A Phytochemical-Halogenated Quinoline Combination Therapy Strategy for the Treatment of Pathogenic Bacteria

• Published in: ChemMedChem Vol. 10; no. 7; pp. 1157 - 1162
• Main Authors: Abouelhassan, Yasmeen, Garrison, Aaron T., Bai, Fang, Norwood IV, Verrill M., Nguyen, Minh Thu, Jin, Shouguang, Huigens III, Robert W.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.07.2015; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Subjects: Acinetobacter baumannii; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antibacterial potentiation; biofilm eradication; Cell Survival - drug effects; Chemistry, Medicinal; combination antibacterial therapy; Dose-Response Relationship, Drug; Drug Combinations; drug discovery; Drug resistance; Gallic Acid - chemistry; Gallic Acid - pharmacology; halogenated quinolones; HeLa Cells; Humans; Klebsiella pneumoniae; Life Sciences & Biomedicine; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - isolation & purification; Microbial Sensitivity Tests; Molecular Structure; Pharmacology & Pharmacy; phytochemicals; Phytochemicals - chemistry; Phytochemicals - pharmacology; Quinolines - chemistry; Quinolines - pharmacology; Science & Technology; Staphylococcus aureus; Structure-Activity Relationship; halogenated quinolones; DISPERSAL; ANTIBIOTICS; ACID; drug discovery; combination antibacterial therapy; antibacterial potentiation; biofilm eradication; BIOFILMS; DRUGS; phytochemicals; ANTIMICROBIAL ACTIVITY
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201500179

With the continued rise of drug‐resistant bacterial infections coupled with the current discouraging state of the antibiotic pipeline, the need for new antibacterial agents that operate through unique mechanisms compared with conventional antibiotics and work in synergy with other agents is at an all‐time high. We have discovered that gallic acid, a plant‐derived phytochemical, dramatically potentiates the antibacterial activities of several halogenated quinolines (up to 11 800‐fold potentiation against Staphylococcus aureus) against pathogenic bacteria, including drug‐resistant clinical isolates. S. aureus demonstrated the highest sensitivity towards gallic acid–halogenated quinoline combinations, including one halogenated quinoline that demonstrated potentiation of biofilm eradication activity against a methicillin‐resistant S. aureus (MRSA) clinical isolate. During our studies, we also demonstrated that these halogenated quionlines operate through an interesting metal(II) cation‐dependent mechanism and display promising mammalian cytotoxicity. Quite the combo! Halogenated quinolines and select phytochemicals, in particular gallic acid (GA), possess unique antibacterial synergy against several pathogenic bacteria, including: Staphylococcus aureus, S. epidermidis, Acinetobacter baumannii and Klebsiella pneumoniae. Here, GA is shown to potentiate the growth inhibitory properties of 1 (>10 000‐fold) against S. aureus while also potentiating biofilm eradication activities against a methicillin‐resistant S. aureus (MRSA) clinical isolate (fourfold).