Abstract:
Development of small chemical-molecule inhibitors of quorum sensing regulator: a novel treatment for
antibiotic resistant bacterial infections submitted for R21: P. aeruginosa (Pa), opportunistic pathogens that
are substantial health threat to nosocomial infections, especially for immunocompromised patients with
burns, cancer, and patients with cystic fibrosis or AIDS. Pa and other pathogens develop antibiotic resistance
mainly through quorum sensing (QS) mechanism and >23,000 deaths per annum are reported. To address
this problem, recently molecule (M64) was discovered that target the Pseudomonas multiple virulence factor
regulator (MvfR). This pharmacologically validated target in infection models exhibits serious solubility issues,
less exposure and mutagenic side effects. Thus, there is an urgent need for the development of novel drugs
that addresses MvfR target, and this is a specific focus of current research proposal. MvfR QS system of Pa
is pivotal for development of antibiotic resistant. It controls expression of a variety of bacterial virulence factors
that are associated with pathogenicity and to elicit drug resistance to traditional antibiotics. Our
pharmacophore docking studies in MvfR-ligand (agonist or antagonist) bound X-ray structures suggested
that, pharmacophore docking and structure activity relationship (SAR) will enable to develop novel and potent
MvfR inhibitors with better pharmacokinetic (PK) than current inhibitors. Building upon preliminary work from
three participating laboratories (Dr. Jadhav, Dr. Deziel and Dr. Diggle), we will use, pharmacophore docking,
and structure-based rational drug design to develop small molecule inhibitors of MvfR. MvfR has been
validated as antibacterial target in a mouse model using M64 and other analogues, but more potent drug with
better PK are required to exploit detail therapeutic potential of this target. In this R21 grant, we will design
and synthesize novel, structurally similar and dissimilar inhibitors using a docking and SAR strategy that has
been applied successfully to related targets in the Dr. Jadhav’s lab. Compounds from SAR will be evaluated
for their activities in HTS at single dose of 1 uM for pyocyanin inhibition that has been established in the Dr.
Deziel’s lab. We will then optimize the in vitro biochemical, cellular, selective pharmacokinetic properties of
the inhibitors to develop lead compounds. Efficacy of lead compounds will be tested for Pa virulence in ex
vivo Pig Lung (EVPL) infection model developed by Dr. Diggle’s Lab. This multidisciplinary collaboration
comprises the necessary combined expertise in medicinal chemistry, computational and biochemistry,
pharmacology, and microbiology. Our long- term goals are to develop advanced drug candidates for further
preclinical and clinical evaluations as novel antibiotics to combat antibiotic resistant P. aeruginosa and other
pathogenic Gram-negative bacteria.
