Antibacterial properties of phenothiazine derivatives against multidrug-resistant Acinetobacter baumannii strains

Aim: As options to treat recalcitrant Bacterial infections which are increasingly limited due to multidrug-resistant strains, searching for new, effective Antibacterial compounds is necessary. One strategy is to generate treatment alternatives by drug repurposing.

Methods and results: In this work, phenotypic microarrays were used for the screening of miscellaneous compounds against the growth and biofilm formation of Acinetobacter baumannii, an important emergent multidrug-resistant opportunistic pathogen. The results showed that the phenothiazine derivatives, such as promethazine, trifluoperazine, thioridazine, and chlorpromazine, inhibited the growth of antibiotic-sensitive and multidrug-resistant strains (showing minimal inhibitory concentrations ranging from 0·05 to 0·6 g l^-1 and minimal bactericidal concentrations ranging from 0·1 to 2·5 g l^-1 ). All phenothiazine derivatives were active against biofilm cells (with minimal biofilm eradication concentrations ranging from 0·5 to >3 g l^-1 ). Chlorpromazine promoted reactive oxigen species (ROS) production, and cell membrane and DNA damage. Chlorpromazine showed synergy with Antibiotics such as ceftazidime, meropenem, and colistin and was an effective treatment for experimentally infected Galleria mellonella when combined with ceftazidime.

Conclusions: It was demonstrated that phenothiazine derivatives, especially chlorpromazine, are drugs with attractive Antibacterial properties against nosocomial MDR strains of A. baumannii, by generating ROS and cell membrane and DNA damage.

Significance and impact of the study: The present study indicates that repurposing phenothiazine derivatives for treating recalcitrant infections by A. baumannii could be promising.