Repurposing of antidiabetics as Serratia marcescens virulence inhibitors.
Animals
Anti-Bacterial Agents
/ chemistry
Bacterial Proteins
/ chemistry
Drug Repositioning
Female
Gene Expression Regulation, Bacterial
/ drug effects
Humans
Hypoglycemic Agents
/ chemistry
Metformin
/ chemistry
Mice
Molecular Docking Simulation
Serratia Infections
/ drug therapy
Serratia marcescens
/ drug effects
Vildagliptin
/ chemistry
Virulence
/ drug effects
Virulence Factors
/ chemistry
Metformin
QS
Serratia marcescens
Sitagliptin
Vildagliptin
Virulence
Journal
Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]
ISSN: 1678-4405
Titre abrégé: Braz J Microbiol
Pays: Brazil
ID NLM: 101095924
Informations de publication
Date de publication:
Jun 2021
Jun 2021
Historique:
received:
12
11
2019
accepted:
28
02
2021
pubmed:
10
3
2021
medline:
8
10
2021
entrez:
9
3
2021
Statut:
ppublish
Résumé
Serratia marcescens becomes an apparent nosocomial pathogen and causes a variety of infections. S. marcescens possess various virulence factors that are regulated by intercellular communication system quorum sensing (QS). Targeting bacterial virulence is a proposed strategy to overcome bacterial resistance. Sitagliptin anti-QS activity has been demonstrated previously and we aimed in this study to investigate the effects of antidiabetic drugs vildagliptin and metformin compared to sitagliptin on S. marcescens pathogenesis. We assessed the effects of tested drugs in subinhibitory concentrations phenotypically on the virulence factors and genotypically on the virulence encoding genes' expressions. The protection of tested drugs on S. marcescens pathogenesis was performed in vivo. Molecular docking study has been conducted to evaluate the interference capabilities of tested drugs to the SmaR QS receptor. Vildagliptin reduced the expression of virulence encoding genes but did not show in vitro or in vivo anti-virulence activities. Metformin reduced the expression of virulence encoding genes and inhibited bacterial virulence in vitro but did not show in vivo protection. Sitagliptin significantly inhibited virulence factors in vitro, reduced the expression of virulence factors and protected mice from S. marcescens. Docking study revealed that sitagliptin is more active than metformin and fully binds to SmaR receptor, whereas vildagliptin had single interaction to SmaR. The downregulation of virulence genes was not enough to show anti-virulence activities. Hindering of QS receptors may play a crucial role in diminishing bacterial virulence.
Sections du résumé
BACKGROUND
BACKGROUND
Serratia marcescens becomes an apparent nosocomial pathogen and causes a variety of infections. S. marcescens possess various virulence factors that are regulated by intercellular communication system quorum sensing (QS). Targeting bacterial virulence is a proposed strategy to overcome bacterial resistance. Sitagliptin anti-QS activity has been demonstrated previously and we aimed in this study to investigate the effects of antidiabetic drugs vildagliptin and metformin compared to sitagliptin on S. marcescens pathogenesis.
METHODS
METHODS
We assessed the effects of tested drugs in subinhibitory concentrations phenotypically on the virulence factors and genotypically on the virulence encoding genes' expressions. The protection of tested drugs on S. marcescens pathogenesis was performed in vivo. Molecular docking study has been conducted to evaluate the interference capabilities of tested drugs to the SmaR QS receptor.
RESULTS
RESULTS
Vildagliptin reduced the expression of virulence encoding genes but did not show in vitro or in vivo anti-virulence activities. Metformin reduced the expression of virulence encoding genes and inhibited bacterial virulence in vitro but did not show in vivo protection. Sitagliptin significantly inhibited virulence factors in vitro, reduced the expression of virulence factors and protected mice from S. marcescens. Docking study revealed that sitagliptin is more active than metformin and fully binds to SmaR receptor, whereas vildagliptin had single interaction to SmaR.
CONCLUSION
CONCLUSIONS
The downregulation of virulence genes was not enough to show anti-virulence activities. Hindering of QS receptors may play a crucial role in diminishing bacterial virulence.
Identifiants
pubmed: 33686563
doi: 10.1007/s42770-021-00465-8
pii: 10.1007/s42770-021-00465-8
pmc: PMC8105466
doi:
Substances chimiques
Anti-Bacterial Agents
0
Bacterial Proteins
0
Hypoglycemic Agents
0
Virulence Factors
0
Metformin
9100L32L2N
Vildagliptin
I6B4B2U96P
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
627-638Commentaires et corrections
Type : ErratumIn
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