Abstract
Antibiotic treatments often fail to completely eradicate a bacterial infection, leaving behind an antibiotic-tolerant subpopulation of intact bacterial cells called persisters. Persisters are considered a major cause for treatment failure and are thought to greatly contribute to the recalcitrance of chronic infections. Pseudomonas aeruginosa infections are commonly associated with elevated levels of drug-tolerant persister cells, posing a serious threat to human health. This study represents the first time a novel large molecule polycationic glycopolymer, poly (acetyl, arginyl) glucosamine (PAAG), has been evaluated against antibiotic and carbonyl cyanide m-chlorophenylhydrazone induced P. aeruginosa persisters. PAAG eliminated eliminated persisters at concentrations that show no significant cytotoxicity on human lung epithelial cells. PAAG demonstrated rapid bactericidal activity against both forms of induced P. aeruginosa persister cells resulting in complete eradication of the in vitro persister cells within 24 h of treatment. PAAG demonstrated greater efficacy against persisters in vitro than antibiotics currently being used to treat persistent chronic infections such as tobramycin, colistin, azithromycin, aztreonam, and clarithromycin. PAAG caused rapid permeabilization of the cell membrane and caused significant membrane depolarization in persister cells. PAAG efficacy against these bacterial subpopulations suggests it may have substantial therapeutic potential for eliminating recurrent P. aeruginosa infections.
Highlights
Pseudomonas aeruginosa is an opportunistic pathogen that often causes nosocomial infections in immunocompromised patients and is one of the primary agents responsible for pulmonary decline and early mortality in patients with cystic fibrosis (CF; Mendelson et al, 1994; Dunn and Wunderink, 1995; Govan and Deretic, 1996; Gibson et al, 2003)
The bacterial cells were exposed to PAAG (Synedgen, Inc.), azithromycin (TCI), tobramycin (Sigma), clarithromycin (Fluka), aztreonam (TCI), and colistin (TCI) at the concentrations and time periods stated throughout the article
Several novel approaches have been suggested for the elimination of these persistent cells, including reverting the phenotype of the bacteria back to a metabolically active state and making it more susceptible to antibiotics by means of chemical compounds or sugars exposure (Pan et al, 2012; Marques et al, 2014; Zhang, 2014)
Summary
Pseudomonas aeruginosa is an opportunistic pathogen that often causes nosocomial infections in immunocompromised patients and is one of the primary agents responsible for pulmonary decline and early mortality in patients with cystic fibrosis (CF; Mendelson et al, 1994; Dunn and Wunderink, 1995; Govan and Deretic, 1996; Gibson et al, 2003). Persisters are a small fraction of non-replicating, metabolically quiescent bacteria tolerant to antibiotic killing (Keren et al, 2004; LaFleur et al, 2010; Mulcahy et al, 2010) These antibiotictolerant bacterial cells have a growth-arrested phenotype and are capable of recommencing growth after a stress event (Lewis, 2007, 2008; Kim and Wood, 2016). Due to their state of metabolic dormancy, persisters have a high tolerance against traditional classes of antibiotics such as fluoroquinolones, aminoglycosides, and beta-lactams, which are only effective against metabolically active cells. Once the local antibiotic concentration drops and the nutrients are available (Kim et al, 2018), persisters can become metabolically active again and reestablish the infection (Lewis, 2007, 2008) causing the relapsing chronic infections often observed in CF patients (Lewis, 2008)
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