Do phenothiazines possess antimicrobial and efflux inhibitory properties?

Abstract

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.

Evidence of Calcium Signaling and Modulation of the LmrS Multidrug Resistant Efflux Pump Activity by Ca2 + Ions in S. aureus

“…As previously stated, Ca 2+ plays a pivotal role in many metabolic pathways including transport systems and are essential for signaling. The antimicrobial properties of the phenothiazines have been described since 1930 and 1940 (Grimsey and Piddock, 2019). The ways by which phenothiazines exert their antimicrobial effect include, damaging cell membranes, inhibiting Ca 2+ -dependent processes, disrupting cationdependent transporters, acting as antagonist of Ca 2+ -binding proteins and in other ways (Grimsey and Piddock, 2019).…”

“…The antimicrobial properties of the phenothiazines have been described since 1930 and 1940 (Grimsey and Piddock, 2019). The ways by which phenothiazines exert their antimicrobial effect include, damaging cell membranes, inhibiting Ca 2+ -dependent processes, disrupting cationdependent transporters, acting as antagonist of Ca 2+ -binding proteins and in other ways (Grimsey and Piddock, 2019). Therefore, we investigated the effect of Ca 2+ on the efflux of EtBr first by analyzing the effect of various divalent metals (Supplementary Material).…”

HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes

“…S2b); however, this concentration did not reduce pKpQIL transconjugants. The concentration range that we tested goes above the peak serum concentrations of chlorpromazine (0.1 g/ml) (63). We aimed to test concentrations of compounds that were within the therapeutic window.…”

Stability of Antimicrobial Drug Molecules in Different Gravitational and Radiation Conditions in View of Applications during Outer Space Missions

“…Studies in the past decades on phenothiazines, primarily used as antipsychotic drugs, but also known for their multifunctionality, have disclosed that not only do they enhancein particular conditions-the effect of antibiotics, but may also have inherent antibacterial properties and therefore may be of help in combating MDR [77]. It has been indicated that phenothiazine derivatives, including fluphenazine, thioridazine (TZ), perphenazine and chlorpromazine (CPZ), can interfere with DNA replication [78,79], may influence cellular energy generation [80,81] and inhibit biofilm production [82,83].…”