Pentagalloyl glucose: An ethnobotanical approach to multidrug resistance Open Access
Lin, Michelle (Spring 2020)
Abstract
Multidrug resistant Acinetobacter baumannii strains pose a significant public health threat in the twenty-first century due to their resistance to multiple antibiotic categories. Effective treatments for nosocomial infections of A. baumannii have dwindled as the evolution of resistance has outpaced the development of novel antimicrobials. Here, I applied an ethnobotanical approach to anti-infective drug discovery for A. baumannii, by (1) investigating the inhibitory activity of pentagalloyl glucose (PGG) isolated from Schinus terebinthifolia (Brazilian peppertree), (2) exploring possible inhibition mechanisms of PGG, and (3) confirming the antimicrobial effects of Rhus coriaria (Sicilian sumac) and Rhus copallinum (winged sumac), both of which are in the same family (Anacardiaceae) as S. terebinthifolia.
Growth inhibition and time-kill assays revealed PGG to be a bacteriostatic agent against A. baumannii strains of varying resistance profiles (MIC 64 to 256 μg/mL), as well as Pseudomonas aeruginosa (MIC 16 μg/mL) and Staphylococcus aureus (MIC 64 μg/mL). Cytotoxicity assays with human keratinocytes revealed an IC50 of 256 μg/mL and a therapeutic index of 32, suggesting therapeutic use as a topical agent. A 21-day resistance passaging assay of PGG did not produce resistant phenotypes. Iron chelation and lipopolysaccharide attachment were identified as PGG's possible mechanism(s) of action. Finally, R. coriaria and R. copallinum extracts inhibited growth of A. baumannii (MICs of 128 μg/mL), P. aeruginosa (MICs of 32 and 64 μg/mL, respectively), and S. aureus (MICs of 64 and 256 μg/mL, respectively). PGG was determined to be a putative active compound in the Rhus extracts. In summation, traditional medicinal plants, like S. terebinthifolia and the Rhus extracts, provide unexplored avenues of research for the fight against multidrug resistance.
Table of Contents
CHAPTER 1: INTRODUCTION 1
Emergence and spread of highly resistant bacteria
Acinetobacter baumannii
Natural products as an alternative to conventional antibiotics
Project aims and research questions
CHAPTER 2: LITERATURE REVIEW 8
Rhus coriaria
Rhus copallinum
CHAPTER 3: MATERIALS AND METHODS 14
Experimental overview
Preparing crude extract from plant material
Growth inhibition assays
Supplementation studies
Biofilm studies
Time-kill assays
Resistance studies
Cytotoxicity assays
HPLC and co-injection studies
CHAPTER 4: RESULTS 31
Extraction and liquid-liquid partitioning
Growth inhibition assays
Biofilm inhibition and eradication assays against Acinetobacter baumannii
Supplementation assays
Time-kill assays
Resistance studies: spontaneous mutant and generational resistance
Cytotoxicity assays
Compound confirmation
CHAPTER 5: DISCUSSION 52
Pentagalloyl glucose (PGG) in natural products
PGG: a promising topical agent for growth inhibition of Acinetobacter baumannii
Iron chelation as a possible mechanism of action
Lipopolysaccharide attachment as a possible mechanism of action
Conclusion
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