Genomic and functional characterization of the respiratory commensal Haemophilus paraphrohaemolyticus reveals production of anti-streptococcal peptides

Abstract Background Antimicrobial resistance continues to threaten global health and fuels the urgent need for novel antimicrobial compounds with unique mechanisms of action. Antimicrobial peptides (AMPs) have emerged as a promising class of molecules due to their structural diversity, potent activity, and reduced propensity for development of resistance. Although multiple members of the human microbiota are known to produce AMPs, the biosynthetic potential of the respiratory tract microbiota remains underexplored. Results We report the characterization of Haemophilus paraphrohaemolyticus (HppH), an understudied bacterial commensal with low abundance isolated from the healthy human nasopharynx. We provide conclusive evidence that HppH represents a distinct species from H. parahaemolyticus by addressing inconsistencies in previous literature and offering supplementary genomic markers to enhance classification algorithms. Further, our findings identify HppH as a source of novel AMPs that selectively target Streptococcus spp., leaving other nasopharyngeal taxa largely unaffected. These AMPs retain a conserved genus specificity despite structural and physicochemical diversity, and were found to be non-cytotoxic towards human epithelial cells. Conclusions This work identifies HppH as a source of novel AMPs with genus-specific activity against Streptococcus spp., including the notorious pathogen Streptococcus pneumoniae . Production of these peptides likely reflects an evolved competitive strategy in dense mucosal communities and highlights low-abundance commensals as potential key modulators of microbial ecology. Beyond their potential for clinical translation, these AMPs might reveal novel and noncanonical mechanisms of action that could guide future design of pneumococcal-targeted antimicrobials.