Physicians Harness Power of Heavy Metal to Fight Bacteria

Lara C. Pullen, PhD

October 04, 2018

Human infections could be treated by targeting nutritional vulnerabilities of bacterial pathogens, according to a study published online September 26 in Science Translational Medicine.

Christopher H. Goss, MD, professor of pediatrics at the University of Washington School of Medicine in Seattle, and colleagues used the heavy metal gallium to safely combat bacterial growth in mice and humans.

A single dose of systemic gallium administered 3 or 12 hours after mice were infected with Pseudomonas aeruginosa increased mouse survival (P < .001) and reduced lung and blood P aeruginosa counts (P < 0.001).

The team hopes that such an unconventional antimicrobial approach could be helpful in the growing public health crisis of antibiotic resistance.

The investigators have built on an antimicrobial strategy originally proposed by Louis Pasteur, and targeted a bacterial vulnerability in iron metabolism. They did this with intravenous gallium nitrate [Ga(NO3)3], a substance that has already been approved by the US Food and Drug Administration for a noninfection indication (hypercalcemia of malignancy).

"It's important to remember that gallium is used pretty regularly in nuclear medicine to image organs, so is a well-established substance in medicine," Amesh A. Adalja, MD, senior scholar, Johns Hopkins Center for Health Security, Bloomberg School of Public Health, Baltimore, Maryland, explained to Medscape Medical News. "The use of gallium to exploit iron pathways in bacteria makes a lot of sense, and it is a promising means to move beyond antibiotics, which are always eclipsed by the evolution of resistance, to develop nontraditional therapies for infections, especially highly consequential ones like Pseudomonas."

Gallium Was Safe and Effective in Humans

After documenting the positive result in mice, the investigators performed a small, unblinded, uncontrolled trial in 20 adults with mild cystic fibrosis and chronic P aeruginosa lung infections. Their primary endpoints were safety, tolerability, and pharmacokinetics. Results from the small phase 1b trial suggested that systemic gallium treatment safely and effectively improved lung function.

Nine patients received 100 mg/m2/day, and 11 patients received 200 mg/m2/day Ga(NO3) by slow continuous intravenous infusion over the course of 5 days. Gallium's elimination half-life was greater than 100 hours in the plasma and greater than 220 hours in the sputum.

The investigators documented no serious adverse events and noted that kidney function, electrolyte concentrations, and blood counts were all unaffected by treatment. Although efficacy was not a primary endpoint, the investigators did document statistically significant increases in lung function 14 and 28 days after a single infusion of gallium (P < .005).

Adalja believes that such an approach should work for other infectious agents as well. "Cystic fibrosis patients, however, are plagued with severe infections and receive frequent courses of antibiotics, making them a good population to study this treatment in," he noted, adding that "cost, availability of alternative agents, resistance levels, and severity of infection will play a role in selecting patients for this therapy."

Resistance to Gallium Developed Slowly

Resistance to gallium emerged at very low rates, possibly a result of the fact that gallium can target so many metabolic pathways in bacteria. Most successful antibiotics inhibit multiple essential bacterial functions, and experts believe this property is important to slow the evolution of drug resistance.

"Gallium's ability to generally substitute for iron suggests that gallium could disrupt several aspects of bacterial physiology, and our experiments and previous gene expression analysis support this idea," explain the authors. "Activity assays indicated that gallium inhibits enzymes mediating bacterial DNA synthesis and antioxidant defense and sensitized bacteria to killing by peroxides. Previous gene expression assays indicated that gallium disrupts carbon utilization and protein synthesis and represses key iron uptake systems including those mediating heme/hemoglobin and pyoverdine uptake."

The investigators measured resistance using three independent assays: spontaneous mutants, passing under selection, and transposon mutagenesis. Approximately 1 in 30 million P aeruginosa cells spontaneously developed resistance to gallium, a number that is approximately half that seen for the other antibiotics tested (tobramycin and aztreonam). Moreover, the strain that was most resistant to gallium had an inhibitory concentration that was only fourfold higher than the gallium-susceptible laboratory strain PA01.

Two coauthors are coinventors on US patent no. 9,539,367: Gallium Inhibits Biofilm Formation. Adalja has disclosed no relevant financial relationships.

Sci Transl Med. Published online September 26, 2018. Full text

For more news, join us on Facebook and Twitter

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....