Abstract
Pseudomonas aeruginosa is one of the six bacterial pathogens, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp., which are commonly associated with antimicrobial resistance, and denoted by their acronym ESKAPE. P. aeruginosa is also recognized as an important cause of chronic infections due to its ability to form biofilms, where the bacteria are present in aggregates encased in a self-produced extracellular matrix and are difficult or impossible to eradicate with antibiotic treatment. P. aeruginosa causes chronic infections in the lungs of patients with cystic fibrosis and chronic obstructive lung disease, as well as chronic urinary tract infections in patients with permanent bladder catheter, and ventilator-associated pneumonia in intubated patients, and is also an important pathogen in chronic wounds. Antibiotic treatment cannot eradicate these biofilm infections due to their intrinsic antibiotic tolerance and the development of mutational antibiotic resistance. The tolerance of biofilms to antibiotics is multifactorial involving physical, physiological, and genetic determinants, whereas the antibiotic resistance of bacteria in biofilms is caused by mutations and driven by the repeated exposure of the bacteria to high levels of antibiotics. In this review, both the antimicrobial tolerance and the development of resistance to antibiotics in P. aeruginosa biofilms are discussed. Possible therapeutic approaches based on the understanding of the mechanisms involved in the tolerance and resistances of biofilms to antibiotics are also addressed.
Highlights
Research done in the last three decades has shown that bacteria in most settings live in the biofilm mode of growth, whereas the planktonic single cell state is considered a transition phase
PQS is positively regulating the production of the extracellular DNA (eDNA) matrix component (Allesen-Holm et al, 2006), whereas the Rhl system regulates rhamnolipid production, which is important for biofilm formation, and the tolerance of P. aeruginosa biofilms to immune cells (Pamp and Tolker-Nielsen, 2007; Van Acker et al, 2009)
Different forms of stresses can induce efflux pumps, such as induction in P. aeruginosa of MexXY-OprM by oxidative stress, MexEFOprN by nitrosative stress, and MexCD-OprJ by membranedamaging agents (Poole, 2014). As these types of stresses might be encountered in biofilms, they might lead to induction of efflux pumps in P. aeruginosa biofilms contributing to antibiotic tolerance
Summary
Research done in the last three decades has shown that bacteria in most settings live in the biofilm mode of growth, whereas the planktonic single cell state is considered a transition phase. PQS is positively regulating the production of the eDNA matrix component (Allesen-Holm et al, 2006), whereas the Rhl system regulates rhamnolipid production, which is important for biofilm formation, and the tolerance of P. aeruginosa biofilms to immune cells (Pamp and Tolker-Nielsen, 2007; Van Acker et al, 2009). The antibiotic-tolerant cells in biofilms are able to survive the high antibiotic concentrations only if embedded in the biofilms Both resistance and tolerance are involved in the recalcitrance of biofilms to antibiotic treatment (Lebeaux et al, 2014). The main clinical consequence of tolerance of biofilms to antibiotics is that the high concentration of antibiotics required for treating biofilm infections [for some antibiotics up to 1,000 times higher than for planktonic cells (Macia et al, 2014)] cannot be achieved in vivo by systemic administration without toxicity (Hengzhuang et al, 2012). Mechanisms involved in development of mutational antibiotic resistance of biofilm cells are described
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