Skin microbiome-editing with novel antibiotics towards lower mosquito attraction

With every mosquito bite comes a potential threat as demonstrated by the countless vector-borne diseases like malaria, dengue and Zika virus affecting the global population. This reality yearly claims millions of lives worldwide, numbers that only rise due to climate change and increased travelling, highlighting the urgent need for effective strategies to overcome this. The use of DEET remains the main method to repel mosquitoes but its long-term use raises concerns due to skin irritation and potential health risks among others. Alternative strategies are being explored to address these limitations. Recent studies have shown that the skin microbiome plays a significant role in the attraction of mosquitoes. More specifically, skin bacteria are able to convert skin compounds like lipids and amino acids into volatile organic compounds (VOCs), serving as attractants/repellents for mosquitoes. Among individuals, variation in the skin microbiome composition influences their odor profile and subsequently makes them more or less attractive to mosquitoes. The skin microbiome of highly attractive individuals contains a greater abundance of Staphylococcus spp., including Staphylococcus epidermidis, one of the most abundant commensal bacteria on the human skin. Modulating skin odor by reducing the abundance of S. epidermidis can be a promising approach to decrease mosquito attraction due to reduced production of mosquito-attracting VOCs. We therefore investigated the use of bacteriophage-encoded (endo)lysins to selectively reduce the presence of Staphylococcus spp. and S. epidermidis. Endolysins are proteins able to selectively break down the peptidoglycan layer of bacterial cells. Unlike broad-spectrum antimicrobials, endolysins may exhibit a remarkable specificity for their target(s), leaving the non-targeted (beneficial) skin microbiota intact, which makes them a promising microbiome modulator in our context. Initially we focused on the expression of naturally occurring endolysins which specifically target staphylococci. When assessing their bacteriolytic and bactericidal activity with turbidity reduction and killing assays respectively, we observed a delayed activity. To develop lysins with potentially improved efficiency and specificity we turned to synthetically engineered endolysins using the VersaTile platform. This is a high-throughput DNA assembly method that can be used for the rapid construction of thousands of different lysin variants in a combinatorial way. By using an iterative in vitro screening procedure, preliminary lysin candidates were selected and further characterized. Identifying an optimal lysin candidate able to lower the abundance of staphylococci could significantly decrease the attractiveness towards mosquitoes and provide a novel and effective solution to the persistent challenge of preventing mosquito-borne diseases.