SAAP-148 and halicin exhibit synergistic antimicrobial activity against antimicrobial-resistant bacteria in skin but not airway epithelial culture models.

BACKGROUND: The escalating global threat of antimicrobial resistance (AMR) necessitates the development of novel antimicrobial agents, innovative strategies, and representative infection models to combat AMR bacterial infections. Host defence peptides (HDPs) and their derivatives have been proposed as complements to conventional antibiotics due to their antibacterial activity and modulation of the immune response. OBJECTIVES: This study investigated the novel use of the HDP-derived synthetic antibacterial and anti-biofilm peptide (SAAP)-148 as a pretreatment in epithelial tissue models to prevent colonization by AMR bacteria. The combined activities of SAAP-148 pretreatment with post-infection halicin to treat infections were also explored. METHODS: Employing cultured human skin equivalents (HSEs) and primary bronchial epithelial cells (PBECs) as models of tissue infection, we examined the prophylactic and therapeutic effects of SAAP-148, both singularly and in combination with the repurposed antibiotic halicin, against AMR bacteria. We additionally interrogated the response of HSE and PBEC cultures to SAAP-148 treatment via confocal microscopy and quantitative PCR of native HDPs and inflammatory cytokine genes. RESULTS: Our findings demonstrated that pretreatment with SAAP-148 significantly reduces colonization of HSEs and PBECs by AMRand. Confocal microscopy revealed differential uptake and localization of SAAP-148 in these tissues, correlating with its distinct activity in these tissues. SAAP-148 exposure temporarily increased expression of the HDPs cathelicidin () and β-defensin 1 (), and the cytokine IL-8 (), which did not correlate with the transient antibacterial activity observed. Sequential treatment with SAAP-148 prior to infection with AMRand post-infection halicin treatment demonstrated synergistic activity in HSEs, whereas this combined activity was indifferent in PBEC cultures. CONCLUSIONS: These results support SAAP-148 as a candidate for pre-infection prophylaxis and synergistic antibiotic therapy with halicin in skin, broadening the potential of both agents to address AMR bacterial infection.