Abstract
Pseudomonas aeruginosa is a pernicious bacterial pathogen that is difficult to treat because of high levels of antibiotic resistance. A promising alternative treatment option for such bacteria is the application of bacteriophages; the correct combination of phages plus antibiotics can produce synergistic inhibitory effects. In this study, we describe morphological changes induced by sub-MIC levels of the antibiotic aztreonam lysine (AzLys) on P. aeruginosa PA01, which may in part explain the observed phage–antibiotic synergy (PAS). One-step growth curves for phage E79 showed increased adsorption rates, decreased infection latency, accelerated time to lysis and a minor reduction in burst size. Phage E79 plus AzLys PAS was also able to significantly reduce P. aeruginosa biofilm growth over 3-fold as compared to phage treatment alone. Sub-inhibitory AzLys-induced filamentation of P. aeruginosa cells resulted in loss of twitching motility and a reduction in swimming motility, likely due to a reduction in the number of polar Type IV pili and flagella, respectively, on the filamented cell surfaces. Phage phiKZ, which uses Type IV pili as a receptor, did not exhibit increased activity with AzLys at lower sub-inhibitory levels, but still produced phage–antibiotic synergistic killing with sub-inhibitory AzLys. A one-step growth curve indicates that phiKZ in the presence of AzLys also exhibits a decreased infection latency and moderately undergoes accelerated time to lysis. In contrast to prior PAS studies demonstrating that phages undergo delayed time to lysis with cell filamentation, these PAS results show that phages undergo accelerated time to lysis, which therefore suggests that PAS is dependent upon multiple factors, including the type of phages and antibiotics used, and the bacterial host being tested.
Highlights
Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that possesses extreme multi-drug resistance (MDR) and is commonly acquired in hospital settings [1].Cystic fibrosis (CF) patients are highly susceptible to lung infections caused by a variety of bacteria, but P. aeruginosa is the most prevalent pathogen causing infection in adultCF patients, and is one of the leading causes of morbidity and mortality in the CF community [2,3]
This is due to intrinsic MDR and adaptability of pathogenic P. aeruginosa, including the ability to establish biofilms that lead to chronic infection [4,5,6]
To investigate whether aztreonam lysine (AzLys) changes the morphology of P. aeruginosa PA01, we observed PA01 grown in the presence or absence of a sub-inhibitory concentration of AzLys using transmission electron microscopy (TEM)
Summary
CF patients, and is one of the leading causes of morbidity and mortality in the CF community [2,3]. This is due to intrinsic MDR and adaptability of pathogenic P. aeruginosa, including the ability to establish biofilms that lead to chronic infection [4,5,6]. Individuals with CF are especially susceptible to lung infections due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding a chloride anion channel; impairment of its function disrupts salt and water transport in the lungs and leads to the build-up of thick, sticky mucus.
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