Abstract
Pseudomonas aeruginosa is a prime opportunistic pathogen, one of the most important causes of hospital-acquired infections and the major cause of morbidity and mortality in cystic fibrosis lung infections. One reason for the bacterium’s pathogenic success is the large array of virulence factors that it can employ. Another is its high degree of intrinsic and acquired resistance to antibiotics. In this review, we first summarise the current knowledge about the regulation of virulence factor expression and production. We then look at the impact of sub-MIC antibiotic exposure and find that the virulence–antibiotic interaction for P. aeruginosa is antibiotic-specific, multifaceted, and complex. Most studies undertaken to date have been in vitro assays in batch culture systems, involving short-term (<24 h) antibiotic exposure. Therefore, we discuss the importance of long-term, in vivo-mimicking models for future work, particularly highlighting the need to account for bacterial physiology, which by extension governs both virulence factor expression and antibiotic tolerance/resistance.
Highlights
Gram-negative bacteria pose a formidable clinical challenge, due to both intrinsic as well as acquired antibiotic resistance [1,2,3,4]
Most studies undertaken to investigate the impact of sub-minimum inhibitory concentration (MIC) antibiotics on virulence in P. aeruginosa have been performed over a short term (
In agreement with these findings, the treatment of P. aeruginosa with sub-MIC AZM has been shown to cause the upregulation of the type-3 secretion system (T3SS) [152,158,167]—a major determinant of the pathogen’s virulence, which facilitates the release of directly cytotoxic proteins into eukaryotic cells upon encounter [24]
Summary
Gram-negative bacteria pose a formidable clinical challenge, due to both intrinsic as well as acquired antibiotic resistance [1,2,3,4]. Hospital-acquired infections by opportunistic Gram-negative pathogens such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii are becoming increasingly difficult to treat, as antibiotic resistance levels have risen alarmingly over recent years [5,6]. P. aeruginosa is a ubiquitous opportunist, able to cause infections in plants, invertebrates, and vertebrate species [8]. In humans, it does not usually present a major burden for immunocompetent people, but can still cause eye, ear, toe, and severe burn wound infections. We were interested in reviewing the current knowledge of pseudomonal virulence and how it is impacted by sub-MIC antibiotics. We have limited the scope of the review to antibiotics and have not looked at papers on phytochemicals and their use as adjuvants, as most of these are not currently in clinical use [13]
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