posted on 2024-01-08, 14:05authored byKristen
G. Rivera, Kari J. Tanaka, Evan R. Buechel, Octavio Origel, Alistair Harrison, Kevin M. Mason, Heather W. Pinkett
Nontypeable Haemophilus influenzae (NTHi)
is an
opportunistic pathogen associated with respiratory diseases, including
otitis media and exacerbations of chronic obstructive pulmonary disease.
NTHi exhibits resistance to killing by host antimicrobial peptides
(AMPs) mediated by SapA, the substrate binding protein of the sensitivity to antimicrobial peptides (Sap) transporter. However, the specific mechanisms
by which SapA selectively binds various AMPs such as defensins and
cathelicidin are unknown. In this study, we report mutational analyses
of both defensin AMPs and the SapA binding pocket to define the specificity
of AMP recognition. Bactericidal assays revealed that NTHi lacking
SapA are more susceptible to human beta defensins and LL-37, while
remaining highly resistant to a human alpha defensin. In contrast
to homologues, our research underscores the distinct specificity of
NTHi SapA, which selectively recognizes and binds to peptides containing
the charged-hydrophobic motif PKE and RRY. These findings provide
valuable insight into the divergence of SapA among bacterial species
and NTHi SapA’s ability to selectively interact with specific
AMPs to mediate resistance.