AUTHOR=Du Han , Puri Sumant , McCall Andrew , Norris Hannah L. , Russo Thomas , Edgerton Mira 

TITLE=Human Salivary Protein Histatin 5 Has Potent Bactericidal Activity against ESKAPE Pathogens

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=7

YEAR=2017

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2017.00041

DOI=10.3389/fcimb.2017.00041

ISSN=2235-2988

ABSTRACT=<p>ESKAPE (<italic><underline>E</underline>nterococcus faecium</italic>, <italic><underline>S</underline>taphylococcus aureus</italic>, <italic><underline>K</underline>lebsiella pneumoniae</italic>, <italic><underline>A</underline>cinetobacter baumanni</italic>, <italic><underline>P</underline>seudomonas aeruginosa</italic>, and <italic><underline>E</underline>nterobacter</italic> species) pathogens have characteristic multiple-drug resistance and cause an increasing number of nosocomial infections worldwide. Peptide-based therapeutics to treat ESKAPE infections might be an alternative to conventional antibiotics. Histatin 5 (Hst 5) is a salivary cationic histidine-rich peptide produced only in humans and higher primates. It has high antifungal activity against <italic>Candida albicans</italic> through an energy-dependent, non-lytic process; but its bactericidal effects are less known. We found Hst 5 has bactericidal activity against <italic>S. aureus</italic> (60–70% killing) and <italic>A. baumannii</italic> (85–90% killing) in 10 and 100 mM sodium phosphate buffer (NaPB), while killing of &gt;99% of <italic>P. aeruginosa</italic>, 60–80% <italic>E. cloacae</italic> and 20–60% of <italic>E. faecium</italic> was found in 10 mM NaPB. Hst 5 killed 60% of biofilm cells of <italic>P. aeruginosa</italic>, but had reduced activity against biofilms of <italic>S. aureus</italic> and <italic>A. baumannii</italic>. Hst 5 killed 20% of <italic>K. pneumonia</italic> biofilm cells but not planktonic cells. Binding and uptake studies using FITC-labeled Hst 5 showed <italic>E. faecium and E. cloacae</italic> killing required Hst 5 internalization and was energy dependent, while bactericidal activity was rapid against <italic>P. aeruginosa</italic> and <italic>A. baumannii</italic> suggesting membrane disruption. Hst 5-mediated killing of <italic>S. aureus</italic> was both non-lytic and energy independent. Additionally, we found that spermidine conjugated Hst 5 (Hst5-Spd) had improved killing activity against <italic>E. faecium, E. cloacae</italic>, and <italic>A. baumannii</italic>. Hst 5 or its derivative has antibacterial activity against five out of six ESKAPE pathogens and may be an alternative treatment for these infections.</p>