ntrol of biofilm formation through inhibition of efflux systems

Biofilm formation is a survival strategy used by bacteria in a range of aquatic settings including on medical devices (1). Bacterial cells use adhesins in their cell walls to colonise surfaces where they secrete exopolysaccharides, securing their attachment (1). The bacteria spread over the surfaces and form populations which are embedded in the polysaccharide matrix (1). The biofilm provides protection from environmental stresses including antibiotic application. Therefore, bacteria that are sensitive to antimicrobials in a laboratory setting can be resistant in a biofilm in vivo (1, 2). Antibiotic resistance is a worldwide health concern with cases of treatment failure of antibiotics of last resort occurring globally (World Health Organization, 2017 (3). Therefore alternative ways of preventing and treating infections are needed and pressure to reduce antibiotic use in clinical practice is increasing (4).
Two examples of medical devices on which biofilms form are urinary catheters (1, 5) and endotracheal tubes (ETTs) (6). In urinary catheters, bacterial species such as Proteus mirabilis and Klebsiella pneumoniae, that produce potent ureases, can lead to the formation of crystalline biofilms (5) . These can instigate significant problems as they encrust and block the catheter lumen which can lead to leaks or bladder distension (5). The formation of biofilms on the surface of ETTs in ventilated patients has been associated with the pathogenesis of ventilator-associated pneumonia (6). It has been proposed that biofilms on ETT can act as a reservoir of bacteria which are subsequently transferred into the lower respiratory tract (7). Due to increasing pressures on antibiotic use more emphasis is being placed on effective infection control (8). Therefore, the prevention of biofilm formation on indwelling medical devices and subsequent infections is of real clinical need.
Bacterial efflux pumps can be either single or multicomponent systems such as multidrug resistance pumps (9). The multicomponent systems export substrates, including a wide range of antibiotics, out of the bacterial cell into the surrounding environment (9). Whilst best known for their role in antimicrobial resistance, efflux pumps have been shown to be important in other cellular process such as biofilm formation and stress response (9, 10). Efflux pump inhibitors (EPIs) block the activity of efflux pumps and several potential candidates for antibacterial applications have been identified. Phenothiazine and thioxanthene compounds, which are in-use antipsychotics, have been shown to have inhibitory effects on efflux-related resistance phenotypes in Staphylococcus aureus (11). There is therefore the potential for efflux pump inhibitors to be used to prevent the formation of biofilms on medical devices as a form of infection control.