Structure−Activity Relationships among Inhibitors of Acinetobacter baumannii and Klebsiella pneumoniae 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase (DXR/IspC) − A Promising Target for Antibiotic Development

Antimicrobial
resistance (AMR) is a critical global health crisis,
responsible for nearly 5 million deaths in 2019 and projected to impose
up to $100 trillion in economic costs by 2050. To address this threat,
we are developing new antibiotics targeting the methylerythritol phosphate
(MEP) pathway in Acinetobacter baumannii and Klebsiella pneumoniae, major
nosocomial pathogens. Our efforts focus on 1-deoxy-d-xylulose
5-phosphate reductoisomerase (IspC/DXR), the committed enzyme in MEP-mediated
isoprenoid biosynthesis and absent in humans, making it an attractive
therapeutic target. Natural products such as fosmidomycin (FOS) and
FR900098 (FR) inhibit IspC but exhibit poor bioavailability. To improve
drug-like properties, we synthesized FOS analogs and analyzed their
structure−activity relationships (SARs) against recombinant
Ab- and Kp-IspC, alongside in vitro susceptibility assays. The most
potent analogs, α,β-unsaturated compounds 4b and 16b, inhibited Ab-IspC (AbIspC) with IC50 values of 0.047 μM and 0.029 μM, and Kp-IspC (KpIspC)
with 0.194 μM and 0.054 μM, respectively. These showed
MICs of 64 μg/mL for A. baumannii and 512 μg/mL for K. pneumoniae. A prodrug series (1d−8d) demonstrated
enhanced activity, with compound 3d exhibiting MICs from
0.25 to 32 μg/mL against A. baumannii. X-ray crystallography of Ab-IspC with selected analogs (2b, 3b, 4b) at 2.0 Å resolution provides
structural insights to guide future IspC inhibitor optimization.