Effect of phenothiazines on Stenotrophomonas maltophilia in planktonic and biofilm forms of growth

• Grant number: 24/18314-6
• Support Opportunities: Scholarships in Brazil - Program to Stimulate Scientific Vocations
• Start date: January 06, 2025
• End date: February 18, 2025
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Principal Investigator: Débora Castelo Branco de Souza Collares Maia
• Grantee: Ana Vitória Strilicherk
• Host Institution: FAC MEDICINA/UFC

Abstract

Stenotrophomonas maltophilia is a Gram-negative, aerobic, non-glucose-fermenting bacterium, considered an emerging pathogen that has raised clinical concern due to its intrinsic resistance to multiple antimicrobials and its ability to form biofilms. This bacterial species can cause a variety of infections, and is most commonly associated with respiratory infections in immunocompromised or hospitalized patients. S. maltophilia has several antibacterial resistance mechanisms, including enzymes that degrade beta-lactams and, mainly, efflux systems. Overall, S. maltophilia genome exhibits 12 efflux pumps, belonging to three families. Furthermore, the ability of this species to adhere to surfaces and form biofilms makes its treatment difficult, as these structures protect them from the action of antimicrobials and the immune system. Thus, S. maltophilia infections represent a clinical challenge, especially in immunocompromised and debilitated individuals, due to limited therapeutic resources. In this context, drug repurposing appears to be an important strategy for the search for therapeutic alternatives against multidrug-resistant bacteria, since the pharmacokinetic and toxicological characteristics of these drugs are already known, speeding up and reducing the costs of the process of the approval for clinical use. Phenothiazines, such as promethazine and chlorpromazine, are clinically used as antihistamines, antipsychotics and/or sedatives, and are known to exhibit antimicrobial activity, through the inhibition of efflux pumps, in addition to other mechanisms of cellular damage. Therefore, the present work aims to evaluate the effect of promethazine and chlorpromazine on S. maltophilia in planktonic and biofilm forms. Initially, microdilution assays will be carried out to determine the minimum inhibitory concentrations (MICs) of promethazine and chlorpromazine against 12 strains of S. maltophilia in planktonic form. Then, the strains will be evaluated for their ability to form biofilms. The biofilm-forming strains will be exposed to promethazine and chlorpromazine to evaluate the effects of these drugs on the formation of biofilms by S. maltophilia and on mature biofilms of this bacterial species. Finally, the interaction between promethazine and chlorpromazine and the antibacterials gentamicin, meropenem, levofloxacin and sulfamethoxazole-trimethoprim against planktonic S. maltophilia will be evaluated. With this proposal, it is expected to understand the activity of promethazine and chlorpromazine against S. maltophilia in planktonic and biofilm form and to elucidate the effect of these drugs on the antimicrobial susceptibility of this bacterium. With these results, it is possible to evaluate the potential of phenothiazines as therapeutic alternatives against S. maltophilia infections.