SIG1459: A novel phytyl‐cysteine derived TLR2 modulator with in vitro and clinical anti‐acne activity

Abstract

Cutibacterium (formerly Propionibacterium acnes) is a major contributor to the pathogenesis of acne. C. acnes initiates an innate immune response in keratinocytes via recognition and activation of toll-like receptor-2 (TLR2), a key step in comedogenesis. Tetramethyl-hexadecenyl-cysteine-formylprolinate (SIG1459), a novel anti-acne isoprenylcysteine (IPC) small molecule, is shown in this study to have direct antibacterial activity and inhibit TLR2 inflammatory signalling. In vitro antibacterial activity of SIG1459 against C. acnes was established demonstrating minimal inhibitory concentration (MIC = 8.5 μmol\L), minimal bactericidal concentration (MBC = 16.1 μmol\L) and minimal biofilm eradication concentration (MBEC = 12.5 μmol\L). To assess SIG1459's anti-inflammatory activity, human keratinocytes were exposed to C. acnes and different TLR2 ligands (peptidoglycan, FSL-1, Pam3CSK4) that induce pro-inflammatory cytokine IL-8 and IL-1α production. Results demonstrate SIG1459 inhibits TLR2-induced IL-8 release from TLR2/TLR2 (IC = 0.086 μmol\L), TLR2/6 (IC = 0.209 μmol\L) and IL-1α from TLR2/TLR2 (IC = 0.050 μmol\L). To assess the safety and in vivo anti-acne activity of SIG1459, a vehicle controlled clinical study was conducted applying 1% SIG1459 topically (n = 35 subjects) in a head-to-head comparison against 3% BPO (n = 15 subjects). Utilizing the Investigator Global Assessment scale for acne as primary endpoint, results demonstrate 1% SIG1459 significantly outperformed 3% BPO over 8 weeks, resulting in 79% improvement as compared to 56% for BPO. Additionally, 1% SIG1459 was well tolerated. Thus, SIG1459 and phytyl IPC compounds represent a novel anti-acne technology that provides a safe dual modulating benefit by killing C. acnes and reducing the inflammation it triggers via TLR2 signalling.

Micro-Current Stimulation Suppresses Inflammatory Responses in Peptidoglycan-Treated Raw 264.7 Macrophages and Propionibacterium acnes-Induced Skin Inflammation via TLR2/NF-κB Signaling Pathway

“…P. acnes , as well as peptidoglycan (PGN) from Gram-positive bacteria, has been mainly used for the efficacy of various drugs or treatment in acne-induced inflammatory reactions [ 22 , 23 , 24 , 25 , 26 ]. P. acnes plays a crucial role in the inflammatory phase of acne through activating innate immunity via toll-like receptor 2 (TLR2), one member of transmembrane proteins that respond to particular pathogen-associated molecular patterns (PAMPs) such as bacterial cell wall components [ 27 , 28 , 29 ].…”

Salicylic acid treats acne vulgaris by suppressing AMPK/SREBP1 pathway in sebocytes

“…Four major pathogenic factors play a vital role in the development of acne: excessive secretion of sebum, hyperkeratinization of follicular keratinocytes, colonization of Propionibacterium acnes ( P acnes ) and inflammatory events . Acne is common in adolescents and young adults; however, it can affect most age groups, even children and middle‐aged . In an Asian community‐based study, the highest prevalence was among 15‐ to 20‐year‐olds …”

Auriculotherapy Modulates Macrophage Polarization to Reduce Inflammatory Response in a Rat Model of Acne

“…Acne vulgaris (AV) is a chronic inflammatory disease [ 16 ]. Propionibacterium acnes plays an important role in the pathogenesis of acne [ 17 ]. Therefore, in the present study, we used a P. acnes bacterial solution injected subcutaneously into the right ear of rats to induce acne.…”