Polycationic Glycopolymer Demonstrates Activity Against Persisters and Biofilms of Non-tuberculosis Mycobacteria Cystic Fibrosis Clinical Isolates in vitro .
| Autor: | Narayanaswamy VP; Synedgen, Inc., Claremont, CA, United States., Townsend SM; Synedgen, Inc., Claremont, CA, United States., Loughran AJ; Synedgen, Inc., Claremont, CA, United States., Wiesmann W; Synedgen, Inc., Claremont, CA, United States., Baker S; Synedgen, Inc., Claremont, CA, United States.; Synspira Therapeutics, Inc., Framingham, MA, United States. |
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| Jazyk: | angličtina |
| Zdroj: | Frontiers in microbiology [Front Microbiol] 2022 Feb 21; Vol. 13, pp. 821820. Date of Electronic Publication: 2022 Feb 21 (Print Publication: 2022). |
| DOI: | 10.3389/fmicb.2022.821820 |
| Abstrakt: | Non-tuberculosis Mycobacterium (NTM) is a group of opportunistic pathogens associated with pulmonary infections that are difficult to diagnose and treat. Standard treatment typically consists of prolonged combination antibiotic therapy. Antibiotic resistance and the role of biofilms in pathogen communities, such as NTM persister cells, is an important unmet challenge that leads to increased toxicity, frequent relapse, poor clinical management, and an extended treatment period. Infection recurrence and relapse are not uncommon among individuals with cystic fibrosis ( CF ) or chronic obstructive pulmonary disease (COPD), where thick mucus supports bacterial biofilm production and impairs mucociliary clearance. The study evaluates a membrane-active cationic glycopolymer [poly (acetyl, arginyl) glucosamine (PAAG)] being developed to support the safe and effective treatment of NTM biofilm infections. PAAG shows antibacterial activity against a wide range of pathogenic bacteria at concentrations non-toxic to human epithelial cells. Time-kill curves demonstrated PAAG's rapid bactericidal potential at concentrations as low as 1X MIC against all NTM strains tested and compared to the standard of care. PAAG treatment prevents persister formation and eradicates antibiotic-induced persister cells in planktonic NTM cultures below the limit of detection (10 colony-forming unit (CFU)/ml). Further, PAAG showed the ability to penetrate and disperse NTM biofilms formed by both rapidly and slowly growing strains, significantly reducing the biofilm biomass ( p < 0.0001) compared to the untreated NTM biofilms. Microscopical examination confirmed PAAG's ability to disrupt and disperse mycobacterial biofilms. A single PAAG treatment resulted in up to a 25-fold reduction in live-labeled NTM and a 78% reduction in biofilm thickness. Similar to other polycationic molecules, PAAG's bactericidal and antibiofilm activities employ rapid permeabilization of the outer membrane of the NTM strains, and subsequently, reduce the membrane potential even at concentrations as low as 50 μg/ml ( p < 0.001). The outcomes of these in vitro analyses suggest the importance of this polycationic glycopolymer, PAAG, as a potential therapeutic agent for opportunistic NTM infections. Competing Interests: The authors are employees and/or shareholders in Synedgen, Inc. These studies were funded by Synedgen, Inc. The funder Synedgen, Inc was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. SB, ST, and WW have ownership and patents affiliated with Synedgen, and SB and WW are board members. The potential conflicts noted have not impacted or influenced the findings of this manuscript. (Copyright © 2022 Narayanaswamy, Townsend, Loughran, Wiesmann and Baker.) |
| Databáze: | MEDLINE |
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