Low-Generation Cationic Phosphorus Dendrimers: Novel Approach to Tackle Drug-Resistant S. aureus In Vitro and In Vivo

The incessant, global increase in antimicrobial resistance(AMR)is a very big challenge for healthcare systems. AMR is predicted togrow at an alarming pace, with a dramatic increase in morbidity, mortality,and a 100 trillion US$ loss to the global economy by 2050. The mortalityrate caused by methicillin-resistant S. aureus (MRSA) is much higher as compared to infections caused by drug-susceptible S. aureus. Additionally, there is a bigpaucity of therapeutics available for treatment of serious infectionscaused by MRSA. Thus, the discovery and development of novel therapiesis an urgent, unmet medical need. In this context, we synthesizedAE4G0, a low-generation cationic-phosphorus dendrimer expressing potentantimicrobial activity against S. aureus and Enterococcus sp., and demonstrating a broadselectivity index against eukaryotic cells. AE4G0 exhibits concentration-dependent,bactericidal activity and synergizes with gentamicin, especially againstgentamicin-resistant MRSA NRS119. Fluorescence and scanning electronmicroscopy demonstrate that treatment with AE4G0 led to the utterdestruction of S. aureus ATCC 29213without inducing resistance, despite repeated exposure. When tested in vivo, AE4G0 demonstrates significant efficacy against S. aureus ATCC 29213, alone and in combinationwith gentamicin against gentamicin-resistant S. aureus NRS119 in the murine skin model of infection. Takentogether, AE4G0 demonstrates the potential to be translated as a noveltherapeutic option for the treatment of topical, drug-resistant S. aureus infections.