Amino Acids (2017) 49:1647–1651
Transdermally administered proline–arginine‑rich host defense
peptides show systemic efﬁcacy in a lethal mouse bacteremia
· Andrea Horvath
· Dora Szabo
· Laszlo Otvos Jr.
Received: 25 April 2017 / Accepted: 21 June 2017 / Published online: 29 June 2017
© Springer-Verlag GmbH Austria 2017
for the treatment of local, predominantly in cutaneous
infections (Steinstraesser et al. 2012; Heunis et al. 2013).
We managed to reduce systemic toxicity and increase the
therapeutic index of proline-rich HDP when moving from
intravenous to intramuscular administration (Ostorhazi
et al. 2010, 2011). The potential reasons for the improve-
ments are targeting intramuscular macrophages as effec-
tors and providing a depot for slow release into the circula-
tion (Mishell 1996). The goal of the current study was to
identify another, potentially not invasive and so far unu-
tilized, administration mode of HDP that allows systemic
efﬁcacy without directly injecting the peptides into the
blood stream. Our selection was transdermal peptide deliv-
ery, known to promote skin absorption of cell penetrating
peptides (CPP, Gautam et al. 2016). We expected our test
peptides, the proline–arginine-rich A3-APO dimer and
its single chain in vivo metabolite Chex1-Arg20 carrying
CPP-type drug delivery properties, such as its templates,
the dimeric pyrrhocoricin analogs do (Otvos et al. 2004).
The model bacterial strain was Acinetobacter baumannii
that is commonly isolated from hospital environments and
patients, resistant to desiccation and harbors many antibi-
otic resistance genes (Merens et al. 2014).
Materials and methods
Bacterial strain and peptides
The carbapenem and colistin-resistant A. baumannii BAA-
1605 strain was purchased from the American Type Culture
Collection, originally isolated from the sputum of a Cana-
dian soldier injured in Afghanistan (Tien et al. 2007).
Peptides A3-APO [(H-Chex-Arg-Pro-Asp-Lys-Pro-Arg-
Abstract Host defense peptides are preferably adminis-
tered as topical therapeutic agents. We have investigated
whether peptide A3-APO can enter the circulation when
applied to the ear skin. Efﬁcacy of peptide monotherapy as
transdermal administration option was assessed in a sys-
temic mouse Acinetobacter baumannii model. A3-APO
reduced mortality and demonstrated a statistically signiﬁ-
cant reduction of blood bacterial counts, regardless whether
it was administered prior or after bacterial challenge. The
peptidic metabolite of A3-APO was efﬁcacious when
applied to the ear or tail.
Keywords Bacterial counts · Multidrug resistance ·
Peptide antibiotic · Skin penetration · Survival
Host defense peptides (HDP), called earlier as antimi-
crobial peptides (Hilchie et al. 2013), exhibit noticeable
efﬁcacies in animal models of systemic human infections
(Schmidt et al. 2016; Noto et al. 2008). However, as it
was observed for decades (Bush et al. 2004), the in vivo
therapeutic index of HDP is less than optimal (Ostorhazi
et al. 2014) making these drugs suitable more preferably
Handling Editor: F. Albericio.
* Laszlo Otvos Jr.
Faculty of Medicine, Institute of Medical Microbiology,
Semmelweis University, Nagyvarad ter 4, 1089 Budapest,
OLPE, LLC, 801 Mockingbird Lane, Audubon, PA 19403,