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Attaching NorA Efflux Pump Inhibitors to Methylene Blue Enhances Antimicrobial Photodynamic Inactivation of Escherichia coli and Acinetobacter baumannii in vitro and in vivo
- Publication Year :
- 2018
-
Abstract
- Resistance of bacteria to antibiotics is a public health concern worldwide due to the increasing failure of standard antibiotic therapies. Antimicrobial photodynamic inactivation (aPDI) is a promising non-antibiotic alternative for treating localized bacterial infections that uses non-toxic photosensitizers and harmless visible light to produce reactive oxygen species and kill microbes. Phenothiazinium photosensitizers like methylene blue (MB) and toluidine blue O are hydrophobic cations that are naturally expelled from bacterial cells by multidrug efflux pumps, which reduces their effectiveness. We recently reported the discovery of a NorA efflux pump inhibitor-methylene blue (EPI-MB) hybrid compound INF55-(Ac)en-MB that shows enhanced photodynamic inactivation of the Gram-positive bacterium methicillin-resistant Staphylococcus aureus (MRSA) relative to MB, both in vitro and in vivo. Here, we report the surprising observation that INF55-(Ac)en-MB and two related hybrids bearing the NorA efflux pump inhibitors INF55 and INF271 also show enhanced aPDI activity in vitro (relative to MB) against the Gram-negative bacteria Escherichia coli and Acinetobacter baumannii, despite neither species expressing the NorA pump. Two of the hybrids showed superior effects to MB in murine aPDI infection models. The findings motivate wider exploration of aPDI with EPI-MB hybrids against Gram-negative pathogens and more detailed studies into the molecular mechanisms underpinning their activity.
- Subjects :
- 0301 basic medicine
Acinetobacter baumannii
Indoles
medicine.drug_class
030106 microbiology
Clinical Biochemistry
Antibiotics
Pharmaceutical Science
Microbial Sensitivity Tests
medicine.disease_cause
Biochemistry
Article
Microbiology
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
Bacterial Proteins
Drug Discovery
medicine
Escherichia coli
Molecular Biology
biology
Dose-Response Relationship, Drug
Molecular Structure
Organic Chemistry
biology.organism_classification
Antimicrobial
Anti-Bacterial Agents
Methylene Blue
030104 developmental biology
chemistry
Staphylococcus aureus
Molecular Medicine
Efflux
Multidrug Resistance-Associated Proteins
Methylene blue
Bacteria
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....b31e23ec97f893897544aa43c6977205