1198 VOLUME 22| NUMBER 11| NOVEMBER 2016 NATURE MEDICINE clinical utility against select gram-negative bacteria. The company’s lead potentiator candidate, SPR741, has been tested in mouse, rat and primate models in conjunction with the macrolide clarithromycin, as well as with rifampicin. Because SPR741 on its own has no antibacterial activity, this potentiator and the companion antibiotic have been administered so far as two separate formulations. But Pucci says that the company might consider combining the two agents into a single drug. In one poster presented at the June 2016 general meeting of the American Society for Microbiology (ASM), Spero demonstrated that the number of bacteria in mice injected with one strain of Escherichia coli was reduced by more than 100-fold after being treated with a combination of SPR741 and clarithromycin. By contrast, treatment with clarithromycin alone did not reduce the burden of bacteria—instead, it resulted in more than a tenfold growth, which suggests that the combination approach might have value. The company plans to file an investigational new drug application with the FDA by the end of this year to begin testing the treatment in humans.

In addition to accelerating antibiotic expansion, Pucci says, the administration of potentiators in combination with existing antibiotics has safety advantages as well. Evidence from animal studies presented at conference poster sessions suggests that Spero’s potentiator candidate, as an analog of a polymyxins, is less toxic than current polymyxins, which can cause nerve injury and kidney damage and thus are not used as potentiators.