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Antibiotics
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Novel Strategies to Combat MDR Pathogens in CF
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Novel Strategies to Combat MDR Pathogens in CF

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

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 17561

Special Issue Editor

Prof. Dr. Paul M. Beringer

E-Mail Website
Guest Editor
Department of Clinical Pharmacy, University of Southern California, Los Angeles, CA 90089-9121, USA
Interests: pharmacokinetics; pharmacodynamics; cystic fibrosis; host defense peptides

Special Issue Information

Dear Colleagues,

Cystic fibrosis (CF) is characterized by a chronic cycle of airway obstruction, inflammation, and infection. The introduction of highly active CFTR modulator therapies has resulted in significant improvements in clinical outcomes in people with CF; however, chronic lung infections persist. Complicating treatment is the presence of multidrug-resistant (MDR) pathogens which contribute to decline in lung function and shortened survival.

In this Special Issue, novel strategies to combat MDR pathogens will be investigated. The use of adjuvants targeting resistance (e.g., inactivating enzymes, antibiotic efflux, permeation) and virulence (e.g., biofilm, iron sequestration) as well as novel antimicrobial therapies including antimicrobial peptides and bacteriophages will be considered. In addition, approaches incorporating pharmacokinetics and pharmacodynamics to optimize antimicrobial dosing and the use of combination therapy to target MDR pathogens are encouraged.

Prof. Paul M. Beringer
Guest Editor

Manuscript Submission Information

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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

  • Adjuvants
  • Antimicrobial combinations
  • Antimicrobial peptides
  • Antivirulence therapies
  • Bacteriophage therapy
  • Pharmacokinetics
  • Pharmacodynamics

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Published Papers (5 papers)

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16 pages, 3100 KiB  
Article
Nano- and Macroscale Imaging of Cholesterol Linoleate and Human Beta Defensin 2-Induced Changes in Pseudomonas aeruginosa Biofilms
by Brent A. Beadell, Andy Chieng, Kevin R. Parducho, Zhipeng Dai, Sam On Ho, Gary Fujii, Yixian Wang and Edith Porter
Antibiotics 2021, 10(11), 1279; https://doi.org/10.3390/antibiotics10111279 - 20 Oct 2021
Cited by 1 | Viewed by 3082
Abstract
The biofilm production of Pseudomonas aeruginosa (PA) is central to establishing chronic infection in the airways in cystic fibrosis. Epithelial cells secrete an array of innate immune factors, including antimicrobial proteins and lipids, such as human beta defensin 2 (HBD2) and cholesteryl lineolate [...] Read more.
The biofilm production of Pseudomonas aeruginosa (PA) is central to establishing chronic infection in the airways in cystic fibrosis. Epithelial cells secrete an array of innate immune factors, including antimicrobial proteins and lipids, such as human beta defensin 2 (HBD2) and cholesteryl lineolate (CL), respectively, to combat colonization by pathogens. We have recently shown that HBD2 inhibits biofilm production by PA, possibly linked to interference with the transport of biofilm precursors. Considering that both HBD2 and CL are increased in airway fluids during infection, we hypothesized that CL synergizes with HBD2 in biofilm inhibition. CL was formulated in phospholipid-based liposomes (CL-PL). As measured by atomic force microscopy of single bacteria, CL-PL alone and in combination with HBD2 significantly increased bacterial surface roughness. Additionally, extracellular structures emanated from untreated bacterial cells, but not from cells treated with CL-PL and HBD2 alone and in combination. Crystal violet staining of the biofilm revealed that CL-PL combined with HBD2 effected a significant decrease of biofilm mass and increased the number of larger biofilm particles consistent with altered cohesion of formed biofilms. These data suggest that CL and HBD2 affect PA biofilm formation at the single cell and community-wide level and that the community-wide effects of CL are enhanced by HBD2. This research may inform future novel treatments for recalcitrant infections in the airways of CF patients. Full article
(This article belongs to the Special Issue Novel Strategies to Combat MDR Pathogens in CF)
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27 pages, 16019 KiB  
Article
Effect of N-Acetylcysteine in Combination with Antibiotics on the Biofilms of Three Cystic Fibrosis Pathogens of Emerging Importance
by Aditi Aiyer, Simone K. Visser, Peter Bye, Warwick J. Britton, Gregory S. Whiteley, Trevor Glasbey, Frederik H. Kriel, Jessica Farrell, Theerthankar Das and Jim Manos
Antibiotics 2021, 10(10), 1176; https://doi.org/10.3390/antibiotics10101176 - 27 Sep 2021
Cited by 10 | Viewed by 4690
Abstract
Cystic fibrosis (CF) is a genetic disorder causing dysfunctional ion transport resulting in accumulation of viscous mucus that fosters chronic bacterial biofilm-associated infection in the airways. Achromobacter xylosoxidans and Stenotrophomonas maltophilia are increasingly prevalent CF pathogens and while Burkholderia cencocepacia is slowly decreasing; [...] Read more.
Cystic fibrosis (CF) is a genetic disorder causing dysfunctional ion transport resulting in accumulation of viscous mucus that fosters chronic bacterial biofilm-associated infection in the airways. Achromobacter xylosoxidans and Stenotrophomonas maltophilia are increasingly prevalent CF pathogens and while Burkholderia cencocepacia is slowly decreasing; all are complicated by multidrug resistance that is enhanced by biofilm formation. This study investigates potential synergy between the antibiotics ciprofloxacin (0.5–128 µg/mL), colistin (0.5–128 µg/mL) and tobramycin (0.5–128 µg/mL) when combined with the neutral pH form of N-Acetylcysteine (NACneutral) (0.5–16.3 mg/mL) against 11 cystic fibrosis strains of Burkholderia, Stenotrophomonas and Achromobacter sp. in planktonic and biofilm cultures. We screened for potential synergism using checkerboard assays from which fraction inhibitory concentration indices (FICI) were calculated. Synergistic (FICI ≤ 0.5) and additive (0.5 > FICI ≥ 1) combinations were tested on irreversibly attached bacteria and 48 h mature biofilms via time-course and colony forming units (CFU/mL) assays. This study suggests that planktonic FICI analysis does not necessarily translate to reduction in bacterial loads in a biofilm model. Future directions include refining synergy testing and determining further mechanisms of action of NAC to understand how it may interact with antibiotics to better predict synergy. Full article
(This article belongs to the Special Issue Novel Strategies to Combat MDR Pathogens in CF)
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15 pages, 1310 KiB  
Article
Pseudomonas aeruginosa mexR and mexEF Antibiotic Efflux Pump Variants Exhibit Increased Virulence
by Mylene Vaillancourt, Sam P. Limsuwannarot, Catherine Bresee, Rahgavi Poopalarajah and Peter Jorth
Antibiotics 2021, 10(10), 1164; https://doi.org/10.3390/antibiotics10101164 - 25 Sep 2021
Cited by 17 | Viewed by 3309
Abstract
Antibiotic-resistant Pseudomonas aeruginosa infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase P. aeruginosa virulence, even in the absence of antibiotics. Moreover, the mechanisms by which [...] Read more.
Antibiotic-resistant Pseudomonas aeruginosa infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase P. aeruginosa virulence, even in the absence of antibiotics. Moreover, the mechanisms by which resistance mutations increase virulence are poorly understood. In this study we tested the hypothesis that mutations affecting efflux pumps can directly increase P. aeruginosa virulence. Using genetics, physiological assays, and model infections, we show that efflux pump mutations can increase virulence. Mutations of the mexEF efflux pump system increased swarming, rhamnolipid production, and lethality in a mouse infection model, while mutations in mexR that increased expression of the mexAB-oprM efflux system increased virulence during an acute murine lung infection without affecting swarming or rhamnolipid gene expression. Finally, we show that an efflux pump inhibitor, which represents a proposed novel treatment approach for P. aeruginosa, increased rhamnolipid gene expression in a dose-dependent manner. This finding is important because rhamnolipids are key virulence factors involved in dissemination through epithelial barriers and cause neutrophil necrosis. Together, these data show how current and proposed future anti-Pseudomonal treatments may unintentionally make infections worse by increasing virulence. Therefore, treatments that target efflux should be pursued with caution. Full article
(This article belongs to the Special Issue Novel Strategies to Combat MDR Pathogens in CF)
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17 pages, 2797 KiB  
Article
Anti-Inflammatory Effects of RTD-1 in a Murine Model of Chronic Pseudomonas aeruginosa Lung Infection: Inhibition of NF-κB, Inflammasome Gene Expression, and Pro-IL-1β Biosynthesis
by Mansour A. Dughbaj, Jordanna G. Jayne, A Young J. Park, Timothy J. Bensman, Marquerita Algorri, Andre J. Ouellette, Michael E. Selsted and Paul M. Beringer
Antibiotics 2021, 10(9), 1043; https://doi.org/10.3390/antibiotics10091043 - 26 Aug 2021
Cited by 3 | Viewed by 2962
Abstract
Vicious cycles of chronic airway obstruction, lung infections with Pseudomonas aeruginosa, and neutrophil-dominated inflammation contribute to morbidity and mortality in cystic fibrosis (CF) patients. Rhesus theta defensin-1 (RTD-1) is an antimicrobial macrocyclic peptide with immunomodulatory properties. Our objective was to investigate the [...] Read more.
Vicious cycles of chronic airway obstruction, lung infections with Pseudomonas aeruginosa, and neutrophil-dominated inflammation contribute to morbidity and mortality in cystic fibrosis (CF) patients. Rhesus theta defensin-1 (RTD-1) is an antimicrobial macrocyclic peptide with immunomodulatory properties. Our objective was to investigate the anti-inflammatory effect of RTD-1 in a murine model of chronic P. aeruginosa lung infection. Mice received nebulized RTD-1 daily for 6 days. Bacterial burden, leukocyte counts, and cytokine concentrations were evaluated. Microarray analysis was performed on bronchoalveolar lavage fluid (BALF) cells and lung tissue homogenates. In vitro effects of RTD-1 in THP-1 cells were assessed using quantitative reverse transcription PCR, enzyme-linked immunosorbent assays, immunoblots, confocal microscopy, enzymatic activity assays, and NF-κB-reporter assays. RTD-1 significantly reduced lung white blood cell counts on days 3 (−54.95%; p = 0.0003) and 7 (−31.71%; p = 0.0097). Microarray analysis of lung tissue homogenates and BALF cells revealed that RTD-1 significantly reduced proinflammatory gene expression, particularly inflammasome-related genes (nod-like receptor protein 3, Mediterranean fever gene, interleukin (IL)-1α, and IL-1β) relative to the control. In vitro studies demonstrated NF–κB activation was reduced two-fold (p ≤ 0.0001) by RTD-1 treatment. Immunoblots revealed that RTD-1 treatment inhibited proIL-1β biosynthesis. Additionally, RTD-1 treatment was associated with a reduction in caspase-1 activation (FC = −1.79; p = 0.0052). RTD-1 exhibited potent anti-inflammatory activity in chronically infected mice. Importantly, RTD-1 inhibits inflammasome activity, which is possibly a downstream effect of NF-κB modulation. These findings support that this immunomodulatory peptide may be a promising therapeutic for CF-associated lung disease. Full article
(This article belongs to the Special Issue Novel Strategies to Combat MDR Pathogens in CF)
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7 pages, 199 KiB  
Case Report
Unknown Renal Impairment: A Rare Case of Inhaled Tobramycin Induced Acute Kidney Injury in a Cystic Fibrosis Patient
by Tyler Miller, Cristina Pastuch, Lisa Garavaglia, Kelley Gannon and Anthony Parravani
Antibiotics 2021, 10(4), 424; https://doi.org/10.3390/antibiotics10040424 - 12 Apr 2021
Cited by 6 | Viewed by 2599
Abstract
Acute kidney injury is a reversible medical condition commonly caused by nephrotoxic agents. The infrequency that a nebulized medication elicits a renal insult presents a rare diagnostic challenge. Within this case, we report a 57-year-old cystic fibrosis patient with chronic kidney disease (CKD) [...] Read more.
Acute kidney injury is a reversible medical condition commonly caused by nephrotoxic agents. The infrequency that a nebulized medication elicits a renal insult presents a rare diagnostic challenge. Within this case, we report a 57-year-old cystic fibrosis patient with chronic kidney disease (CKD) Stage G3b (baseline 1.5–1.6 mg/dL) who developed an acute kidney injury (AKI) with a serum creatinine elevation to 4.08 mg/dL and associated worsening vestibular dysfunction related to twice-daily nebulized tobramycin inhalation solution (TIS). The patient was found to have a tobramycin serum level of 4.2 μg/mL 2.5 h after TIS dosing, with elevation remaining present at 1.1 μg/mL 24 h after discontinuation of therapy. Laboratory values at one month continued to show elevated creatinine levels at 2.1 mg/dL, suggesting progression of his baseline CKD. This case supports the benefit of obtaining tobramycin serum levels and vestibular/audiology function testing when evaluating patients on chronic nebulized TIS who present with acute or chronic renal dysfunction. From these serum levels, adjustments to daily dosing, regular monitoring of tobramycin serum levels, or discontinuation of treatment should be made to prevent permanent renal damage in patients with CKD. Calculated Naranjo ADR Probability Scale: 9; Definite. Full article
(This article belongs to the Special Issue Novel Strategies to Combat MDR Pathogens in CF)
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