Peptide-Based Efflux Pump Inhibitors of the Small Multidrug Resistance Protein from Pseudomonas aeruginosa

Mitchell, Chloe J.; Stone, Tracy A.; Deber, Charles M.

doi:10.1128/aac.00730-19

Cited by 20 publications

(32 citation statements)

References 41 publications

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“…These small peptides can function as novel bioactive molecules that regulate several biological processes 42 – 44 . Small peptides can act as a hormone 45 , 46 , biocide 47 , and as an anti-cancer therapeutic agent 48 , 49 . The presence of these small peptides and their activity can have a significant impact on the physiology of an organism.…”

Section: Resultsmentioning

confidence: 99%

Virtual 2-D map of the fungal proteome

Mohanta

Mishra

Khan

et al. 2021

Sci Rep

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The molecular weight and isoelectric point (pI) of the proteins plays important role in the cell. Depending upon the shape, size, and charge, protein provides its functional role in different parts of the cell. Therefore, understanding to the knowledge of their molecular weight and charges is (pI) is very important. Therefore, we conducted a proteome-wide analysis of protein sequences of 689 fungal species (7.15 million protein sequences) and construct a virtual 2-D map of the fungal proteome. The analysis of the constructed map revealed the presence of a bimodal distribution of fungal proteomes. The molecular mass of individual fungal proteins ranged from 0.202 to 2546.166 kDa and the predicted isoelectric point (pI) ranged from 1.85 to 13.759 while average molecular weight of fungal proteome was 50.98 kDa. A non-ribosomal peptide synthase (RFU80400.1) found in Trichoderma arundinaceum was identified as the largest protein in the fungal kingdom. The collective fungal proteome is dominated by the presence of acidic rather than basic pI proteins and Leu is the most abundant amino acid while Cys is the least abundant amino acid. Aspergillus ustus encodes the highest percentage (76.62%) of acidic pI proteins while Nosema ceranae was found to encode the highest percentage (66.15%) of basic pI proteins. Selenocysteine and pyrrolysine amino acids were not found in any of the analysed fungal proteomes. Although the molecular weight and pI of the protein are of enormous important to understand their functional roles, the amino acid compositions of the fungal protein will enable us to understand the synonymous codon usage in the fungal kingdom. The small peptides identified during the study can provide additional biotechnological implication.

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Section: Resultsmentioning

confidence: 99%

Virtual 2-D map of the fungal proteome

Mohanta

Mishra

Khan

et al. 2021

Sci Rep

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“…Our results showed that niosome‐encapsulated tobramycin could reduce the EtBr MIC value by two to four times which is indicating the efflux pump inhibitory of niosome encapsulated tobramycin. Efflux pump systems in P. aeruginosa strains expel antimicrobial agents out the cells, contribute to the intrinsic resistance of bacteria 57,58 . Moreover, biofilm formation reduces the efficacy of antimicrobial agents and several studies showed the relationship between biofilm formation and antibiotic resistance 59 .…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, biofilm formation reduces the efficacy of antimicrobial agents and several studies showed the relationship between biofilm formation and antibiotic resistance 59 . Efflux pump inhibition is a valuable approach to overcome antibiotic resistance 57 . Recently, most of researchers is focused on the development of efflux inhibitors especially RND efflux pump inhibitors 57,60 .…”

Section: Discussionmentioning

confidence: 99%

“…Efflux pump inhibition is a valuable approach to overcome antibiotic resistance 57 . Recently, most of researchers is focused on the development of efflux inhibitors especially RND efflux pump inhibitors 57,60 . Many chemically, natural derivative substances and antibiotics have been reported which have efflux pump inhibitory activity 60 .…”

Section: Discussionmentioning

confidence: 99%

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Niosome‐encapsulated tobramycin reduced antibiotic resistance and enhanced antibacterial activity against multidrug‐resistant clinical strains of Pseudomonas aeruginosa

Hedayati

Targhi

Shamsi

et al. 2020

J Biomedical Materials Res

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In the current study, niosome‐encapsulated tobramycin based on Span 60 and Tween 60 was synthesized and its biological efficacies including anti‐bacterial, anti‐efflux, and anti‐biofilm activities were investigated against multidrug resistant (MDR) clinical strains of Pseudomonas aeruginosa. The niosomal formulations were characterized using scanning electron microscopy, transmission electron microscopy, and dynamic light scattering measurement. The encapsulation efficiency was found to be 69.54% ±; 0.67. The prepared niosomal formulations had a high storage stability to 60 days with small changes in size and drug entrapment, which indicates that it is a suitable candidate for pharmaceutical applications. The results of biological study showed the anti‐bacterial activity via reduction of antibiotic resistance, enhanced anti‐efflux and anti‐biofilm activities by more folds in comparison to free tobramycin. In addition, niosome encapsulated tobramycin down‐regulated the MexAB‐OprM efflux genes, pslA and pelA biofilm related genes in MDR P. aeruginosa strains. The anti‐proliferative activity of formulation was evaluated against HEK293 cell lines, which exhibited negligible cytotoxicity against HEK293 cells. The finding of our study shows that encapsulation of tobramycin in niosome enhanced the antibacterial activity and reduced antibiotic resistance in MDR strains of P. aeruginosa comparing to free tobramycin and it can be considered as a favorable drug delivery system.

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“…For example, MdtIJ, a heterodimer classified as EmrE-like via sequence, was shown to transport spermidine, a metabolite, rather than acting as a multidrug transporter (20,21). This raises the question of how much functional variation exists within each subfamily, and how well functional phenotypes correlate with bioinformatic classifications, since experimental assessment of transport or drug resistance phenotypes has only been performed for a relatively small number SMR homologs and limited number of substrates (1,9,15,(22)(23)(24)(25)(26). Here we experimentally confirm the EmrE-like classification of two SMR homologs from bacterial pathogens, SMRSa from Staphylococcus aureus and SMRFt from Francisella tularensis by comparing the results of resistance assays of these SMRs to EmrE.…”

mentioning

confidence: 99%

Functional phenotyping of small multidrug resistance proteins fromStaphylococcus aureusandFrancisella tularensisreveals functional homology to EmrE

Spreacker¹,

Beeninga²,

Young³

et al. 2021

Preprint

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Small multidrug resistance (SMR) transporters efflux toxic substrates from bacterial cells. These transporters were recently divided into two subfamilies: the GdX-like and EmrE-like SMRs. The EmrE-like subfamily of SMRs is predicted to contain transporters that are highly promiscuous in both substrate specificity and mechanism based on extensive characterization of the founding member of this subfamily, EmrE. However, there is only limited functional analysis of other members of this family from pathogenic strains such as Staphylococcus aureus and Francisella tularensis. Here, we use a small compound screen to explore the substrate specificity and diversity of EmrE-subfamily SMRs from these two bacterial species and confirm that they are functionally more like EmrE than the GdX-like subfamily of toxic-metabolite transporters. The results of these experiments lay the foundation for understanding the complex substrate specificity profiles of SMR family transporters and assess the potential for targeting these transporters for future antibiotic development, either broadly or in a species-specific manner.

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Peptide-Based Efflux Pump Inhibitors of the Small Multidrug Resistance Protein from Pseudomonas aeruginosa

Cited by 20 publications

References 41 publications

Virtual 2-D map of the fungal proteome

Virtual 2-D map of the fungal proteome

Niosome‐encapsulated tobramycin reduced antibiotic resistance and enhanced antibacterial activity against multidrug‐resistant clinical strains of Pseudomonas aeruginosa

Functional phenotyping of small multidrug resistance proteins fromStaphylococcus aureusandFrancisella tularensisreveals functional homology to EmrE

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