Modular antibiotic has improved potency

A modular compound acts as both a potent therapeutic and a radiotracer in mouse studies, researchers reported at the American Chemical Society Fall 2021 meeting. The compound consists of a gallium-bound complex attached via a cleavable linker to the antibiotic ciprofloxacin.

Bacteria scavenge iron from their hosts using iron-binding complexes called siderophores which they release into their surroundings and recapture. By linking siderophores to other compounds, the siderophores can be used to target drugs to bacteria. In addition, the siderophores can bind the chemically similar gallium instead. But unlike iron, which bacteria use in many redox reactions, gallium gums up cellular processes and ultimately kills the microbes. “The bacteria can’t really tell it’s gallium until they internalize it, and then they’re stuck with something that’s not redox active,” said Eszter Boros, a radiochemist at Stony Brook University.

Boros’s group previously reported a gallium-binding siderophore linked to the antibiotic ciprofloxacin, but its antimicrobial activity was less potent than they wanted (J. Med. Chem. 2019, DOI: 10.1021/acs.jmedchem.9b01388). To improve the potency, they added a serine linker that is enzymatically cleaved and releases the ciprofloxacin once inside the bacteria. The inspiration for the linker came from the natural product albomycin, which led the researchers to call their molecule galbofloxacin. The resulting construct was 4–10 times as effective at killing Staphylococcus aureus bacteria in cell culture experiments as ciprofloxacin alone. Boros presented her team’s research Monday in a session organized by the Division of Biological Chemistry; graduate student Apurva Pandey presented related work on Wednesday in the Division of Inorganic Chemistry.

Boros and coworkers are currently using ⁶⁷Ga, a long-lived isotope that can be used as a tracer in a method called single-photon emission computed tomography. Using the ⁶⁷Ga-labeled version of galbofloxacin in mice with S. aureus infections in muscle tissue, the researchers determined that the drug is primarily eliminated via urine but also accumulates in the infection site. Galbofloxacin was effective at doses at which ciprofloxacin alone was ineffective. Without gallium bound to the siderophore, the construct was less effective.

The team eventually wants to use ⁶⁸Ga, which has a shorter half-life and can be used in positron-emission tomography (PET), to use the compound to monitor the targeting of the antibiotic to an infection site in a host.

“Combining the short-lived ⁶⁷Ga and ⁶⁸Ga isotopes with siderophore-antibiotic conjugates is a clever approach to both track specific microbial infections in vivo and inhibit microbial growth. The initial results are quite exciting,” Alison Butler, an expert on siderophores at the University of California, Santa Barbara, told C&EN.

“The gallium approach throws a double punch by bringing in two antibiotic species that have different mechanisms of action: the conjugated antibiotic and the coordinated Ga(III),” Katherine J. Franz, a bioinorganic chemist at Duke University, told C&EN. “Going forward, it will be interesting to figure out which targets gallium is actually hitting inside the cell to have its effect.”