Do phenothiazines possess antimicrobial and efflux inhibitory properties?

Antibiotic resistance is a global health concern; the rise of drug-resistant bacterial infections is compromising the medical advances that resulted from the introduction of antibiotics at the beginning of the 20th century. Considering that the presence of mutations within individuals in a bacterial population may allow a subsection to survive and propagate in response to selective pressure, as long as antibiotics are used in the treatment of bacterial infections, development of resistance is an inevitable evolutionary outcome. This, combined with the lack of novel antibiotics being released to the clinical market, means the need to develop alternative strategies to treat these resistant infections is critical. We discuss how the use of antibiotic adjuvants can minimise the appearance and impact of resistance. To this effect, several phenothiazine-derived drugs have been shown to potentiate the activities of antibiotics used to treat infections caused by Gram-positive and Gram-negative bacteria. Outside of their role as antipsychotic medications, we review the evidence to suggest that phenothiazines possess inherent antibacterial and efflux inhibitory properties enabling them to potentially combat drug resistance. We also discuss that understanding their mode of action is essential to facilitate the design of new phenothiazine derivatives or novel agents for use as antibiotic adjuvants.