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Promysalin is a salicylate-containing antimicrobial with a cell-membrane-disrupting mechanism of action on Gram-positive bacteria.

ABSTRACT: Promysalin was previously described as a narrow spectrum molecule with a unique species-specific activity against Pseudomonas aeruginosa. Here we demonstrate that promysalin is active against Gram-positive and Gram-negative bacteria using a microdilution assay. Promysalin acts on Gram-positive bacteria with a mechanism of action involving cell membrane damage with leakage of intracellular components. The evaluation of MICs and MBCs on 11 promysalin analogs, synthesized utilizing diverted total synthesis, allowed the identification of the structural moieties potentially involved in cell membrane interaction and damage. The mechanism of action of promysalin against Gram-negative bacteria is still not clarified, even if a synergistic effect with the bisguanidine chlorhexidine on cell membrane disruption has been observed.

SUBMITTER: Kaduskar RD

PROVIDER: S-EPMC5562885 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Promysalin is a salicylate-containing antimicrobial with a cell-membrane-disrupting mechanism of action on Gram-positive bacteria.

Kaduskar Rahul D RD Scala Giulia Della GD Al Jabri Zaaima J H ZJH Arioli Stefania S Musso Loana L Oggioni Marco R MR Dallavalle Sabrina S Mora Diego D

Scientific reports 20170818 1

Promysalin was previously described as a narrow spectrum molecule with a unique species-specific activity against Pseudomonas aeruginosa. Here we demonstrate that promysalin is active against Gram-positive and Gram-negative bacteria using a microdilution assay. Promysalin acts on Gram-positive bacteria with a mechanism of action involving cell membrane damage with leakage of intracellular components. The evaluation of MICs and MBCs on 11 promysalin analogs, synthesized utilizing diverted total s ...[more]

PMID: 28821717

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Project description:With the increasing reports of community-acquired and nosocomial infection caused by multidrug-resistant Gram-positive pathogens, there is an urgent need to develop new antimicrobial agents with novel antibacterial mechanisms. Here, we investigated the antibacterial activity of the natural product ginkgolic acid (GA) (15:1), derived from Ginkgo biloba, and its potential mode of action against the Gram-positive bacteria Enterococcus faecalis and Staphylococcus aureus. The MIC values of GA (15:1) against clinical E. faecalis and S. aureus isolates from China were ≤4 and ≤8 μg/mL, respectively, from our test results. Moreover, GA (15:1) displayed high efficiency in biofilm formation inhibition and bactericidal activity against E. faecalis and S. aureus. During its inhibition of the planktonic bacteria, the antibacterial activity of GA (15:1) was significantly improved under the condition of abolishing iron homeostasis. When iron homeostasis was abolished, inhibition of planktonic bacteria by GA (15:1) was significantly improved. This phenomenon can be interpreted as showing that iron homeostasis disruption facilitated the disruption of the functions of ribosome and protein synthesis by GA (15:1), resulting in inhibition of bacterial growth and cell death. Genetic mutation of ferric uptake regulator (Fur) led to GA (15:1) tolerance in in vitro-induced resistant derivatives, while overexpression of Fur led to increased GA (15:1) susceptibility. Additionally, GA (15:1) significantly decreased the bacterial loads of S. aureus strain USA300 in the lung tissues of mice in a pneumonic murine model. Conclusively, this study revealed an antimicrobial mechanism of GA (15:1) involving cross talk with iron homeostasis against Gram-positive pathogens. In the future, the natural product GA (15:1) might be applied to combat infections caused by Gram-positive pathogens. IMPORTANCE The increasing emergence of infectious diseases associated with multidrug-resistant Gram-positive pathogens has raised the urgent need to develop novel antibiotics. GA (15:1) is a natural product derived from Ginkgo biloba and possesses a wide range of bioactivities, including antimicrobial activity. However, its antibacterial mechanisms remain unclear. Our current study found that the function of ferric uptake regulator (Fur) was highly correlated with the antimicrobial activity of GA (15:1) against E. faecalis and that the antibacterial activity of GA (15:1) could be strengthened by the disruption of iron homeostasis. This study provided important insight into the mode of action of GA (15:1) against Gram-positive bacteria and suggested that GA (15:1) holds the potential to be an antimicrobial treatment option for infection caused by multidrug-resistant Gram-positive pathogens.

Project description:Surveillance data are considered essential to appropriate empiric antibiotic therapy and stewardship. The objective of this study was to determine if a change in the rates of antibiotic resistance impacts antibiotic use in European hospitals. Glycopeptides use was selected to study the correlation between resistance rates and antibiotic use because of the restricted spectrum against resistant gram positive bacteria. PubMed, ECDC databases and national/regional surveillance systems were searched to identify glycopeptides´ consumption in defined daily dose per 1000 inhabitant-days (DID) and rate of methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase negative staphylococci (MRCoNS), and vancomycin-resistant enterococci (VRE) in bloodstream infections (BSIs) in European countries between 1997 and 2015. Time trends were studied and associations between DID and BSI resistance rates were tested using multi-level mixed effect models. To account for the gap in the publication and dissemination of the yearly resistance data, a 2-year lag in the resistance rates was applied. Data on glycopeptides´ DID and resistance rates of target microorganisms in blood cultures were identified among 31 countries over a 19-year period. Glycopeptides use significantly increased (p<0·0001) while rates of MRSA BSIs decreased in majority of the countries (p<0·0001) and MRCoNS and VRE BSIs remained stable. Variation in glycopeptides' DID was not associated with variation in BSIs due to MRSA (p = 0·136) and VRE (p = 0·613). After adjusting for MRCoNS and VRE resistance rates, among 21 countries, 11 (52%) had a concordant and 10 (48%) a discordant trend in yearly glycopeptides´ DID and MRSA BSI rates. No correlation was found between resistance rates and DID data even among 8 countries with more than 5% decrease in MRSA rates over time. (RC -0·009, p = 0·059). Resistance rate of MRSA, MRCoNS, and VRE BSIs does not impact DID of glycopeptides in European hospitals. This finding is key to redefining the role and structure of antimicrobial surveillance and stewardship programmes.

Dataset Information

Promysalin is a salicylate-containing antimicrobial with a cell-membrane-disrupting mechanism of action on Gram-positive bacteria.

Publications

Promysalin is a salicylate-containing antimicrobial with a cell-membrane-disrupting mechanism of action on Gram-positive bacteria.

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