Fatty Acid Comprising Lysine Conjugates: Anti-MRSA Agents That Display In Vivo Efficacy by Disrupting Biofilms with No Resistance Development.

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) has developed resistance to antibiotics of last resort such as vancomycin, linezolid, and daptomycin. Additionally, their biofilm forming capability has set an alarming situation in the treatment of bacterial infections. Herein we report the potency of fatty acid comprising lysine conjugates as novel anti-MRSA agents, which were not only capable of killing growing planktonic MRSA at low concentration (MIC = 3.1-6.3 μg/mL), but also displayed potent activity against nondividing stationary phase cells. Furthermore, the conjugates eradicated established biofilms of MRSA. The bactericidal activity of d-lysine conjugated tetradecanoyl analogue (D-LANA-14) is attributed to its membrane disruption against these metabolically distinct cells. In a mouse model of superficial skin infection, D-LANA-14 displayed potent in vivo anti-MRSA activity (2.7 and 3.9 Log reduction at 20 mg/kg and 40 mg/kg, respectively) without showing any skin toxicity even at 200 mg/kg of the compound exposure. Additionally, MRSA could not develop resistance against D-LANA-14 even after 18 subsequent passages, whereas the topical anti-MRSA antibiotic fusidic acid succumbed to rapid resistance development. Collectively, the results suggested that this new class of membrane targeting conjugates bear immense potential to treat MRSA infections over conventional antibiotic therapy.