Targeting PolyP Accumulation in E. coli Using PPK Inhibitors to Disrupt Antibiotic Resistance Mechanisms
DOI:
https://doi.org/10.18192/osurj.v5i2.8075Abstract
Polyphosphates (polyP) are linear chains of inorganic phosphate (Pi) that are highly conserved
among various organisms. In Escherichia coli, PolyP is synthesized primarily by polyphosphate
kinase 1 (PPK1, encoded by ppk) in response to environmental stressors. PolyP contributes to
bacterial survival by regulating biofilm formation, stress responses, and antibiotic resistance.
The mechanisms controlling PolyP accumulation and its effects on bacterial physiology and
resistance remain incompletely understood. Notably, PPK-mediated PolyP accumulation
modulates lipopolysaccharide (LPS) structure, contributing to polymyxin resistance during
starvation stress.
Compared to the wild-type (WT) strain, Δppk mutants exhibit significant growth defects when
transferred to MOPS minimal medium, whereas WT cells show minimal growth defects under
this nutrient-starved condition. This differential phenotype serves as a useful readout for
evaluating PPK inhibitors. Deletion of the low-affinity phosphate transporter PitA rescues the
growth defect of Δppk mutants; this interaction is still under investigation.
Different repurposed drugs act as PPK inhibitors, including mesalamine (widely used to treat
inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis) and gallein
(originally a histological dye and Gβγ inhibitor). Both compounds inhibit bacterial PPK enzymes.
In this study, we evaluated the effects of mesalamine and gallein on the growth phenotypes of
four E. coli strains (WT, Δppk, ΔpitA, and the double mutant ΔppkΔpitA) under nutrient-starved
conditions (MOPS minimal medium). Both inhibitors produced only mild, non-specific growth
impairment across strains, and the result was not improved by higher concentrations of drug
use. Gallein treatment showed no clear effect on PolyP levels, and polyP levels following
mesalamine treatment has not been evaluated. These preliminary results highlighted the need
for optimized drug delivery or alternative inhibition strategies to fully recapitulate the phenotypes
of genetic PolyP deficiency.
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