5-(3, 4-methylenedioxyphenyl)-4-ethyl-2E, 4E-pentadienoic acid piperidide as MdeA efflux pump inhibitor of Staphylococcus aureus

Abstract

The analogue of piperine 5-(3,4-methylenedioxyphenyl)-4-ethyl-2E,4E-pentadienoic acid piperidide (IIIM-1133), was evaluated in this in combination with pseudomonic acid A, commonly known as mupirocin against of S. aureus including Methicillin Resistant S. aureus (MRSA). Initial screening of compound revealed an increase in the potency of mupirocin, with a reduction in the minimum inhibitory concentration (MIC) values from 0.25 μg/mL to 0.06 μg/mL in case of wild type and MRSA strains of S. aureus and from 256 μg/mL to 32 μg/mL in mup^r-1 strain. The combination decreased the mutation frequency against mupirocin in wild-type S. aureus. The demonstrated ability of IIIM-1133 to suppress ethidium bromide efflux in MdeA-overexpressing S. aureus Mup^r-1 substantiated its effectiveness as an efflux pump inhibitor. Docking studies demonstrated that IIIM-1133 binds strongly in the substrate pocket of the MdeA efflux pump, highlighting its potential as an efflux pump inhibitor. IIIM-1133 alone and in combination with mupirocin was found to be nontoxic when tested on RAW 264.7 cells lines. A topical formulation of 2 % mupirocin with 0.5 % IIIM-1133 showed better efficacy in reducing the bacterial load in the infected site and sterilizing the infected patch. Furthermore, the formulation revealed better tissue healing potential with an anti-inflammatory activity by suppressing Il-6 and TNF-α. This formulation exhibited better efficacy than markedly available 2 % mupirocin.