Aim and objective: Overexpression of efflux pumps belonging to the
Resistance Nodulation cell Division (RND) family is the most important intrinsic
resistance mechanism of Pseudomonas aeruginosa. Hence, it is imperative to
identify suitable efflux pump inhibitors (EPI) that can lead to increased intracellular
concentration of antibiotics by blocking the pump. This study was undertaken to
identify a putative plant based efflux pump inhibitor for RND efflux pump of P.
Material and method: Using molecular docking approach, 328 secondary plant
metabolites have been screened for their inhibitory activity against cytoplasmic
exporter protein MexB of MexAB-OprM efflux pump of P. aeruginosa. After the
initial in silico screening, the shortlisted compounds were subjected to in vitro test for efflux pump
inhibitory activity using double disc synergy test. A combinatorial library of 1000 molecules was
generated from active p-coumaric acid and docked with MexB protein to find a suitable EPI with better
binding efficacy compared to the p-coumaric acid.
Results: Preliminary screening resulted in five plant-based natural products with significant docking
score and were subsequently subjected to double disc synergy test. p-Coumaric acid , amongst the five,
was found to potentiate activity of ciprofloxacin in MexAB-OprM overexpressing P. aeruginosa strain.
Library compound 482, i.e 4-(4-((Z)-2-carboxy-2-((Z)-2,3-dihydrobenzo[e][1,4]diazepin-1-yl)-1-(4-
hydroxyphenyl)vinylamino) phenylsulfonamido)-2-hydroxybenzoic acid, a derivative of p-coumaric
acid exhibited the highest docking score of -42.1030 Kcal/mol, which was much higher than parent
compound (-17.9403 Kcal/mol) and also known EPI, MC-207,110 (-28.0960 Kcal/mol).
Conclusion: p-Coumaric acid and its derivative, 4-(4-((Z)-2-carboxy-2-((Z)-2,3-dihydrobenzo[e][1,4]
diazepin-1-yl)-1-(4-hydroxyphenyl)vinylamino)phenylsulfonamido)-2-hydroxybenzoic acid may be
used as potential lead molecules for effective RND efflux pump inhibition in P. aeruginosa.