
Antibiotics 2020, 9(11), 749; https://doi.org/10.3390/antibiotics9110749 - 29 Oct 2020
Cited by 15 | Viewed by 2687
Abstract
Effective antimicrobials are crucial for managing Staphylococcus aureus implant-associated bone infections (IABIs), particularly for infections due to rifampin-resistant S. aureus (RRSA). Failure to remove the implant results in persistent infection; thus, prolonged suppressive antibiotic therapy may be a reasonable alternative. However, a high [...] Read more.
Effective antimicrobials are crucial for managing Staphylococcus aureus implant-associated bone infections (IABIs), particularly for infections due to rifampin-resistant S. aureus (RRSA). Failure to remove the implant results in persistent infection; thus, prolonged suppressive antibiotic therapy may be a reasonable alternative. However, a high incidence of adverse events can necessitate the discontinuation of therapy. In this scenario, commercial Staphylococcal bacteriophage Sb-1 combined with antibiotics is an option, showing a promising synergistic activity to facilitate the treatment of biofilm infections. Therefore, we evaluated the efficacy of the inhibitory activity of five antibiotics (doxycycline, levofloxacin, clindamycin, linezolid, and rifampin) alone or combined with phage Sb-1 (106 PFU/mL) in a simultaneous and staggered manner, to combat five clinical RRSA strains and the laboratory strain MRSA ATCC 43300 in 72 h by isothermal microcalorimetry. The synergistic effects were observed when phage Sb-1 (106 PFU/mL) combined with antibiotics had at least 2 log-reduction lower concentrations, represented by a fractional biofilm inhibitory concentration (FBIC) of <0.25. Among the antibiotics that we tested, the synergistic effect of all six strains was achieved in phage/doxycycline and phage/linezolid combinations in a staggered manner, whereas a distinctly noticeable improvement in inhibitory activity was observed in the phage/doxycycline combination with a low concentration of doxycycline. Moreover, phage/levofloxacin and phage/clindamycin combinations also showed a synergistic inhibitory effect against five strains and four strains, respectively. Interestingly, the synergistic inhibitory activity was also observed in the doxycycline-resistant and levofloxacin-resistant profile strains. However, no inhibitory activity was observed for all of the combinations in a simultaneous manner, as well as for the phage/rifampin combination in a staggered manner. These results have implications for alternative, combined, and prolonged suppressive antimicrobial treatment approaches. Full article
(This article belongs to the Special Issue Development of Effective Antibacterial Treatment: Lessons from the Past and Novel Approaches)
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11 pages, 1726 KiB  
Article
Combination Therapy Using Low-Concentration Oxacillin with Palmitic Acid and Span85 to Control Clinical Methicillin-Resistant Staphylococcus aureus
by Hun-Suk Song, Tae-Rim Choi, Shashi Kant Bhatia, Sun Mi Lee, Sol Lee Park, Hye Soo Lee, Yun-Gon Kim, Jae-Seok Kim, Wooseong Kim and Yung-Hun Yang
Antibiotics 2020, 9(10), 682; https://doi.org/10.3390/antibiotics9100682 - 8 Oct 2020
Cited by 17 | Viewed by 2755
Abstract
The overuse of antibiotics has led to the emergence of multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). MRSA is difficult to kill with a single antibiotic because it has evolved to be resistant to various antibiotics by increasing the PBP2a (mecA [...] Read more.
The overuse of antibiotics has led to the emergence of multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). MRSA is difficult to kill with a single antibiotic because it has evolved to be resistant to various antibiotics by increasing the PBP2a (mecA) expression level, building up biofilm, introducing SCCmec for multidrug resistance, and changing its membrane properties. Therefore, to overcome antibiotic resistance and decrease possible genetic mutations that can lead to the acquisition of higher antibiotic resistance, drug combination therapy was applied based on previous results indicating that MRSA shows increased susceptibility to free fatty acids and surfactants. The optimal ratio of three components and the synergistic effects of possible combinations were investigated. The combinations were directly applied to clinically isolated strains, and the combination containing 15 μg/mL of oxacillin was able to control SCCmec type III and IV isolates having an oxacillin minimum inhibitory concentration (MIC) up to 1024 μg/mL; moreover, the combination with a slightly increased oxacillin concentration was able to kill SCCmec type II. Phospholipid analysis revealed that clinical strains with higher resistance contained a high portion of 12-methyltetradecanoic acid (anteiso-C15:0) and 14-methylhexadecanoic acid (anteiso-C17:0), although individual strains showed different patterns. In summary, we showed that combinatorial therapy with a low concentration of oxacillin controlled different laboratory and highly diversified clinical MRSA strains. Full article
(This article belongs to the Special Issue Development of Effective Antibacterial Treatment: Lessons from the Past and Novel Approaches)
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21 pages, 4249 KiB  
Article
The Antibacterial and Anti-Biofilm Activity of Metal Complexes Incorporating 3,6,9-Trioxaundecanedioate and 1,10-Phenanthroline Ligands in Clinical Isolates of Pseudomonas aeruginosa from Irish Cystic Fibrosis Patients
by Megan O’Shaughnessy, Pauraic McCarron, Livia Viganor, Malachy McCann, Michael Devereux and Orla Howe
Antibiotics 2020, 9(10), 674; https://doi.org/10.3390/antibiotics9100674 - 5 Oct 2020
Cited by 11 | Viewed by 4180
Abstract
Chronic infections of Pseudomonas aeruginosa in the lungs of cystic fibrosis (CF) patients are problematic in Ireland where inherited CF is prevalent. The bacteria’s capacity to form a biofilm in its pathogenesis is highly virulent and leads to decreased susceptibility to most antibiotic [...] Read more.
Chronic infections of Pseudomonas aeruginosa in the lungs of cystic fibrosis (CF) patients are problematic in Ireland where inherited CF is prevalent. The bacteria’s capacity to form a biofilm in its pathogenesis is highly virulent and leads to decreased susceptibility to most antibiotic treatments. Herein, we present the activity profiles of the Cu(II), Mn(II) and Ag(I) tdda-phen chelate complexes {[Cu(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (Cu-tdda-phen), {[Mn(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (Mn-tdda-phen) and [Ag2(3,6,9-tdda)(phen)4]·EtOH (Ag-tdda-phen) (tddaH2 = 3,6,9-trioxaundecanedioic acid; phen = 1,10-phenanthroline) towards clinical isolates of P. aeruginosa derived from Irish CF patients in comparison to two reference laboratory strains (ATCC 27853 and PAO1). The effects of the metal-tdda-phen complexes and gentamicin on planktonic growth, biofilm formation (pre-treatment) and mature biofilm (post-treatment) alone and in combination were investigated. The effects of the metal-tdda-phen complexes on the individual biofilm components; exopolysaccharide, extracellular DNA (eDNA), pyocyanin and pyoverdine are also presented. All three metal-tdda-phen complexes showed comparable and often superior activity to gentamicin in the CF strains, compared to their activities in the laboratory strains, with respect to both biofilm formation and established biofilms. Combination studies presented synergistic activity between all three complexes and gentamicin, particularly for the post-treatment of established mature biofilms, and was supported by the reduction of the individual biofilm components examined. Full article
(This article belongs to the Special Issue Development of Effective Antibacterial Treatment: Lessons from the Past and Novel Approaches)
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Review

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11 pages, 619 KiB  
Review
The Safety and Efficacy of Phage Therapy for Bone and Joint Infections: A Systematic Review
by Alex L. Clarke, Steven De Soir and Joshua D. Jones
Antibiotics 2020, 9(11), 795; https://doi.org/10.3390/antibiotics9110795 - 10 Nov 2020
Cited by 35 | Viewed by 4640
Abstract
Bacterial resistance to antibiotics has catalysed interest in alternative antimicrobial strategies. Bacteriophages (phages) are viruses of bacteria with a long history of successful therapeutic use. Phage therapy is a promising antibacterial strategy for infections with a biofilm component, including recalcitrant bone and joint [...] Read more.
Bacterial resistance to antibiotics has catalysed interest in alternative antimicrobial strategies. Bacteriophages (phages) are viruses of bacteria with a long history of successful therapeutic use. Phage therapy is a promising antibacterial strategy for infections with a biofilm component, including recalcitrant bone and joint infections, which have significant social, financial and human impacts. Here, we report a systematic review of the safety and efficacy of phage therapy for the treatment of bone and joint infections. Three electronic databases were systematically searched for articles that reported primary data about human phage therapy for bone and joint infections. Two authors independently assessed study eligibility and performed data extraction. Seventeen reports were eligible for inclusion in this review, representing the treatment of 277 patients. A cautionary, crude, efficacy estimate revealed that 93.1% (n = 258/277) achieved clinical resolution, 3.3% (n = 9/277) had improvement and 3.6% (n = 10/277) showed no improvement. Seven of the nine reports that directly commented on the safety of phage therapy did not express safety concerns. The adverse effects reported in the remaining two were not severe and were linked to the presence of contaminating endotoxins and pre-existing liver pathology in a patient treated with high-titre intravenous phage therapy. Three other reports, from 1940–1987, offered general comments on the safety of phage therapy and documented adverse effects consistent with endotoxin co-administration concomitant with the use of raw phage lysates. Together, the reports identified by this review suggest that appropriately purified phages represent a safe and highly efficacious treatment option for complex and intractable bone and joint infections. Full article
(This article belongs to the Special Issue Development of Effective Antibacterial Treatment: Lessons from the Past and Novel Approaches)
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14 pages, 443 KiB  
Review
The Safety and Efficacy of Phage Therapy for Superficial Bacterial Infections: A Systematic Review
by Angharad Steele, Helen J. Stacey, Steven de Soir and Joshua D. Jones
Antibiotics 2020, 9(11), 754; https://doi.org/10.3390/antibiotics9110754 - 29 Oct 2020
Cited by 42 | Viewed by 5639
Abstract
Superficial bacterial infections, such as dermatological, burn wound and chronic wound/ulcer infections, place great human and financial burdens on health systems globally and are often complicated by antibiotic resistance. Bacteriophage (phage) therapy is a promising alternative antimicrobial strategy with a 100-year history of [...] Read more.
Superficial bacterial infections, such as dermatological, burn wound and chronic wound/ulcer infections, place great human and financial burdens on health systems globally and are often complicated by antibiotic resistance. Bacteriophage (phage) therapy is a promising alternative antimicrobial strategy with a 100-year history of successful application. Here, we report a systematic review of the safety and efficacy of phage therapy for the treatment of superficial bacterial infections. Three electronic databases were systematically searched for articles that reported primary data about human phage therapy for dermatological, burn wound or chronic wound/ulcer infections secondary to commonly causative bacteria. Two authors independently assessed study eligibility and performed data extraction. Of the 27 eligible reports, eight contained data on burn wound infection (n = 156), 12 on chronic wound/ulcer infection (n = 327) and 10 on dermatological infections (n = 1096). Cautionary pooled efficacy estimates from the studies that clearly reported efficacy data showed clinical resolution or improvement in 77.5% (n = 111) of burn wound infections, 86.1% (n = 310) of chronic wound/ulcer infections and 94.14% (n = 734) of dermatological infections. Over half of the reports that commented on safety (n = 8/15), all published in or after 2002, did not express safety concerns. Seven early reports (1929–1987), described adverse effects consistent with the administration of raw phage lysate and co-administered bacterial debris or broth. This review strongly suggests that the use of purified phage to treat superficial bacterial infections can be highly effective and, by various routes of administration, is safe and without adverse effects. Full article
(This article belongs to the Special Issue Development of Effective Antibacterial Treatment: Lessons from the Past and Novel Approaches)
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22 pages, 1059 KiB  
Review
Metal–Peptide Complexes as Promising Antibiotics to Fight Emerging Drug Resistance: New Perspectives in Tuberculosis
by Concetta Di Natale, Ilaria De Benedictis, Arianna De Benedictis and Daniela Marasco
Antibiotics 2020, 9(6), 337; https://doi.org/10.3390/antibiotics9060337 - 18 Jun 2020
Cited by 32 | Viewed by 5330
Abstract
In metal-peptide interactions, cations form stable complexes through bonds with coordinating groups as side chains of amino acids. These compounds, among other things, exert a wide variety of antimicrobial activities through structural changes of peptides upon metal binding and redox chemistry. They exhibit [...] Read more.
In metal-peptide interactions, cations form stable complexes through bonds with coordinating groups as side chains of amino acids. These compounds, among other things, exert a wide variety of antimicrobial activities through structural changes of peptides upon metal binding and redox chemistry. They exhibit different mechanisms of action (MOA), including the modification of DNA/RNA, protein and cell wall synthesis, permeabilization and modulation of gradients of cellular membranes. Nowadays, the large increase in antibiotic resistance represents a crucial problem to limit progression at the pandemic level of the diseases that seemed nearly eradicated, such as tuberculosis (Tb). Mycobacterium tuberculosis (Mtb) is intrinsically resistant to many antibiotics due to chromosomal mutations which can lead to the onset of novel strains. Consequently, the maximum pharmaceutical effort should be focused on the development of new therapeutic agents and antimicrobial peptides can represent a valuable option as a copious source of potential bioactive compounds. The introduction of a metal center can improve chemical diversity and hence specificity and bioavailability while, in turn, the coordination to peptides of metal complexes can protect them and enhance their poor water solubility and air stability: the optimization of these parameters is strictly required for drug prioritization and to obtain potent inhibitors of Mtb infections with novel MOAs. Here, we present a panoramic review of the most recent findings in the field of metal complex-peptide conjugates and their delivery systems with the potential pharmaceutical application as novel antibiotics in Mtb infections. Full article
(This article belongs to the Special Issue Development of Effective Antibacterial Treatment: Lessons from the Past and Novel Approaches)
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