Inhibition of the Yersinia pestis Methylerythritol Phosphate Pathway of Isoprenoid Biosynthesis by α-Phenyl-Substituted Reverse Fosmidomycin Analogues

Abstract

Fosmidomycin inhibits IspC (1-deoxy-D-xylulose 5-phosphate reductoisomerase), the first committed enzyme in the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis. The MEP pathway of isoprenoid biosynthesis is essential to the causative agent of the plague, Yersinia pestis, and is entirely distinct from the corresponding mammalian pathway. To further drug development, we established structure−activity relationships of fosmidomycin analogues by assessing a suite of 17 α-phenylsubstituted reverse derivatives of fosmidomycin against Y. pestis IspC. Several of these compounds showed increased potency over fosmidomycin with IC 50 values in the nanomolar range. Additionally, we performed antimicrobial susceptibility testing with Y. pestis A1122 (YpA1122). The bacteria were susceptible to several compounds with minimal inhibitory concentration (MIC) values ranging from 128 to 512 μg/mL; a correlation between the IC 50 and MIC values was observed.

The Multifaceted MEP Pathway: Towards New Therapeutic Perspectives

“…Indeed, compound 16 ( Figure 2 ) exhibited IC 50 values almost two orders of magnitude lower than fosmidomycin with respect to the enzymes of E. coli and M. tuberculosis [ 43 ]. This compound also inhibited the DXR of Y. pestis with a potency about three times higher than that of fosmidomycin, and it suppressed the growth of this pathogen with a similar efficiency [ 44 ].…”

Sonochemical Assisted Leaching of Aluminium Oxide Nanoparticles from Domestic Aluminium Wastes as Non-Toxic Electrode Material for Energy Storage Application

“…Briefly, 50 mg of Al 2 O 3 NP's were dispersed by continuous sonication for 20 min in 10 ml of deionized water to achieve 500 μg ml −1 of suspension. 36 Simultaneously, test organisms were prepared in nutrient broth with 1 × 10 6 cells ml −1 and distributed over 96 well plates. Additionally two fold, serially diluted Al 2 O 3 NP's were added in all the wells and were allowed to grow.…”

Inhibition of DXR in the MEP pathway with lipophilic N-alkoxyaryl FR900098 analogs

“…We and others have synthesized analogs in which all of these moieties were modified, and the resulting analogs were tested for activity against Mtb and Pf . 33–53 Additionally, these compounds (for example, 3 and 4 ) often have better cell permeability due to increased lipophilicity. 29,54…”