BPH-1358 is a Dual FPPS and UPPS Inhibitor

As we all know, Farnesyl diphosphate synthase(FPPS) is an important drug target for bone resorption, cancer, and some infectious diseases. Besides, FPPS and undecaprenyl diphosphate synthase (UPPS) involves in bacterial cell wall biosynthesis.
The two targets inhibition can lead to “resistance reversal” in resistant bacteria therapy. And since humans do not possess a UPPS gene, it is important to find an FPPS or UPPS inhibitor.

BPH-1358 (NSC50460) is a lipophilic FPPS inhibitor(IC50=2 nM), it also has potent activity against human FPPS and is hydrophobic, enabling soft tissue penetration. Besides, this compound inhibits UPPS activity with an IC50 value of 100 nM.

In this text, we will introduce BPH-1358 in vitro and Vivo for its anti-bacterial activity.

First of all, in vitro, this compound has an inhibitory effect on the enzyme from E.coli UPPS, S.aureus UPPS (IC50s=0.11 μM). Moreover, cell growth inhibition results show that BPH-1358 is against two bacteria, the Gram-negative E. coli, and the Gram-positive, S. aureus. It shows <1  µM activity against both organisms.

Nextly, in vivo.Fractional inhibitory concentration index (FICI) is the fractional inhibitory concentration of drugs.
FICI values <0.5 represent synergism, and ≥2 represents drug antagonism. BPH displays strongly synergistic activity (FICI = 0.25) with methicillin in an MRSA strain otherwise resistant to the antibiotic. Thus represents strong synergism, opening up the probability of restoring drug sensitivity in drug-resistant strains.

Benzoic acids, as well as tetratomic acids, have strong activity against bacteria. However, there have been no previous reports of in vivo activity, due to strong binding to plasma proteins.

In a mouse model of infection with the USA200 Sanger 252 (MRSA) strain of S. aureus. mice treated postinfection with vehicle only all died, whereas BPH has no apparent adverse reactions on mice.

In conclusion, BPH-1358 inhibits UPPS and FPPS in vitro and in vivo. It also shows strongly synergistic activity (FICI = 0.25) with methicillin in an MRSA strain otherwise resistant to the antibiotic.
These results open up additional routes to anti-infective therapies targeting bacterial isoprenoid biosynthesis. Targeting DNA and lipid membrane structure has the potential for bacterial infection treatment.

Liu YL, et al. ACS Med Chem Lett. 2015 Jan 29;6(3):349-54.