Deploying Soft Drugs in the Fight against MRSA with Detailed Biological Evaluation of 4-(n-Alkoxy)-phenoxy Betaine Amphiphiles Active against MDR Staphylococcus aureus and Enterococcus sp.

Antimicrobial resistance is one of the major challenges faced worldwide by the healthcare systems, negatively impinging upon global health and the economy. Methicillin-resistant Staphylococcus aureus (MRSA), which causes skin and mucosal infections, contributes to 64% more death as compared to drug-susceptible infections, which forces researchers to continuously search for new antimicrobials. In this context, we report the synthesis and antimicrobial activity of novel amphiphilic cationic 1,4-alkoxy-phenol derivatives. We synthesized a library of 12 small amphiphilic compounds containing an l-carnitine or betaine as a cationic headgroup and investigated the effect of the hydrocarbon chain length on the antimicrobial activity against a critical and high-priority human pathogen panel. The amphiphilic molecules with a C-10 alkyl chain length (2f and 3f) showed substantial antibacterial activity at very low concentrations (1–2 μg/mL). Based on low cytotoxicity (Selectivity Index 20) and MIC of amphiphilic series, we further explored 3f, which shows a concentration-dependent bactericidal activity at 10× MIC; it completely wiped out S. aureus ATCC 29213 at 1 h, and when combined with daptomycin, it showed a reduction of ∼6 log₁₀ CFU/mL as compared with untreated at 24 h against S. aureus ATCC 29213 even at 1× MICs. In order to discriminate between nonspecificity in detergent-like action, we further determined the CMC of 3f and found that it is 36-fold higher than MIC, thus further emphasizing its specificity. 3f exhibits biofilm eradication properties that are comparable to levofloxacin and better than vancomycin while intracellular killing efficacy of 3f was found to be better than vancomycin and similar to levofloxacin. When tested in vivo in the murine skin infection model, it shows activity comparable to fusidic acid as it reduces ∼2 log₁₀ CFU/g compared with that untreated. Considering the potent antimicrobial properties of 3f, we hypothesize that it opens up a new avenue for discovery and development of novel antimicrobials active against MDR S. aureus and Enterococcus sp.