Abstract
The skin-associated microbiome plays an important role in general well-being and in a variety of treatable skin conditions. In this regard, endogenous antimicrobial peptides have both a direct and indirect role in determining the composition of the microbiota. We demonstrate here that certain small molecular species can amplify the antimicrobial potency of naturally occurring antimicrobial peptides. In this study, we have used niacinamide, a form of vitamin B3 naturally found in foods and widely used in cosmetic skincare products, and two of its structural analogs, to investigate their cooperativity with the human antimicrobial peptide LL37 on the bacterium Staphylococcus aureus. We observed a clear synergistic effect of niacinamide and, to some extent, N-methylnicotinamide, whereas isonicotinamide showed no significant cooperativity with LL37. Adaptively biased molecular dynamics simulations using simplified model membrane substrates and single peptides revealed that these molecules partition into the headgroup region of an anionic bilayer used to mimic the bacterial membrane. The simulated effects on the physical properties of the simulated model membrane are well correlated with experimental activity observed in real biological assays despite the simplicity of the model. In contrast, these molecules have little effect on zwitterionic bilayers that mimic a mammalian membrane. We conclude that niacinamide and N-methylnicotinamide can therefore potentiate the activity of host peptides by modulating the physical properties of the bacterial membrane, and to a lesser extent through direct interactions with the peptide. The level of cooperativity is strongly dependent on the detailed chemistry of the additive, suggesting an opportunity to fine-tune the behavior of host peptides.
Highlights
It is increasingly recognized that consumer well-being issues such as body malodor [1], dandruff [2], and conditions such as atopic dermatitis [3] are commonly associated with imbalances in the skin microbiome
Niacinamide has no effect on the recovery rate by itself, it increases the measured activity of LL37 compared with LL37 alone
We considered the interaction of a single antimicrobial peptides (AMPs), as exemplified by LL-37, with the POPC and POPG model membranes in the absence of additive molecules
Summary
It is increasingly recognized that consumer well-being issues such as body malodor [1], dandruff [2], and conditions such as atopic dermatitis [3] are commonly associated with imbalances in the skin microbiome. There is increasing recognition of the link between high Staphylococcus aureus populations and human skin conditions such as atopic dermatitis [3,4]. The human body has evolved defenses that modulate the human-associated microbiome through mechanisms including the production of antimicrobial peptides (AMPs)—a family of small, endogenously produced compounds released through sweat and sebaceous secretions [7]. They are a primitive form of defense mechanism and part of the innate immune system. Commensal and pathogenic staphylococci have been shown to activate different pathways in human keratinocytes, and commensals are able to amplify the innate immune response of keratinocytes to pathogens [11]
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