Ferulic acid derivative inhibits NorA efflux and in combination with ciprofloxacin curtails growth of MRSA in vitro and in vivo

Publication date: Available online 15 August 2018Source: Microbial PathogenesisAuthor(s): Niranjana Sri Sundarmoorthy, Karthik Mithra, Jayasankari Senthil Ganesh, Himesh Makala, Robert Lotha, Shamprasad R. Bhanuvalli, Venkatasubramanian Ulaganathan, Vaidehi Thirunaukarasu, Aravind Sivasubramanian, Saisubramanian NagarajanAbstractA series of ferulic acid (FA) derivatives were synthesized and evaluated for its ability to inhibit NorA efflux in methicillin resistant Staphylococcus aureus (MRSA), by in silico docking analysis. Based on prediction from glide scores and ability to reduce EtBr MIC, two of the ten derivatives S3- [4-((E)-2-(diethylcarbamoyl)vinyl)-2-methoxyphenyl acetate] and S6- [(E)-methyl 3-(4-((p-tolylcarbamoyl)methoxy)-3-methoxyphenyl)acrylate] were chosen as putative efflux pump inhibitors (EPI's). Time dependent accumulation studies revealed that S6 caused enhanced EtBr accumulation relative to standard NorA efflux inhibitor reserpine in clinical isolate of MRSA (CIMRSA) and in NorA overexpressed strain of S. aureus (SA1199B). S6 also exhibited synergy with Ciprofloxacin (CPX) against NorA overexpressed strain (SA1199B) of S. aureus but not in NorA knock out strain (K1758). MIC reversal studies showed that S3 in CIMRSA and S6 in NorA overexpressed strain of S. aureus (SA1199B), caused a 4 fold reduction in ciprofloxacin (CPX) MIC. In vitro time kill studies revealed that both S3 and S6 with sub MIC of CPX caused a significant 4 log CFU decline in CIMRSA. A dec...
Source: Microbial Pathogenesis - Category: Infectious Diseases Source Type: research