A drug once rejected for toxic side effects could see new life in battle against antibiotic resistance

Scientists have a lead in the ever-more-urgent hunt for antibiotics that can combat multidrug-resistant bacteria—and this one is a throwback.

In a PLOS Biology article published May 16, a team of scientists led by researchers from Beth Israel Deaconess Medical Center and Harvard Medical School described how it characterized the antibacterial activity of streptothricin, a molecule with efficacy against hard-to-kill Gram-negative bacteria. Originally discovered as an antibiotic in the early 1940s but abandoned on account of its potential toxicity, the researchers found that one particular form of streptothricin, the F form, was strong enough to kill drug-resistant bacteria in mice without causing side effects.

“Based on unique, promising activity, we believe [streptothricin F] … deserves further preclinical exploration as a potential therapeutic for the treatment of multidrug-resistant, Gram-negative bacteria,” lead researcher James Kirby, M.D., said in a press release.

Streptothricin is a component of the compound nourseothricin, a natural byproduct of a soil fungus called Streptomyces noursei. Back in 1942, scientists Selman Waksman, Ph.D. and H. Boyd Woodruff, Ph.D.—best known for their seminal contributions to the discovery of the antibiotic streptomycin—published the first paper describing streptothricin’s activity. They noted that it was particularly powerful against E. coli and other gram-negative bacteria. The New York Times in 1944 described it as a potential “weapon against typhoid fever, dysentery and infection of wounds and burns.” Merck & Co. picked up the drug for its pipeline.

But a few years later, studies on the drug hinted at some disturbing side effects. A publication in the Proceedings of the Local Branches of the Society of American Bacteriologists noted that both oral and intravenous injections of streptothricin damaged the stomach, liver and kidneys of rabbits, ultimately killing them. Merck abandoned development after a small human trial showed that the drug caused irreversible kidney damage in patients. Data from the trial were never published.

More recently, research has found some errors in the older work. As it turned out, nourseothricin wasn’t composed of just one form of streptothricin, but several—all with distinct toxicity profiles. Early studies had used impure mixtures of different streptothricins at high doses in animals, resulting in misleading conclusions about their side effects. New experiments looking at each type individually found that streptothricin F was less likely to be toxic than the others.

Building on this work, Kirby's lab and colleagues from Case Western Reserve and Northeastern universities set out to thoroughly characterize streptothricin F’s activity, alongside a second form of the molecule called streptothricin D. A series of cell culture analysis examining the drugs’ activity against Enterobacterales—a group of Gram-negative bacteria that includes E. coli, salmonella and pneumonia-causing Klebsiella pneumoniae—showed that streptothricin D was six times more effective than streptothricin F. However, it was also more damaging to kidney cells at far lower doses. In contrast, streptothricin F didn’t cause toxicity even at high enough levels to knock out the Nevada strain of Carbapenem-resistant Enterobacterales, or CRE, a “nightmare” superbug that is resistant to all antibiotics currently in use.

The researchers next looked at streptothricin F’s activity in five mice infected with Nevada CRE. Their results mirrored what they had seen in the culture studies: A single dose of the drug at levels high enough to wipe out the bacteria completely in three of the five models didn’t harm them.

When the researchers took a closer look at streptothricin F’s mechanism of action, they found that it behaved differently from other antibiotics normally used to treat Gram-negative bacteria. Gram-negative antibiotics—called aminoglycosides—work by interrupting the work of an organelle called the ribosome, which facilitates protein synthesis by translating RNA into amino acids. They do this in a somewhat indirect way by altering how adjoining ribosomal RNA interacts with the part of the ribosome that “decodes” the bacteria’s RNA sequence, essentially causing a “misreading of the genetic blueprint,” Kirby explained in an email to Fierce Biotech Research.

Streptothricin F, on the other hand, takes no chances: It interrupts translation by inserting itself directly into the decoding center. While the end result is the same, this unique mechanism could make streptothricins a good choice when other aminoglycosides have failed, the researchers suggested.

Kirby’s team has already figured out how to synthesize streptothricin F from scratch and is now in the process of building new variants of the molecule.

“The goal will be to find variants with even better properties that could be advanced as therapeutics,” Kirby said.