Propionibacterium acnes is a major contributing factor to acne vulgaris, a common disorder that is estimated to affect 9.4% of the global population. P. acnes colonize and proliferate within the pilosebaceous follicles causing the induction of local inflammatory response. This is mediated through the interaction of P. acnes with epidermal keratinocytes leading to activation of toll-like receptors and later resulting in the production and secretion of pro-inflammatory mediators. Isoprenylcysteine (IPC) small molecules represent a novel class of topically applied non-steroidal anti-inflammatories that can be used in consumer products and more potent derivatives for drug development to treat skin diseases. Here we report IPC derivative, SIG1459, downregulates these inflammatory signaling pathways and directly decreases P. acnes viability. Keratinocytes exposed to P. acnes, peptidoglycan and FSL-1 released pro-inflammatory cytokines and were inhibited by SIG1459 with IC50 values in the nanomolar range. In an in vitro growth inhibition assay of cultured P. acnes, SIG1459 outperformed anti-acne agents, benzoyl peroxide (BPO) and salicylic acid, exhibiting a strong MIC of 5 μM, MBC of 10 μM, and eradicating P. acnes biofilm formation (MBEC) at 21 μM. Lastly, 1% SIG1459 formulation in an 8-week single blind, vehicle controlled study was shown to significantly outperform 3% BPO using an investigator global assessment acne scale. SIG1459 (n= 35) resulted in a ~2-grade reduction after 8 weeks, while BPO (n=15) resulted in a 1.5-grade reduction. Moreover, SIG1459 was well tolerated with no adverse reactions (stinging, burning, dryness, staining), which as expected were reported by subjects in BPO arm of the study. These data demonstrate that phytyl-cysteine derived IPCs, SIG1459 represent a novel chemical-class that provides a dual modulating benefit to acne by limiting bacterial proliferation and inhibiting inflammation.

SIG-1459 and SIG-1460: Novel anti-acne isoprenylcysteine compounds