Abstract
ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, and Enterobacter 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 Candida albicans through an energy-dependent, non-lytic process; but its bactericidal effects are less known. We found Hst 5 has bactericidal activity against S. aureus (60–70% killing) and A. baumannii (85–90% killing) in 10 and 100 mM sodium phosphate buffer (NaPB), while killing of >99% of P. aeruginosa, 60–80% E. cloacae and 20–60% of E. faecium was found in 10 mM NaPB. Hst 5 killed 60% of biofilm cells of P. aeruginosa, but had reduced activity against biofilms of S. aureus and A. baumannii. Hst 5 killed 20% of K. pneumonia biofilm cells but not planktonic cells. Binding and uptake studies using FITC-labeled Hst 5 showed E. faecium and E. cloacae killing required Hst 5 internalization and was energy dependent, while bactericidal activity was rapid against P. aeruginosa and A. baumannii suggesting membrane disruption. Hst 5-mediated killing of S. aureus was both non-lytic and energy independent. Additionally, we found that spermidine conjugated Hst 5 (Hst5-Spd) had improved killing activity against E. faecium, E. cloacae, and A. baumannii. Hst 5 or its derivative has antibacterial activity against five out of six ESKAPE pathogens and may be an alternative treatment for these infections.
Highlights
Bacteria causing nosocomial infections are increasingly becoming drug resistant, posing a serious health concern, especially in the Intensive Care Units (ICUs) and in surgical wards
Killing against some ESKAPE pathogens was lytic in nature; as for C. albicans, more than one mechanism of killing seems to be involved in Histatin 5 (Hst 5) activity against ESKAPE bacteria
In order to determine the bactericidal activity of Hst 5 against ESKAPE pathogens, six clinical isolates (Table 1) were tested using bactericidal assays to determine percent bacterial killing following incubation for 1 min, 1, and 5 h with 30 μM Hst 5
Summary
Bacteria causing nosocomial infections are increasingly becoming drug resistant, posing a serious health concern, especially in the Intensive Care Units (ICUs) and in surgical wards. Two-thirds of all healthcare-associated infections are ESKAPE related (Boucher et al, 2009), and many of these bacteria use multiple drug resistance mechanisms to “eskape” killing by both conventional and some newer generation antibiotics (Rice, 2008). E. faecium, K. pneumoniae, P. aeruginosa, and Enterobacter species are common residents of mucosal surfaces such as the oral cavity and the gastrointestinal tract (Keller et al, 1998; Podschun and Ullmann, 1998; Rice, 2010; Vu and Carvalho, 2011). Salivary innate immunity is the first line of defense against transient and pathobionts in the oral cavity (Salvatori et al, 2016) This is illustrated by the example of salivary Histatin 5 (Hst 5), a cationic protein that has strong fungicidal activity against C. albicans (Puri and Edgerton, 2014). Killing against some ESKAPE pathogens was lytic in nature; as for C. albicans, more than one mechanism of killing seems to be involved in Hst 5 activity against ESKAPE bacteria
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