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Antiviral Drug Candidate Repositioning for Streptococcus suis Infection in Non-Tumorigenic Cell Models
Ashley Anzet van Niekerk1, Sara Maluck1, Patrik Mag1,2
1Department of Pharmacology and Toxicology, University of Veterinary Medicine, István utca 2, H-1078 Budapest, Hungary.
Abstract:
The increasing prevalence of antimicrobial resistance against zoonotic bacteria, including Streptococcus (S.) suis, highlights the need for new therapeutical strategies, including the repositioning of drugs. In this study, susceptibilities of bacterial isolates were tested toward ten different 3-amidinophenyalanine (Phe(3-Am)) derivatives via determination of minimum inhibitory concentration (MIC) values. Some of these protease inhibitors, like compounds MI-432, MI-471, and MI-476, showed excellent antibacterial effects against S. suis. Their drug interaction potential was investigated using human liver microsomal cytochrome P450 (CYP450) measurements. In our work, non-tumorigenic IPEC-J2 cells and primary porcine hepatocytes were infected with S. suis, and the putative beneficial impact of these inhibitors was investigated on cell viability (Neutral red assay), on interleukin (IL)-6 levels (ELISA technique), and on redox balance (Amplex red method). The antibacterial inhibitors prevented S. suis-induced cell death (except MI-432) and decreased proinflammatory IL-6 levels. It was also found that MI-432 and MI-476 had antioxidant effects in an intestinal cell model upon S. suis infection. Concentration-dependent suppression of CYP3A4 function was found via application of all three inhibitors. In conclusion, our study suggests that the potential antiviral Phe(3-Am) derivatives with 2',4' dichloro-biphenyl moieties can be considered as effective drug candidates against S. suis infection due to their antibacterial effects.
Insights
New drug candidates, 3-amidinophenylalanine (Phe(3-Am)) derivatives, show potent antibacterial effects against Streptococcus suis. These compounds may offer novel therapeutic strategies for zoonotic bacterial infections.
Area of Science:
- Microbiology and Infectious Diseases
- Pharmacology and Drug Discovery
Background:
- Rising antimicrobial resistance in zoonotic bacteria like Streptococcus suis necessitates novel therapeutic approaches.
- Drug repositioning is a promising strategy to identify new treatments for resistant bacterial infections.
Purpose of the Study:
- To evaluate the antibacterial efficacy of 3-amidinophenylalanine (Phe(3-Am)) derivatives against Streptococcus suis.
- To investigate the impact of these compounds on host cell responses, including viability, inflammation, and oxidative stress.
- To assess the drug interaction potential of promising candidates using cytochrome P450 (CYP450) assays.
Main Methods:
- Minimum Inhibitory Concentration (MIC) assays were performed to determine bacterial susceptibility.
- Cell viability (Neutral red assay), IL-6 levels (ELISA), and redox balance (Amplex red) were measured in infected cells.
- Human liver microsomal cytochrome P450 (CYP450) inhibition assays were conducted.
Main Results:
- Several Phe(3-Am) derivatives, notably MI-432, MI-471, and MI-476, demonstrated significant antibacterial activity against S. suis.
- These compounds reduced S. suis-induced cell death and decreased proinflammatory interleukin-6 (IL-6) levels.
- MI-432 and MI-476 exhibited antioxidant effects in intestinal cells, while all three tested compounds inhibited CYP3A4 activity.
Conclusions:
- 3-amidinophenylalanine (Phe(3-Am)) derivatives with dichloro-biphenyl moieties possess potent antibacterial properties against S. suis.
- These compounds demonstrate potential for therapeutic use by mitigating host inflammatory responses and oxidative stress.
- Further investigation into these Phe(3-Am) derivatives is warranted for developing novel treatments against S. suis infections.
