Synthesis of tetrahydroquinoline derivatives re-sensitising methicillin-resistant Staphylococcus aureus to cefuroxime

Abstract

The methicillin-resistant Staphylococcus aureus (MRSA) infections are becoming more and more difficult to treat due to the reduced number of effective antibiotics available. The restoration of antibiotic sensitivity to drugresistant bacterial strains by antibiotic adjuvants is a potent strategy. Six tetrahydroquinoline derivatives (1)- (6) were synthesised based on a nucleophilic substitution reaction (S_N). The structures of the studied compounds were elucidated by spectroscopic methods. The cefuroxime adjuvant activity was investigated using the broth microdilution method against 3 MRSA strains: ATCC 33591 and two clinical strains (MRSA 29 and MRSA 84), which were isolated from human nasal cavities at Clinical Department 3, Ho Chi Minh City Hospital of Dermato Venereology, from June to September 2022 (in accordance with the Ethics Committee approval No. CAIN457F2342). The fractional inhibitory concentration (FIC) value of the potential combination was determined according to the checkerboard method. At a concentration below 1/4 of the minimum inhibitory concentration (MIC), compounds (1) and (3) demonstrated synergistic action with cefuroxime on two clinical strains, 29 and 84. Structure activity relationship study suggests that tetrahydroquinoline derivatives containing an ortho-substituted benzyl group have the ability to sensitise MRSA to cefuroxime.