Title:Recent Advances in the Development of Undecaprenyl Pyrophosphate Synthase Inhibitors as Potential Antibacterials
Volume: 23
Issue: 5
Author(s): Marko Jukic, Kaja Rozman and Stanislav Gobec
Affiliation:
Keywords:
Undecaprenyl pyrophosphate synthase, isoprenoid, peptidoglycan, cell wall, UppS inhibitors, antibacterials,
antibiotics.
Abstract: Expanding antibiotic use in clinical practice and emergence of bacterial resistance are fueling research
efforts for the development of novel antibacterials. Underexploited or completely novel mechanistic
approaches and biological targets are of especial interest. Undecaprenyl pyrophosphate synthase (UppS) is an
essential enzyme in the biosynthesis of the bacterial cell wall. Although UppS is a validated target, no selective
inhibitors occur in materia medica. Nevertheless, several native substrate analogues have been reported
and used in enzyme kinetics studies or as pharmacological probes. The majority of small-molecule UppS inhibitors
belong to the well-known class of bisphosphonates that are primarily used for treatment of bone resorption
disorders. The most potent compound of this class has an IC50 of 0.59 µM. Inherently, the selectivity
and suitability of such compounds for antimicrobial drug design can be questioned. Therefore, highthroughput
and virtual screenings for non-bisphosphonate inhibitors were performed, and nanomolar inhibitors
of UppS were identified, some with antimicrobial activities towards clinically relevant strains. The reported
scaffolds belong to tetramic and tetronic acids with IC50 in the 100-nM range, and to dihydropyridines
with IC50 down to 40 nM, all with antibacterial activity. Aryl-diketo acids are also potent inhibitors with
MRSA antimicrobial activity, with the allosteric inhibitor methylisoxazole-4-carboxamide (IC50, 50 nM) active
on several pathogenic Streptococcus pneumoniae strains. Clomiphene is a well-known oestrogen receptor
modulator, and it has been reported to inhibit UppS. Although conclusions on the structure activity relationships
cannot be drawn from all these data, these compound series represent an important contribution to the
field of antibiotics.