A study by Australian microbiologists at Queensland, Melbourne and Griffiths universities has shown that the candidate neurodegenerative disease drug PBT-2, combined with a polymyxin antibiotic, induced potent antimicrobial activity against polymyxin-resistant gram-negative pathogens.

Reported in the November 18, 2020, edition of Science Translational Medicine, this finding highlights the potential for combining PBT-2 with next-generation polymyxins for treating severe infections caused by multidrug-resistant (MDR) gram-negative bacteria in humans.

"This is the first study to show that combining PBT-2 with a polymyxin can overcome MDR in gram-negative bacterial pathogens," said study leader Mark Walker, a professor at the University of Queensland in Brisbane.

This is a timely discovery, as carbapenem-resistant, extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae represent an increasingly serious threat to human health worldwide, according to the WHO.

The emergence of polymyxin resistance in ESBL-producing Enterobacteriaceae, due to either spontaneous chromosomal mutation of mgrB or plasmid-borne mobile colistin resistance (mcr) genes, is particularly problematic, given that polymyxins such as colistin are currently antibiotics of last resort.

Novel strategies are therefore urgently needed to target MDR human pathogens and include the repurposing of noninfectious disease treatments, in this case PBT-2 [2-(dimethylamino)methyl-5,7-dichloro-8- hydroxyquinoline].

PBT-2

PBT-2 is an orally bioavailable second-generation hydroxyquinoline analogue ionophore, which can mediate the transfer of metal ions such as zinc across biological membranes.

Originally developed as a potential treatment for Huntington's and Alzheimer's diseases, PBT-2 has progressed to phase II trials for those indications, with once-daily oral doses having been shown to be safe and well tolerated when administered for 6-24 months.

University of Queensland researchers have recently demonstrated that antibiotic resistance in select gram-positive bacterial pathogens could be overcome by repurposing PBT-2 in combination with zinc.

This suggested that PBT-2 might also be effective in the treatment of infections caused by gram-negative polymyxin-resistant pathogens.

Moreover, "we have previously observed efficacy for PBT-2 combined with a topical antibiotic treatment for wound infections, so we decided to test PBT-2 plus polymyxin combinations against systemic infection," said Walker.

Therefore, in the new Science Translational Medicine study, the researchers investigated the ability of PBT-2 to restore antibiotic sensitivity in various polymyxin-resistant, ESBL-producing, gram-negative human pathogens.

PBT-2 was shown in vitro to resensitize the gram-negative bacteria Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa to polymyxin antibiotics, including the next-generation polymyxin derivative, FADDI-287.

"We demonstrated polymyxin resensitization against K. pneumoniae, E. coli, A. baumannii and P. aeruginosa in laboratory studies using minimal inhibitory concentrations (MICs)," Walker told BioWorld Science.

Importantly, the researchers were unable to select for mutants resistant to combined PBT-2/FADDI-287 in polymyxin-resistant E. coli containing a plasmid-borne mcr-1 gene or K. pneumoniae carrying a chromosomal mgrB mutation.

"Demonstrating that antimicrobial resistance does not develop is significant, as it suggests that the bacteria cannot become resistant to the treatment," Walker told BioWorld Science.

Moreover, using a highly invasive K. pneumoniae strain bioengineered for polymyxin resistance through mgrB mutation, the researchers then successfully demonstrated the efficacy of PBT-2 plus either colistin or FADDI-287 for the treatment of gram-negative sepsis in immune competent mice.

Compared with polymyxin alone, the combination of PBT-2 plus a polymyxin improved survival and reduced bacterial dissemination to the lungs and spleen in infected mice.

"Polymyxin alone was only partially effective for the treatment of polymyxin-resistant Klebsiella sepsis, whereas the combination of PBT-2 and a polymyxin was significantly more effective at clearing infection," said Walker.

In terms of safety, "in animal studies, the PBT-2 plus polymyxin combination treatment was well tolerated, although clinical trials would be required to establish the safety profile in humans."

Walker estimated that such clinical trials could begin in about a year, "given adequate resourcing."

Meanwhile, he said, "we want to investigate which other antibiotics PBT-2 might potentiate and against how many other bacterial pathogens this treatment might be effective." (De Oliveira, D.M.P. et al. Sci Transl Med 2020, 12: eabb3791).

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