Infections of intact and damaged skin barriers and keratin are frequently associated with complex biofilm communities containing bacteria and fungi, yet there are limited options for successful management. This study intended to focus on the utility of some novel proprietary lactam molecules, quorum sensing (QS)–derived halogenated furanones, which act to block the QS pathway, against key fungal pathogens of the skin (Candida albicans, Malassezia furfur and Microsporum gypseum). Moreover, we aimed to assess how these actives performed against complex interkingdom biofilms in a clinically relevant model. Two lactam derivatives were tested against a panel of important fungal pathogens and then quantitatively assessed against simple and increasingly complex interkingdom biofilm models on polystyrene coverslips and a novel keratin hydrogel system. The lactams were shown to be effective against a wide range of fungal species in the planktonic and biofilm forms, with no ability to regrow. The fungal component of the multispecies biofilm models was significantly reduced with lactam treatment. Lactam treatment was also comparably effective compared to the non-prescription topical antifungal ‘Lamisil’ against C. albicans early and late biofilms. This study highlights the effectiveness of lactams as a novel antimicrobial for the management of the polymicrobial and interkingdom multispecies biofilms.