Special Issue "Updates on Novel Antimicrobial Agents and Strategies Against Pathogenic Bacteria"

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Novel Antimicrobial Agents".

Deadline for manuscript submissions: closed (30 September 2019).

Special Issue Editor

Dr. Marco Maria D'Andrea
Website
Guest Editor
Department of Biology, University of “Tor Vergata”, Rome, Italy
Interests: antibiotic resistance mechanisms; genetic bases for the diffusion of antibiotic resistance genes; microbial bioinformatics; new antimicrobial drugs; bacteriophages; bacteriophages as tools for phage therapy
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

The problem of antibiotic resistance in bacterial pathogens has reached alarming levels, with the emergence and diffusion at worldwide scale of strains displaying complex antibiotic resistance phenotypes which seriously impede the effective treatment of some bacterial infections. A number of international bodies, such as the World Health Organization and the American Center for Disease Control and Prevention, forecast that this ‘antibiotic resistance crisis’ will lead to the death of several million people per year in the 21th century. Therefore, there is an urgent need to develop novel antibiotics and innovative antimicrobial approaches to avoid the return to the “pre-antibiotic era”.

This Special Issue aims to provide an update about original approaches to fight bacterial pathogens. It is expected that this Special Issue will collect research articles on new molecules with antimicrobial activity, including new conventional antibiotics of either synthetic or natural origin, modified drugs with augmented potency to be used alone or in synergy, innovative alternatives such bacteriophages or components thereof, enzybiotics, and probiotics able to displace the pathogenic microflora.

Dr. Marco Maria D'Andrea
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 papers will be 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 1600 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
  • antimicrobial drugs
  • infection
  • new antimicrobials
  • bacteriophages
  • enzybiotics
  • lysins
  • depolymerases

Published Papers (11 papers)

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Editorial

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Open AccessEditorial
The Urgent Need for Novel Antimicrobial Agents and Strategies to Fight Antibiotic Resistance
Antibiotics 2019, 8(4), 254; https://doi.org/10.3390/antibiotics8040254 - 06 Dec 2019
Cited by 1
Abstract
Antibiotic resistance in bacterial pathogens has currently reached very high and alarming levels [...] Full article

Research

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Open AccessCommunication
Novel Small-molecule Antibacterials against Gram-positive Pathogens of Staphylococcus and Enterococcus Species
Antibiotics 2019, 8(4), 210; https://doi.org/10.3390/antibiotics8040210 - 02 Nov 2019
Cited by 2
Abstract
Defeat of the antibiotic resistance of pathogenic bacteria is one great challenge today and for the future. In the last century many classes of effective antibacterials have been developed, so that upcoming resistances could be met with novel drugs of various compound classes. [...] Read more.
Defeat of the antibiotic resistance of pathogenic bacteria is one great challenge today and for the future. In the last century many classes of effective antibacterials have been developed, so that upcoming resistances could be met with novel drugs of various compound classes. Meanwhile, there is a certain lack of research of the pharmaceutical companies, and thus there are missing developments of novel antibiotics. Gram-positive bacteria are the most important cause of clinical infections. The number of novel antibacterials in clinical trials is strongly restricted. There is an urgent need to find novel antibacterials. We used synthetic chemistry to build completely novel hybrid molecules of substituted indoles and benzothiophene. In a simple one-pot reaction, two novel types of thienocarbazoles were yielded. Both indole substituted compound classes have been evaluated as completely novel antibacterials against the Staphylococcus and Enterococcus species. The evaluated partly promising activities depend on the indole substituent type. First lead compounds have been evaluated within in vivo studies. They confirmed the in vitro results for the new classes of small-molecule antibacterials. Full article
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Open AccessArticle
Bactericidal Activity of Lactic Acid against Clinical, Carbapenem-Hydrolyzing, Multi-Drug-Resistant Klebsiella pneumoniae Planktonic and Biofilm-Forming Cells
Antibiotics 2019, 8(4), 181; https://doi.org/10.3390/antibiotics8040181 - 09 Oct 2019
Cited by 2
Abstract
Carbapenem resistant Klebsiella pneumoniae has been highlighted to be a critical pathogen by the World Health Organization. The objectives of this study were to assess the efficacy of lactic acid (LA) against planktonic cells and biofilms formed by carbapenem-hydrolyzing K. pneumoniae isolates obtained [...] Read more.
Carbapenem resistant Klebsiella pneumoniae has been highlighted to be a critical pathogen by the World Health Organization. The objectives of this study were to assess the efficacy of lactic acid (LA) against planktonic cells and biofilms formed by carbapenem-hydrolyzing K. pneumoniae isolates obtained from the nares of preterm neonates. Time-kill assays with graded percentages of (v/v) LA in water were initially carried out against planktonic cells of a meropenem (MRP)-resistant K. pneumoniae isolate, JNM11.C4. The efficacy parameters such as optimal incubation time and minimum inhibitory concentration were determined by comparing colony-forming unit counts (log(10) CFU). Scanning electron microscopy was used to visualize cell damage. Likewise, JNM11.C4 biofilms were treated with graded series of (v/v) LA. Six carbapenem-hydrolyzing isolates were next used to validate the results. A reduction of 3.6 ± 0.6 log(10) CFU/mL in JNM11.C4 planktonic cells and >3 ± 0.03log(10) CFU/mL in biofilm-forming cells were observed using 0.225% and 2% LA, respectively, after three hours. Similar decreases in viable cell-counts were observed both in the case of planktonic (˃3.6 ± 0.3log(10) CFU/mL) and biofilm-forming cells (3.8 ± 0.3log(10) CFU/mL) across all the six clinical isolates. These results indicate that LA is an effective antimicrobial against planktonic carbapenem-hydrolyzing K. pneumoniae cells and biofilms. Full article
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Open AccessArticle
New Urea Derivatives as Potential Antimicrobial Agents: Synthesis, Biological Evaluation, and Molecular Docking Studies
Antibiotics 2019, 8(4), 178; https://doi.org/10.3390/antibiotics8040178 - 09 Oct 2019
Cited by 6
Abstract
A series of new urea derivatives, containing aryl moieties as potential antimicrobial agents, were designed, synthesized, and characterized by 1H NMR, 13C NMR, FT-IR, and LCMS spectral techniques. All newly synthesized compounds were screened in vitro against five bacterial strains ( [...] Read more.
A series of new urea derivatives, containing aryl moieties as potential antimicrobial agents, were designed, synthesized, and characterized by 1H NMR, 13C NMR, FT-IR, and LCMS spectral techniques. All newly synthesized compounds were screened in vitro against five bacterial strains (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Staphylococcus aureus) and two fungal strains (Candida albicans and Cryptococcus neoformans). Variable levels of interaction were observed for these urea derivatives. However, and of major importance, many of these molecules exhibited promising growth inhibition against Acinetobacter baumannii. In particular, to our delight, the adamantyl urea adduct 3l demonstrated outstanding growth inhibition (94.5%) towards Acinetobacter baumannii. In light of this discovery, molecular docking studies were performed in order to elucidate the binding interaction mechanisms of the most active compounds, as reported herein. Full article
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Open AccessArticle
The Effect of 2-Thiocyanatopyridine Derivative 11026103 on Burkholderia Cenocepacia: Resistance Mechanisms and Systemic Impact
Antibiotics 2019, 8(4), 159; https://doi.org/10.3390/antibiotics8040159 - 21 Sep 2019
Cited by 1
Abstract
Bacteria of the Burkholderia cepacia complex (Bcc) are associated with significant decline of lung functions in cystic fibrosis patients. Bcc infections are virtually impossible to eradicate due to their irresponsiveness to antibiotics. The 2-thiocyanatopyridine derivative 11026103 is a novel, synthetic compound active against [...] Read more.
Bacteria of the Burkholderia cepacia complex (Bcc) are associated with significant decline of lung functions in cystic fibrosis patients. Bcc infections are virtually impossible to eradicate due to their irresponsiveness to antibiotics. The 2-thiocyanatopyridine derivative 11026103 is a novel, synthetic compound active against Burkholderia cenocepacia. To characterize mechanisms of resistance to 11026103, B. cenocepacia was subjected to chemical mutagenesis, followed by whole genome sequencing. Parallel mutations in resistant isolates were localized in a regulatory protein of the efflux system Resistance-Nodulation-Division (RND)-9 (BCAM1948), RNA polymerase sigma factor (BCAL2462) and its cognate putative anti-sigma factor (BCAL2461). Transcriptomic analysis identified positive regulation of a major facilitator superfamily (MFS) efflux system BCAL1510-1512 by BCAL2462. Artificial overexpression of both efflux systems increased resistance to the compound. The effect of 11026103 on B. cenocepacia was analyzed by RNA-Seq and a competitive fitness assay utilizing an essential gene knockdown mutant library. 11026103 exerted a pleiotropic effect on transcription including profound downregulation of cluster of orthologous groups (COG) category “Translation, ribosomal structure, and biogenesis”. The competitive fitness assay identified many genes which modulated susceptibility to 11026103. In summary, 11026103 exerts a pleiotropic cellular response in B. cenocepacia which can be prevented by efflux system-mediated export. Full article
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Open AccessArticle
Using Colistin as a Trojan Horse: Inactivation of Gram-Negative Bacteria with Chlorophyllin
Antibiotics 2019, 8(4), 158; https://doi.org/10.3390/antibiotics8040158 - 20 Sep 2019
Cited by 3
Abstract
Colistin (polymyxin E) is a membrane-destabilizing antibiotic used against Gram-negative bacteria. We have recently reported that the outer membrane prevents the uptake of antibacterial chlorophyllin into Gram-negative cells. In this study, we used sub-toxic concentrations of colistin to weaken this barrier for a [...] Read more.
Colistin (polymyxin E) is a membrane-destabilizing antibiotic used against Gram-negative bacteria. We have recently reported that the outer membrane prevents the uptake of antibacterial chlorophyllin into Gram-negative cells. In this study, we used sub-toxic concentrations of colistin to weaken this barrier for a combination treatment of Escherichia coli and Salmonella enterica serovar Typhimurium with chlorophyllin. In the presence of 0.25 µg/mL colistin, chlorophyllin was able to inactivate both bacteria strains at concentrations of 5–10 mg/L for E. coli and 0.5–1 mg/L for S. Typhimurium, which showed a higher overall susceptibility to chlorophyllin treatment. In accordance with a previous study, chlorophyllin has proven antibacterial activity both as a photosensitizer, illuminated with 12 mW/cm2, and in darkness. Our data clearly confirmed the relevance of the outer membrane in protection against xenobiotics. Combination treatment with colistin broadens chlorophyllin’s application spectrum against Gram-negatives and gives rise to the assumption that chlorophyllin together with cell membrane-destabilizing substances may become a promising approach in bacteria control. Furthermore, we demonstrated that colistin acts as a door opener even for the photodynamic inactivation of colistin-resistant (mcr-1-positive) E. coli cells by chlorophyllin, which could help us to overcome this antimicrobial resistance. Full article
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Open AccessArticle
Characterization of LysBC17, a Lytic Endopeptidase from Bacillus cereus
Antibiotics 2019, 8(3), 155; https://doi.org/10.3390/antibiotics8030155 - 19 Sep 2019
Cited by 2
Abstract
Bacillus cereus, a Gram-positive bacterium, is an agent of food poisoning. B. cereus is closely related to Bacillus anthracis, a deadly pathogen for humans, and Bacillus thuringenesis, an insect pathogen. Due to the growing prevalence of antibiotic resistance in bacteria, [...] Read more.
Bacillus cereus, a Gram-positive bacterium, is an agent of food poisoning. B. cereus is closely related to Bacillus anthracis, a deadly pathogen for humans, and Bacillus thuringenesis, an insect pathogen. Due to the growing prevalence of antibiotic resistance in bacteria, alternative antimicrobials are needed. One such alternative is peptidoglycan hydrolase enzymes, which can lyse Gram-positive bacteria when exposed externally. A bioinformatic search for bacteriolytic enzymes led to the discovery of a gene encoding an endolysin-like endopeptidase, LysBC17, which was then cloned from the genome of B. cereus strain Bc17. This gene is also present in the B. cereus ATCC 14579 genome. The gene for LysBC17 encodes a protein of 281 amino acids. Recombinant LysBC17 was expressed and purified from E. coli. Optimal lytic activity against B. cereus occurred between pH 7.0 and 8.0, and in the absence of NaCl. The LysBC17 enzyme had lytic activity against strains of B. cereus, B. anthracis, and other Bacillus species. Full article
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Open AccessArticle
Tedizolid Versus Linezolid for the Treatment of Acute Bacterial Skin and Skin Structure Infection: A Systematic Review and Meta-Analysis
Antibiotics 2019, 8(3), 137; https://doi.org/10.3390/antibiotics8030137 - 04 Sep 2019
Cited by 4
Abstract
This meta-analysis aims to assess the efficacy and safety of tedizolid, compared to linezolid, in the treatment of acute bacterial skin and skin structure infection (ABSSSI). PubMed, Web of Science, EBSCO (Elton B. Stephens Co.), Cochrane Library, Ovid Medline and Embase databases were [...] Read more.
This meta-analysis aims to assess the efficacy and safety of tedizolid, compared to linezolid, in the treatment of acute bacterial skin and skin structure infection (ABSSSI). PubMed, Web of Science, EBSCO (Elton B. Stephens Co.), Cochrane Library, Ovid Medline and Embase databases were accessed until 18 July 2019. Only randomized controlled trials (RCTs) comparing the efficacy of tedizolid with linezolid for adult patients with ABSSSIs were included. The outcomes included the clinical response, microbiological response, and risk of adverse events (AEs). A total of four RCTs involving 2056 adult patients with ABSSSI were enrolled. The early clinical response rate was 79.6% and 80.5% for patients receiving tedizolid and linezolid, respectively. The pooled analysis showed that tedizolid had a non-inferior early clinical response rate to linezolid (odds ratio (OR) = 0.96, 95% confidence interval (CI) = 0.77–1.19, I2 = 0%). The early response rate was similar between tedizolid and linezolid among patients with cellulitis/erysipelas (75.1% vs. 77.1%; OR = 0.90, 95% CI = 0.64–1.27, I2 = 25%), major cutaneous abscess (85.1% vs. 86.8%; OR = 0.93, 95% CI = 0.42–2.03, I2 = 37%) and wound infection (85.9% vs. 82.6%; OR = 1.29, 95% CI = 0.66–2.51, I2 = 45%). For methicillin-resistant Staphylococcus aureus patients, tedizolid had a favorable microbiological response rate of 95.2% which was comparable to linezolid (94%) (OR = 1.19, 95% CI = 0.49–2.90, I2 = 0%). In addition to the similar risk of treatment-emergent AEs (a serious event, the discontinuation of the study drug due to AEs and mortality between tedizolid and linezolid), tedizolid was associated with a lower risk of nausea, vomiting and abnormal neutrophil count than linezolid. In conclusion, once-daily tedizolid (200 mg for six days) compared to linezolid (600 mg twice-daily for 10 days) was non-inferior in efficacy in the treatment of ABSSSI. Besides, tedizolid was generally as well tolerated as linezolid, and had a lower incidence of gastrointestinal AEs and bone marrow suppression than linezolid. Full article
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Open AccessArticle
Comparative In Vitro Activities of First and Second-Generation Ceragenins Alone and in Combination with Antibiotics Against Multidrug-Resistant Klebsiella pneumoniae Strains
Antibiotics 2019, 8(3), 130; https://doi.org/10.3390/antibiotics8030130 - 27 Aug 2019
Cited by 5
Abstract
Objectives: The ceragenins, or CSAs, were designed to mimic the activities of antimicrobial peptides and represent a new class of antimicrobial agent. The aim of this study was to comparatively investigate the antimicrobial activities of first/second generation ceragenins and various antibiotics against multidrug-resistant [...] Read more.
Objectives: The ceragenins, or CSAs, were designed to mimic the activities of antimicrobial peptides and represent a new class of antimicrobial agent. The aim of this study was to comparatively investigate the antimicrobial activities of first/second generation ceragenins and various antibiotics against multidrug-resistant (MDR) Klebsiella pneumoniae, including colistin-resistant bacteria. Also, the synergistic effects of two ceragenins with colistin or meropenem were investigated with six K. pneumoniae strains presenting different resistant patterns. Methods: Minimal inhibition concentrations (MICs) were determined by the microdilution method according to the CLSI. Antibiotic combination studies were evaluated by the time–kill curve method. Results: MIC50 and MIC90 values of tested ceragenins ranged from 8 to 32 mg/L and 16 to 128 mg/L. Overall, among the ceragenins tested, CSA-131 showed the lowest MIC50 and MIC90 values against all microorganisms. The MICs of the ceragenins were similar or better than tested antibiotics, except for colistin. Synergistic activities of CSA-131 in combination with colistin was found for strains both at 1× MIC and 4× MIC. No antagonism was observed with any combination. Conclusions: First-generation ceragenins CSA-13 and CSA-44 and second-generation ceragenins CSA-131, CSA-138 and CSA-142 have significant antimicrobial effects on MDR K. pneumoniae. Mechanisms allowing resistance to clinical comparator antibiotics like colistin did not impact the activity of ceragenins. These results suggest that ceragenins may play a role in treating infections that are resistant to known antibiotics. Full article
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Open AccessArticle
In Vitro Synergism of Colistin and N-acetylcysteine against Stenotrophomonas maltophilia
Antibiotics 2019, 8(3), 101; https://doi.org/10.3390/antibiotics8030101 - 25 Jul 2019
Cited by 5
Abstract
Stenotrophomonas maltophilia is an emerging global opportunistic pathogen, responsible for a wide range of human infections, including respiratory tract infections. Intrinsic multidrug resistance and propensity to form biofilms make S. maltophilia infections recalcitrant to treatment. Colistin is among the second-line options in case [...] Read more.
Stenotrophomonas maltophilia is an emerging global opportunistic pathogen, responsible for a wide range of human infections, including respiratory tract infections. Intrinsic multidrug resistance and propensity to form biofilms make S. maltophilia infections recalcitrant to treatment. Colistin is among the second-line options in case of difficult-to-treat S. maltophilia infections, with the advantage of being also administrable by nebulization. We investigated the potential synergism of colistin in combination with N-acetylcysteine (NAC) (a mucolytic agent with antioxidant and anti-inflammatory properties) against S. maltophilia grown in planktonic phase and biofilm. Eighteen S. maltophilia clinical isolates (comprising three isolates from cystic fibrosis (CF) and two trimethoprim-sulfamethoxazole (SXT)-resistant strains) were included. Checkerboard assays showed a synergism of colistin/NAC combinations against the strains with colistin Minimum Inhibitory Concentration (MIC) >2 µg/mL (n = 13), suggesting that NAC could antagonize the mechanisms involved in colistin resistance. Nonetheless, time–kill assays revealed that NAC might potentiate colistin activity also in case of lower colistin MICs. A dose-dependent potentiation of colistin activity by NAC was also clearly observed against S. maltophilia biofilms, also at sub-MIC concentrations. Colistin/NAC combinations, at concentrations likely achievable by topical administration, might represent a valid option for the treatment of S. maltophilia respiratory infections and should be examined further. Full article
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Other

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Open AccessBrief Report
In Vitro Antimicrobial Activity of the Decontaminant HybenX® Compared to Chlorhexidine and Sodium Hypochlorite against Common Bacterial and Yeast Pathogens
Antibiotics 2019, 8(4), 188; https://doi.org/10.3390/antibiotics8040188 - 17 Oct 2019
Cited by 3
Abstract
The recent increase in infections mediated by drug-resistant bacterial and fungal pathogens underlines the urgent need for novel antimicrobial compounds. In this study, the antimicrobial activity (inhibitory and cidal) of HybenX®, a novel dessicating agent, in comparison with commonly used sodium [...] Read more.
The recent increase in infections mediated by drug-resistant bacterial and fungal pathogens underlines the urgent need for novel antimicrobial compounds. In this study, the antimicrobial activity (inhibitory and cidal) of HybenX®, a novel dessicating agent, in comparison with commonly used sodium hypochlorite and chlorhexidine, against a collection of bacterial and yeast strains representative of the most common human pathogenic species was evaluated. The minimal inhibitory, bactericidal, and fungicidal concentrations (MIC, MBC, and MFC, respectively) of the three different antimicrobial agents were evaluated by broth microdilution assays, followed by subculturing of suitable dilutions. HybenX® was active against 26 reference strains representative of staphylococci, enterococci, Enterobacterales, Gram-negative nonfermenters, and yeasts, although at higher concentrations than sodium hypochlorite and chlorhexidine. HybenX® MICs were 0.39% for bacteria (with MBCs ranging between 0.39% and 0.78%), and 0.1–0.78% for yeasts (with MFCs ranging between 0.78% and 1.6%). HybenX® exhibited potent inhibitory and cidal activity at low concentrations against several bacterial and yeast pathogens. These findings suggest that HybenX® could be of interest for the treatment of parodontal and endodontic infections and also for bacterial and fungal infections of other mucous membranes and skin as an alternative to sodium hypochlorite and chlorhexidine. Full article
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