Abstract:
Ubiquitous, mobile, opportunistic pathogen named Pseudomonas aeruginosa which is gram
negative is well-known for causing a plethora of nosocomial infections. It poses serious threats
in immunocompromised hosts and is very difficult to treat in patients. It has become extremely
difficult to eradicate it from hospitals due to its resistance towards antibiotics and disinfectants.
Therefore, there is a dire need of innovative therapies to treat the multi-drug resistant bacterium.
This pathogen easily develops biofilm which shows prominent resistance to antibiotics and this
is why WHO has classified it as one of the ESKAPE infections. PAO1 has been of good use
in understanding the biology of pseudomonas and is helpful in assessing the novel treatment.
We used a rational drug design approach, in this study, to inhibit quorum sensing pathway, rhl,
in pseudomonas aeruginosa PAO1 which is responsible for biofilm formation and rhamnolipid
synthesis. We did so by suggesting inhibitory molecules against the two enzymes,
Rhamnosyltransferase subunit A which is encoded by the gene rhlA and Regulatory protein
RHLR encoded by the gene rhlR. Homology modelling was performed to obtain the 3D
structure of the target proteins which were then refined. Various tools such as ERRAT and
Ramachandran plot were used to assess the quality of the protein. Seventeen compounds for
rhlA and eight for rhlR were extracted using Chembl and PubChem. Castp was used to analyze
the ligand binding domain. Site specific docking was carried out to find the ligand showing the
most negative binding affinity value with the enzyme that has been targeted. Two compounds
against each protein were selected with the most negative binding affinity. These compounds
were then checked for ADMET properties and bioavailability. Molecular dynamic simulation
results further calculated the stability of the complex. The compounds explored are expected
to be an effective drug against the target proteins in blocking the rhamnolipid synthesis and
biofilm formation. Detailed laboratory experimentation is always necessary to bridge the gap
between wet and dry laboratory studies and to ensure the validity of the obtained results.
