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Published on: April 18, 2019
Antibiotics potentiating potential of catharanthine against superbug Pseudomonas aeruginosa
Gaurav Raj Dwivedi1, Rekha Tyagi2, Sanchita3
1a Microbiology Department , ICMR-Regional Medical Research Centre Bhubaneswar , Bhubaneswar 751023 , Odisha , India.
Abstract:
Multidrug resistance (MDR) put an alarming situation like preantibiotic era which compels us to invigorate the basic science of anti-infective chemotherapy. Hence, the drug resistant genes/proteins were explored as promising drug targets. Keeping this thing in mind, proteome of Pseudomonas aeruginosa PA01 was explored, which resulted in the identification of tripartite protein complexes (MexA, MexB, and OprM) as promising drug target for the screening of natural and synthetic inhibitors. The purpose of present investigation was to explore the drug resistance reversal potential mechanism of catharanthine isolated from the leaves of Catharanthus roseous. Hence, the test compound catharanthine was in silico screened using docking studies against the above receptors, which showed significant binding affinity with these receptors. In order to validate the in silico findings, in vitro evaluation of the test compound was also carried out. In combination, catharanthine reduced the minimum inhibitory concentration MIC of tetracycline (TET) and streptomycin up to 16 and 8 folds, respectively. Further, in time kill assay, catharanthine in combination with TET reduced the cell viability in concentration dependent manner and was also able to reduce the mutation prevention concentration of TET. It was also deduced that drug resistance reversal potential of catharanthine was due to inhibition of the efflux pumps.
Insights
Multidrug resistance is a growing threat. Catharanthine, from *Catharanthus roseus*, reverses resistance in *Pseudomonas aeruginosa* by inhibiting efflux pumps, offering new hope against drug-resistant infections.
Area of Science:
- Antimicrobial chemotherapy
- Molecular biology
- Pharmacology
Background:
- Multidrug resistance (MDR) poses a significant global health challenge, necessitating novel anti-infective strategies.
- Drug-resistant genes and proteins are critical targets for developing new therapeutic agents.
- The proteome of *Pseudomonas aeruginosa* PA01 revealed tripartite protein complexes (MexA, MexB, OprM) as potential drug targets.
Purpose of the Study:
- To investigate the drug resistance reversal potential of catharanthine, a compound isolated from *Catharanthus roseus* leaves.
- To elucidate the mechanism by which catharanthine overcomes multidrug resistance.
Main Methods:
- In silico screening using docking studies to assess catharanthine's binding affinity to target proteins.
- In vitro evaluation, including minimum inhibitory concentration (MIC) assays and time-kill assays.
- Assessment of catharanthine's effect on the mutation prevention concentration (MPC) of antibiotics.
Main Results:
- Catharanthine demonstrated significant binding affinity to MexA, MexB, and OprM target proteins in silico.
- In vitro, catharanthine reduced the MIC of tetracycline and streptomycin by 16-fold and 8-fold, respectively.
- Catharanthine, in combination with tetracycline, reduced bacterial cell viability and the MPC of tetracycline in a dose-dependent manner.
Conclusions:
- Catharanthine exhibits significant potential for reversing multidrug resistance in *Pseudomonas aeruginosa*.
- The primary mechanism of action involves the inhibition of efflux pumps.
- Catharanthine represents a promising natural compound for developing novel anti-infective therapies against MDR pathogens.
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