An experimental drug being tested for neurodegenerative disease may help in the fight against life-threatening antibiotic-resistant in bacteria, report researchers from Australia. They found the drug PBT2, when combined with a polymyxin antibiotic, can disrupt and kill gram-negative bacteria that cause pneumonia, bloodstream infections and meningitis. The emergence of polymyxin resistance in carbapenem-resistant and extended-spectrum beta-lactamase (ESBL)-producing bacteria is "a critical threat to human health, and alternative treatment strategies are urgently required," Dr. Mark Walker of the University of Queensland in Brisbane and colleagues write in Science Translational Medicine. PBT2 - or 2-(dimethylamino) methyl-5,7-dichloro-8-hydroxyquinoline - is an orally bioavailable hydroxyquinoline analogue ionophore capable of mediating the transfer of metal ions such as zinc across biological membranes. PBT2 is in phase-2 testing in patients with Huntington disease and Alzheimer disease, with once-daily oral doses of 250 mg shown to be safe and well tolerated when given for periods of up to 24 months. In an earlier study, Dr. Walker and colleagues found that antibiotic resistance in select gram-positive bacterial pathogens could be overcome by repurposing PBT2 in combination with zinc. In their latest study, they investigated the ability of PBT2 to restore antibiotic sensitivity in polymyxin-resistant, ESBL-producing, carbapenem-resistant gram-negative human pathogens. In vitro, PBT2 was shown to re-sensitize Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa to "last-resort" polymyxin-class antibiotics, including the next-generation polymyxin derivative FADDI-287, the researchers report. Furthermore, using a highly invasive K. pneumoniae strain engineered for polymyxin resistance, they showed that PBT2 plus polymyxin (colistin or FADDI-287) could successfully treat gram-negative sepsis in immunocompetent mice. Compared with giving the mice polymyxin alone, administering the combination of PBT2 plus polymyxin improved survival and reduced bacterial dissemination to the lungs and spleen, they report. "The mechanism of action responsible for this effect appears to be mediated through dysregulation of bacterial metal ion homeostasis," the researchers write. This study provides an important "demonstration of in vivo efficacy against Klebsiella sepsis in a mouse model (and) provides a new strategy for rescuing antibiotics that have lost efficacy due to antibiotic resistance development," Dr. Walker told Reuters Health by email. "We are looking towards undertaking a human trial of antibiotic in combination with PBT2," he added. Funding for this research was provided by the National Health and Medical Research Council of Australia. Dr. Walker and three colleagues are co-inventors on a patent associated with this work. —Megan Brooks Source
