Abstract
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.
Highlights
Non-tuberculosis Mycobacterium (NTM) are opportunistic human pathogens capable of causing chronic pulmonary infections, in populations with underlying lung diseases, such as cystic fibrosis (CF), chronic obstructive pulmonary disorder (COPD), and non-CF bronchiectasis (Park et al, 2016; Skolnik et al, 2016; Liu et al, 2018)
PAAG (200 μg/ml) was associated with a 75%–78% reduction in NTM biofilm thickness in 1 h, compared to the 23%–62% observed upon treatment with PAAG (50 μg/ml), in a strain dependent manner (Figure 8)
A 1-h treatment of preformed biofilms with PAAG resulted in disruption of the biofilm structure formed by clinical isolates of M. avium and M. abscessus as shown in Figures 9C,D,G,H compared to the untreated control (Figures 9A,B,E,F)
Summary
NTM (non-tuberculosis mycobacterium) are opportunistic human pathogens capable of causing chronic pulmonary infections, in populations with underlying lung diseases, such as cystic fibrosis (CF), chronic obstructive pulmonary disorder (COPD), and non-CF bronchiectasis (Park et al, 2016; Skolnik et al, 2016; Liu et al, 2018). Studies show that 12.7% of US CF patients were culture positive with NTM (Cystic Fibrosis Foundation, 2017), and longitudinal data reveal that 19% had one or more NTM species isolated over 4 years (Martiniano et al, 2017). These patients had a higher rate of annual decline in predicted forced expiratory volume (FEV1) than those with no NTM infection (Esther Jr et al, 2010; Huitt, 2015; Skolnik et al, 2016). Resistance to commonly used antibiotics often frequently complicate RGM treatment regimens (Ferro et al, 2015)
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