Gorr 2011

J Clin Periodontol 2011; 38 (Suppl. 11): 126–141 doi: 10.1111/j.1600-051X.2010.01664.
Antimicrobial peptides and Sven-Ulrik Gorr and Mahsa

Abdolhosseini
Department of Diagnostic and Biological
periodontal disease Sciences, University of Minnesota School of

Dentistry, Minneapolis, MN, USA
Gorr S-U, Abdolhosseini M. Antimicrobial peptides and periodontal disease. J Clin

Periodontol 2011; 38 (Suppl. 11): 126–141. doi: 10.1111/j.1600-051X.2010.01664.x.
Abstract
Aims: The goal of this review is to identify the antimicrobial proteins in the oral
fluids, saliva and gingival crevicular fluid and identify functional families and
candidates for antibacterial treatment.
Results: Periodontal biofilms initiate a cascade of inflammatory and immune
processes that lead to the destruction of gingival tissues and ultimately alveolar bone
loss and tooth loss. Treatment of periodontal disease with conventional antibiotics does
not appear to be effective in the absence of mechanical debridement. An alternative
treatment may be found in antimicrobial peptides and proteins, which can be
bactericidal and anti-inflammatory and block the inflammatory effects of bacterial
toxins. The peptides have co-evolved with oral bacteria, which have not developed
significant peptide resistance. Over 45 antibacterial proteins are found in human saliva
and gingival crevicular fluid. The proteins and peptides belong to several different
functional families and offer broad protection from invading microbes. Several
antimicrobial peptides and proteins (AMPs) serve as templates for the development of
therapeutic peptides and peptide mimetics, although to date none have demonstrated
Key words: antibacterial; antibiotics;
efficacy in human trials.
antimicrobial peptides; cathelicidin; defensin;
Conclusions: Existing and newly identified AMPs may be developed for therapeutic lipopolysaccharide; peptide mimetics
use in periodontal disease or can serve as templates for peptide and peptide mimetics
with improved therapeutic indices. Accepted for publication 7 November 2010
Periodontitis is an inflammatory disease in Europe indicates that, on average, biological paradigm in innate immunity
that affects approximately half of US 60% of the adult population has clinical and as a potential source of novel anti-
adults over 30 years of age. Similarly, attachment loss of 43 mm (König et al. biotics (e.g., Brogden 2005, Ganz 2005,
54% of subjects examined in the 1998 2010). Periodontal disease is character- Gordon et al. 2005, Wheeler and Hood
UK Adult Dental Health survey exhib- ized by the formation of mixed biofilms 2005, Dale et al. 2006, Peschel and Sahl
ited at least moderate pocketing on one on the teeth and gingival tissues. The 2006, Schroder and Harder 2006, Talbot
or more teeth (Morris et al. 2001). A oral cavity is an environment exposed to et al. 2006, Kinane et al. 2007, Hirsch
systematic review of periodontal health a multitude of bacteria with over 700 et al. 2008, Kinane et al. 2008, Sorensen
possible resident species of which 150– et al. 2008, Gorr 2009). These AMPs
Conflict of interest and source of 200 are typically found in most indivi- presumably protect oral tissues from
funding statement duals. It is thought that this bacterial infection as minor cuts and abrasions
flora is controlled initially by the innate or even tooth extractions, which create
The author’s work on Parotid Secretory
Protein and antimicrobial peptides was
immune system of oral epithelia, saliva large lesions in the oral epithelium,
supported by PHS Grant numbers 2R01 and gingival crevicular fluid, which is typically resolve without major infec-
DE012205 and 1R01 DE017989 from the rich in antimicrobial proteins and pep- tion or inflammation (Zasloff 2002b).
National Institute for Dental and Cranio- tides (AMPs) (Table 1). These AMPs On the other hand, the normal oral flora
facial Research at the National Institutes constitute a diverse class of host-defense is in a balance between pathogens and
of Health. Additional support from the molecules that act early to combat inva- commensals that requires regular clean-
University of Louisville and University sion and infection by bacteria and other ing to be maintained. A decrease in oral
of Minnesota Schools of Dentistry is microorganisms, with over 45 identified hygiene is quickly followed by the
gratefully acknowledged. This supplement to date (Table 2). This group of proteins build-up of oral biofilms on tooth sur-
was supported by an unrestricted grant and peptides has engendered consider- faces and, if left untreated, will progress
from Colgate.
able interest in the past decade as a to gingival inflammation and possibly
126 r 2011 John Wiley & Sons A/S
Antimicrobial peptides 127
periodontitis, alveolar bone loss and loss found in every individual. As an example, biotic treatment difficult. Traditional
of teeth. Thus, it appears that the AMPs in one study 69 of the 400 periodontal antibiotics were often selected against
in the oral cavity do not solely control bacteria were found in multiple subjects metabolically active bacteria in a plank-
bacterial growth and prevent biofilm (Paster et al. 2006). However, only tonic state and are therefore less effec-
build-up. This critical narrative review about eight bacterial species have con- tive against the physiologically dormant
catalogs the AMPs found in saliva and sistently been associated with the devel- bacteria encapsulated in a biofilm (Ten
gingival crevicular fluid and points to opment of periodontitis, including Cate 2006). As an example, the suscept-
potential roles and uses in control of oral Actinobacillus actinomycetemcomitans, ibility of A. actinomycetemcomitans to
bacteria and periodontal disease. A Porphyromonas gingivalis, Tannerella several antibiotics decreases as the bio-
combination of search strategies was forsythia, Treponema denticola, Fuso- film matures (Takahashi et al. 2007).
used in an effort to obtain a comprehen- bacterium nucleatum, Eubacterium Thus, plaque is typically removed by
sive view of the existing literature: nodatum, Prevotella intermedia and mechanical debridement, which also
PubMed was searched with the MeSH Prevotella nigrescens (Periodontics remains the main treatment option for
terms ‘‘periodontitis’’ and ‘‘anti-bacter- 1996, Socransky et al. 1998, Teles et periodontitis. Depending on the extent
ial agents’’; previous reviews were con- al. 2006). The first three are consensus of the gingival infection and attendant
sulted for relevant proteins and recent pathogens (Periodontics 1996) while P. inflammation, surgery and tissue regen-
updates on specific proteins were iden- gingivalis, T. forsythia and T. denticola eration are further treatment option for
tified by a PubMed search for each AMP belong to the red complex described by periodontitis.
limited to the publication years 2009– Socransky et al.(1998).
2010. Clinical Trials were initially iden- The periodontal pathogens are typi-
tified in ‘‘clinicaltrials.gov’’. In some cally found in gingival crevices and
cases, these searches were broadened by periodontal pockets of both healthy The Role of Antimicrobial Proteins in
searching Google using specific protein and diseased sites (Colombo et al. Periodontal Disease
or drug names in combination with 2006, Teles et al. 2006) and population Human saliva and gingival fluid con-
‘‘periodontal’’ or ‘‘periodontitis’’. studies have identified population sub- tains at least 45 different AMPs that
groups with high, moderate or low sus- belong to several different functional
ceptibility to inflammatory diseases, classes, ranging from small cationic
including periodontitis (Loe et al. peptides to enzymes and large aggluti-
Oral Bacteria and Infection 1986). Thus, it is likely that differences nating proteins (Table 1). It is thought
The oral cavity and airways are exposed in host-defense mechanisms, including that this functional and structural diver-
to many of the same bacteria, which are antimicrobial protein profiles, determine sity is necessary to protect the oral
either ingested or inhaled. However, whether bacterial colonization pro- epithelia from the large number of pos-
while the lower airways are essentially gresses to overt disease. Similar differ- sible invading microbes and maintain
sterile (Diamond et al. 2008), indicating ences in host-defenses may play a role the oral homeostasis of commensal and
that airway host-defenses effectively in the age differences noted for perio- pathogenic bacteria. Moreover, the
clear invading bacteria, the oral cavity dontal disease, which is predominantly expression of anti-microbial proteins is
is host to over 700 species of bacteria, associated with A. actinomycetemcomi- differentially regulated by different
with about 400 found in the periodontal tans in the young while P. gingivalis is periodontal pathogens (Handfield et al.
pocket. Newer pyrosequencing techni- the dominant bacterial agent later in life 2005) (Table 2), suggesting that a spe-
ques using short sequence tags for the (Slots and Ting 1999). cific antimicrobial ‘‘cocktail’’ constitu-
16S rDNA V6 region have led to even tes the physiological response to
higher estimates of microbial diversity in individual pathogens. This mix may
saliva and plaque (Keijser et al. 2008). A also play a role in maintaining an appro-
preliminary estimate identified 5669 and Biofilms and Periodontitis priate balance between oral pathogens
10,052 phylotypes (species) in saliva and Dental plaque is a mixed microbial and commensals.
plaque, respectively, using operational biofilm that can be composed of hun- Proteomic analyses have identified
taxonomic units (OTUs) at 3% differ- dreds of bacterial species (Kolenbrander differences in antimicrobial protein
ence. This may represent about 50% of et al. 2006). The biofilm bacteria and expression in periodontal patients com-
the total species present (Keijser et al. their toxins perturb gingival epithelial pared with healthy or treated controls. A
2008). However, 95% of the sequences cells as the first stage in a cascade of proteomic analysis of salivary proteins
were represented by the 1000 most abun- inflammatory and immune processes from aggressive periodontitis and nor-
dant OTUs, which approximates previous that lead to the destruction of gingival mal controls revealed differential
estimates. Importantly, in the absence of tissues and ultimately, in susceptible expression of 11 proteins (Wu et al.
mechanical or chemical removal of oral patients, alveolar bone loss and tooth 2009b), including the antimicrobial pro-
bacteria, they quickly form biofilms on loss as a result of periodontal disease. teins lactotransferrin and PSP/
tooth surfaces. These biofilms can lead to Mixed biofilms are communities of SPLUNC2. A similar study analysed
gingival infections, periodontitis and loss bacteria that communicate by quorum the expression of salivary proteins
of alveolar bone and teeth. Indeed, oral sensing to change the bacterial physiol- from periodontitis patients before and
infections and attendant inflammatory ogy. The biofilm contains channels to after treatment (Haigh et al. 2010). PSP/
diseases are among the most common aid nutrient transport and is typically SPLUNC2, which is up-regulated in
human infections. encapsulated by an extracellular poly- periodontitis, was down-regulated after
Of the 400 species of bacteria found saccharide matrix (Ten Cate 2006). treatment while the calgranulins
in the periodontal pocket not all are These features combine to make anti- S100A8 and A9 were up-regulated after
r 2011 John Wiley & Sons A/S
128 Gorr & Abdolhosseini
Table 1. Functional classes of antimicrobial proteins

Cationic Bacterial agglutination Metal ion Peroxidases Protease Activity against
peptides and adhesion chelators inhibitors bacterial cell walls
1 Adrenomedullin b-2-microglobulin Calgranulin A Lactoperoxidase Cystatin A Lysozyme C

Protein S100-A8 Salivary peroxidase
2 Azurocidin Fibronectin Calgranulin B Myeloperoxidase Cystatin B Peptidoglycan
CAP37 Protein S100-A9 recognition protein 1
Heparin-binding protein
3 b defensin-1 Mucin 7 Lactoferrin Cystatin C Peptidoglycan
hBD-1 Lactotransferrin recognition protein 3
4 b defensin-4A Prolatin-inducible protein Psoriasin Cystatin D Peptidoglycan
b-defensin-2 Protein S100-A7 recognition protein 4
hBD-2
5 b Defensin 103 Proline-rich proteins Transferrin Cystatin S
b-defensin-3 Serotransferrin
hBD-3
6 Calcitonin gene-related Salivary agglutinin Cystatin SA
peptide 1 GP340 DMBT1
7 Cathelicidin Surfactant protein A Cystatin SN
(LL-37) pulmonary surfactant-
associated protein A1
8 C-C motif chemokine 28 Secretory leukoprotease
inhibitor protein
9 Hemoglobin Skin-derived
b-globin antileukoproteinase
a globin Elafin
10 Heparin binding growth factor
Fibroblast growth factor
11 Histatin 1
12 Histatin 3
(Histatin 5)
13 HNP-1
Neutrophil defensin 1
14 HNP-2
15 HNP-3
16 HNP-4
17 Neuropeptide Y
18 Statherin
19 (Substance P)
Protachykinin-1
20 Vasoactive intestinal peptide
See Table 2 for additional details for individual proteins.
treatment (Haigh et al. 2010). Direct these differences could lead to the Antimicrobial Protein Deficiency and
analysis of the antimicrobial peptide development of salivary markers for Periodontitis
LL-37 in gingival crevicular fluid diagnosis of periodontal disease (Gian-
showed that the peptide is significantly nobile et al. 2009). Several systemic diseases are associated
elevated in patients with chronic perio- Antimicrobial proteins exhibit strik- with an increased risk for periodontitis.
dontitis compared with the other groups. ing variation in their ability to kill In some cases this appears to correlate
Moreover, a positive relationship was different species of oral bacteria or with reduced expression of antimicro-
found between levels of LL-37 and different strains of the same species bial proteins.
probing depth, clinical attachment level, (Diamond et al. 2009). As an example, Diabetes is associated with an
plaque index, bleeding on probing and Streptococcus gordonii is not suscepti- increased risk for periodontitis, even in
papilla bleeding index at sampled sites ble to hBD-3 or LL-37 while S. gordonii children (Lalla et al. 2007). In a proteo-
(Turkoglu et al. 2009). In addition to 10558 exhibits minimal inhibitory con- mic study of saliva from diabetic chil-
understanding the role of specific AMPs centrations of 15–31 mg/ml for both pep- dren and matched controls, it was noted
in the pathology of periodontal disease, tides (Ji et al. 2007a). that the levels of statherin, proline-rich
Table 2. Antibacterial proteins in saliva and gingival crevicular fluid
Protein Gene Saliva References GCF References Targets Dose References Change in periodontitis References
4
Adrenomedullin ADM 0.06 mg/ml Kapas et al. 1.8 mg/ml Lundy et al. P. gingivalis MIC 7.75 10 mg/ml Allaker et al. Up-regulated twofold Lundy et al. (2006)
(2004) (2006) S. mutans MIC 12.5 mg/ml (1999) P. gingivalis Kapas et al. (2001)
up-regulates
Azurocidin AZU1 MS E. coli LD50 1.3 mg/ml Almeida et al.
CAP37 (1996)
Heparin-binding protein
Bactericidal BPI 0.078 mg/ml Bartunkovaa et Gram-negative bacteria
Permeability-Increasing al. (2004)

protein
Bactericidal/ BPIL1 MS
permeability-increasing
protein-like 1
b-2-microglobulin B2M 0.38 mg/ml Michelis et al. 9.4 mg/ml Mogi et al. S. mutans Ericson, 3–10-fold up-regulated Mogi et al. (1999)
(2007) (1999) (1984)
b defensin-1 DEFB1 0.15 mg/ml Mathews et al. 1 Diamond et al. P. gingivalis MIC 50 mg/ml Ouhara et al. Up-regulated by Vankeerberghen et
hBD-1 (1999) (2001) A. actinomycetemcomitans MIC 50 mg/ml (2005) P. gingivalis, P. intermedia al. (2005), Ji et al.
F. nucleatum MIC 20 mg/ml Down-regulated by (2007b)
T. denticola Ji et al. (2007b)
Not changed by Ji et al. (2007b)
T forsythia, and
F. nucleatum
b defensin-4 DEFB4A 0.15 mg/ml Mathews et al. 1 Diamond et al. P. gingivalis MIC 34.6-4250 mg/ml Joly et al. Up-regulated by Laube et al. (2008),
b-defensin-2 (1999) (2001) S. mutans MIC 4–8 mg/ml (2004) A. actinomycetemcomitans, Ouhara et al. (2006),
hBD-2 P. gingivalis, Chung and Dale
F. nucleatum, and (2004),
P. intermedia Krisanaprakornkit et
Not changed by al. (2000), Ji et al.
T. forsythia and (2007b)
T. denticola Brissette et al. (2008)
Ji et al. (2007b)
b Defensin 103 DEFB103A 0.31 mg/ml Tao et al. (2005) P. gingivalis MIC 42.1 mg/ml Ji et al. Up-regulated by Ji et al. (2007b),
b-defensin-3 A. Actinomycetemcomitans MIC 45.6 mg/ml (2007a) A. actinomycetemcomitans, Ouhara et al. (2006),
hBD-3 S. mutans MIC 3–5 mg/ml Joly et al. P. gingivalis, F. nucleatum Vankeerberghen et
T. Denticola MIC 15.7 mg/ml (2004) and P. intermedia al. (2005)
F. nucleatum MIC 4.5–7.8 mg/ml Garcia et al. Down-regulated by Ji et al. (2007b)
B. cepacia MIC 6.6 mg/ml (2001) T. forsythia, and
S. sanguinis MIC 31.3 mg/ml T. denticola
P. intermedia MIC 15.7 mg/ml
6
Calcitonin gene-related CALCA 23.5 10 Dawidson et al. 0.013–0.7 mg/ml Lundy et al. P. aeruginosa MIC 5.9 mg/ml El Karim Decreased (Not detected) Lundy et al. (1999)
peptide 1 (1997) (1999, S. mutans MIC4500 mg/ml et al. (2008) Decreased 20-fold in
[10]Awawdeh gingivitis
et al. (2002)
Calgranulin A S100A8 1.93 mg/ml Kleinegger et al. 240 mg/ml Lundy et al. P. gingivalis MIC 64 mg/ml Nisapakultorn Increase 2–3-fold Lundy et al. (2001),
Protein S100-A8 (2001) (Calprotectin: (2001) S. aureus et al. (2001) Increased after therapy Kojima et al. (2000),
570 mg/ml) Kido et al. Brandtzaeg Up-regulated by Lundy et al. (2000a)
(1999) et al. (1995) P. gingivalis and Haigh et al. (2010)
F. nucleatum (Calgranulin) Milward et al. (2007)
Calgranulin B S100A9 1.93 mg/ml Kleinegger et al. 1 Kido et al. See Calgranulin A Increased in periodontitis, Kojima et al. (2000)
Antimicrobial peptides
Protein S100-A9 (2001) (Calprotectin: (1999) (Calprotectin) decreased 2–3-fold after Haigh et al. (2010)
570 mg/ml) periodontal therapy
Increased after therapy
CAMP 1.6 mg/ml 1
129
Table 2. (Contd.) 130
Cathelicidin Tao et al. (2005), Puklo et al. P. gingivalis MIC4125 mg/ml Ji et al. Up-regulated (Aggressive Puklo et al. (2008)
(LL-37) Bachrach et al. (2008) A. actinomycetemcomitans MIC 37.8 mg/ml (2007a) and Chronic periodontitis) Ji et al. (2007b)
(2006) S. gordonii MIC 102.6 mg/ml Up-regulated by Ji et al. (2007b)
P. intermedia MIC 15.7 mg/ml F. nucleatum and
F. nucleatum MIC 4.9 mg/ml P. intermedia
S. sanguinis MIC 31.3 mg/ml Not affected by
P. gingivalis, T forsythia or T.
denticola
C–C motif chemokine 28 CCL28 0.9 mg/ml Hieshima et al. S. mutans IC50 1.7 mM Hieshima et al. (2003)
(2003)
Cystatin A CSTA 93 U/mg protein Blankenvoorde 24 U/mg protein Blankenvoorde
Gorr & Abdolhosseini
et al. (1997) et al. (1997)

Cystatin B CSTB MS
Cystatin C CST3 0.9 mg/ml van Gils et al. 1.15 mg/ml Ulker et al. P. gingivalis Blankenvoorde Down-regulated by Elkaim et al. (2008)
(2003), Henskens (children) (2008) et al. (1998) P. gingivalis
et al. (1996)
Cystatin D CST5 3.8 mg/ml Freije et al.
(1993)
Cystatin S CST4 53 (stim)- Baron et al. ND Blankenvoorde P. ginigvalis Blankenvoorde Up-regulated in saliva
116 mg/ml (1999), Henskens et al. (1997) et al. (1998)
et al. (1996)
Cystatin SA CST2 78 mg/ml (stim) Baron et al.
(1999)
Cystatin SN CST1 39 mg/ml (stim) Baron et al. ND Blankenvoorde
(1999) et al. (1997)
Fibronectin FN1 1.2–0.13 Llena-Puy et al. 106 mg/ml Lopatin et al. P. gingivalis Murakami et Decrease 2-fold with less Lopatin et al. (1989)
(stim) mg/ml (2004), Tynelius- (1989) S. mutans al. (1998) intact fibronectin in Lopatin et al. (1989)
Bratthall et al. Llena-Puy periodontitis Wang et al. (2001)
(1986) et al. (2000) Decrease 30-fold in gingivitis
Down-regulated by
A. actinomycetemcomitans
protease
Hemoglobin HBB 1 MS E. coli Parish et al. Increased due to bleeding
b-globin HBA1 (2001)
a globin HBA2
Heparin binding growth FGF1 0.87 pg/ml Ishizaki et al. MS (FGF1) E. coli Malmsten
factor FGF2 (FGF2) (2000) P. aeruginosa et al. (2007)
Fibroblast growth factor B. subtilis
Histatin 1 HTN1 10.1 mg/ml Johnson et al.
(parotid) (2000)
34.7 mg/ml
(SM/SL)
Histatin 3 HTN3 7.3 mg/ml Johnson et al. A. actinomycetemcomitans Murakami
(Histatin 5) (Parotid) (2000) Neutralizes leukotoxin et al. (2002b)
10.2mg/ml
(SM/SL)
HNP-1 DEFA1 8.6 mg/ml Goebel et al. 0.0012 mg/mln Puklo et al. S. mutans MIC 4.1 mg/ml Lundy et al. 15-fold up-regulated Puklo et al. (2008)
Neutrophil defensin 1 (2000) (2008) P. aeruginosa MIC 10.3 mg/ml (2008), (aggressive perio.)n
A. actinomycetemcomitans No activity (4500 mg/ Miyasaki et al. 60-fold up-regulated (chronic
P. gingivalis ml) (1990) perio.)n
No activity Raj et al.
(4200 mM) (2000)

5.6 mg/ml 0.0012 mg/mln Puklo et al. (2008)
HNP-2 DEFA1 Goebel et al. Puklo et al. P. gingivalis No activity Raj et al. 15-fold up-regulated
Neutrophil defensin 2 DEFA3 (2000) (2008) A. actinomycetemcomitans (4200 mM) (2000) (aggressive perio.)n
No activity (4500 mg/ Miyasaki et al. 60-fold up-regulated (chronic
ml) (1990) perio.)n
HNP-3 DEFA3 0–2.7 mg/ml Gardner et al. 0.0012 mg/mln Puklo et al. P. gingivalis No activity Raj et al. 15-fold up-regulated Puklo et al. (2008)
Neutrophil defensin 3 (2009) (2008) A. actinomycetemcomitans (4200 mM) (2000) (aggressive perio.)n
No activity (4500 mg/ Miyasaki et al. 60-fold up-regulated
ml) (1990) (chronic perio.)n
HNP-4 DEFA4 MS E. coli LD50 0.085 m mg/ml Wilde et al.
Neutrophil defensin 4 (1989)
Lactoferrin LTF 20 mg/ml Shugars et al. 600 m/ml but Jentsch et al. P. gingivalis 35% growth inhibition Aguilera et al. Down-regulated 1.7-fold Wu et al. (2009b)
Lactotransferrin (2001) concentration (2004) A. actinmomycetemcomitans at 2 mg/ml apoLf (1998) Highly variable Friedman et al.

highly variable Friedman et al. 1.9 mM apoLf (iron- Kalmar and (1983),
(1983), free) kills 99.9% in 3 h Arnold, 1988) Adonogianaki et al.
Adonogianaki (1993), Jentsch et al.
et al. (1993) (2004),
Adonogianaki
et al. (1996)
Lactoperoxidase LPO 1.9 mg/ml Thomas et al. 1 Ashby, 2008) A. actinomycetemcomitans Ihalin et al.
Salivary peroxidase (1994a) Oral Streptococci (2003)
P. gingivalis Thomas et al.
(1994b)
Ihalin et al.
(2001)
Long palate, lung and LPLUNC1 MS
nasal epithelium
carcinoma-associated
protein 1
Von Ebner minor
salivary gland protein
Lysozyme C LYZ 40 mg/ml Allgrove et al. 1 Friedman et al. Gram-positive bacteria Down-regulated in Ito et al. (2008)
(2008), Klimiuk (1983), Jentsch periodontitis Friedman et al.
et al. (2006), et al. (2004) Increased in juvenile (1983)
Shugars et al. periodontitis
(2001), Rudney
and Smith (1985)
Mucin 7 MUC7 4–10 mg% Payment et al. Oral Streptococci Amerongen
MG2 (2001) A. actinomycetemcomitans et al. (1995)
Groenink et al.
(1996)
Myeloperoxidase MPO 3 mg/ml (stim) Thomas et al. 0.3–5.5 mg/ml Ortiz et al. A. actinomycetemcomitans Miyasaki et al. Decrease after Kaner et al. (2006)
(1994a) (1997), Puklo Oral Streptococci (1986) periodontal therapy
et al. (2008) P. gingivalis Ihalin et al.
(2001)
Neuropeptide Y NPY 41.4 Dawidson et al. P. aeruginosa MIC 134.3 mg/ml El Karim et al.
10 6 mg/ml (1997) S. mutans MIC 210.9 mg/ml (2008)
Palate lung nasal PLUNC MS
epithelium clone
palate, lung and nasal
epithelium carcinoma-
associated protein
Peptidoglycan PGLYRP1 MS (SM/SL) MS S. aureus LD99 60 mg/ml Wang et al.
recognition protein 1 E. coli (2007)
Antimicrobial peptides
LD99 30 mg/ml
Peptidoglycan PGLYRP3 S. aureus LD99 45 mg/ml Wang et al.
recognition protein 3 Gram-negative bacteria LD99 30 mg/ml (2007)
Peptidoglycan PGLYRP4 S. aureus LD99 45 mg/ml Wang et al.
131
recognition protein 4 Gram-negative bacteria LD99 200 mg/ml (2007)

Table 2. (Contd.)
132
Prolatin-inducible PIP MS Streptococci Nistor et al.

protein (2009)
Proline-rich proteins PRH1 MS MS Oral bacteria Lamkin and
PRH2 Oppenheim
PRB1 (1993)
PRB3
PRB2
PRB4
Psoriasin S100A7 MS E. coli MBC 100 mg/ml Michalek et al.

Protein S100-A7 (2009)
Gorr & Abdolhosseini
Salivary agglutinin DMBT1 MS Oral streptococci Ligtenberg et

GP340 A. actinomycetemcomitans al. (2007)
DMBT1 Groenink et al.
(1996)
Secretory leukoprotease SLPI 2.9 mg/ml Shugars et al. P. aeruginosa LD95 2.5 mM Simpson et al. 79.7 pg/ml in periodontitis Nakamura-Minami et
inhibitor protein (2001), Lin et al. P. gingivalis (1999) Increased 3–4-fold post- al. (2003)
(2004) S. aureus treatment
Short palate, lung and SPLUNC2 MS P. aeruginosa Geetha et al. Up-regulated 3.3-fold Wu et al. (2009b)
nasal epithelium (2003) Up-regulated by P. gingivalis Shiba et al. (2005)
carcinoma-associated
protein 2
Parotid Secretory Protein
SKALP Skin-derived PI3 0.02 mg/ml Tjabringa et al. P. aeruginosa LD96 2.5 mM Simpson et al. Up-regulated by P. gingivalis
anti-leukoproteinase (2005) (1999) Degraded by gingipain
Elafin Lee et al. (2002)
Statherin STATH 26.5 mg/ml Contucci et al. MS Oral anaerobes MICo12.5 mg/ml, Kochanska et
(2005) 4100 mg/ml al. (2000)
(Substance P) TAC1 7.5 Dawidson et al. 0.061–0.11 mg/ Awawdeh et P. aeruginosa MIC 15.7 mg/ml El Karim et al. No change Linden et al. (1997)
Protachykinin-1 10 6 mg/ml (1997) ml al. (2002) S. mutans MIC 171.6 mg/ml (2008) Decreased post-treatment Lundy et al. (2000b)
Linden et al.
(1997)
Surfactant Protein A SFTPA1 0.9 mg/ml Simpson et al. Bacteria Korfhagen
Pulmonary surfactant- (2005) (2001)
associated protein A1
Transferrin TF 6.5 mg/ml Suh et al. (2009) MS
Serotransferrin (blood
contamination?)
Vasoactive Intestinal VIP 39.9 Dawidson et al. P. aeruginosa MIC 4.1 mg/ml El Karim et al.
Peptide 10 6 mg/ml (1997) S. mutans MIC 150.7 mg/ml (2008)
1, present; *, HNP 1–3 (neutrophil defensins).

MIC, minimal inhibitory concentration; MBC, minimal bactericidal concentration; MFC, minimal fungicidal concentration; LDxx, concentration that kills XX% of bacteria; HNP, human neutrophil peptide;
a-defensin, MS, mass spectrometry detection of proteins in unstimulated whole saliva (Xie et al., 2005, [193]Wilmarth et al., 2004).
Gingival crevicular fluid MS data are from (Ngo et al., 2010).
A. actinomycetemcomitans, Actinobacillus actinomycetemcomitans; B. cepacia, Burkholderia cepacia; B. subtilis, Bacillus subtilis; E. coli, Escherichia coli; F. nucleatum, Fusobacterium nucleatum;
P. aeruginosa, Pseudomonas aeruginosa; P. gingivalis, Porphyromonas gingivalis; P. intermedia, Prevotella intermedia; S. aureus, Staphylococcus aureus; S. gordonii, Streptococcus gordonii; S. mutans,
Streptococcus mutans; S. sanguinis, Streptococcus sanguinis; T. denticola, Treponema denticola; T. forsythia, Tannerella forsythia.

peptides P-B and P-C, Histatin 1 and 3 and calcitonin gene-related peptide Cationic peptides
were significantly reduced in diabetes (CGRP) are 100–10,000-fold higher in
(Cabras et al. 2010). In contrast, human gingival crevicular fluid than whole Cationic peptides is a large functional
neutrophil peptide (HNP)-1,2,4 and saliva. In contrast, the concentrations family that is represented in oral cavity
S100A9 were up-regulated in diabetic of the a-defensins are 1000-fold lower and airways. Depletion of cationic
patients compared with controls. Thus, in gingival crevicular fluid than saliva. AMPs from human airway fluid also
the altered complement of salivary anti- The high expression of some antimicro- eliminates the antibacterial activity
microbial proteins may contribute to bial peptides in gingival crevicular fluid (Cole et al. 2002). It is not clear if the
periodontal disease in young diabetic may be due to high local expression cationic proteins in saliva play a similar
patients. rather than saliva contamination of gin- role. However, ion-exchange fractiona-
Morbus Kostmann disease is a severe gival crevicular fluid samples (Griffiths tion of human saliva identified fractions
congenital neutropenia that is associated et al. 1992). Alternatively, AMPs may that exhibited antimicrobial activity,
with severe periodontitis (Putsep et al. be selectively sequestered by binding to which was not apparent in the starting
2002). The saliva, plasma and neutro- the tissue in the gingival pocket. material (S.-U. Gorr, unpublished obser-
phils from Kostmann patients are defi- The diversity of AMP gene products vation).
cient in LL-37 and patients exhibit a is further amplified by post-translational The cationic peptide functional
30% decrease in a-defensins. This is not modifications (Ramachandran et al. family consists of peptides that typically
an across-the-board reduction in anti- 2006, Messana et al. 2008) or gene are bactericidal and/or bacteriostatic and
microbial proteins because plasma polymorphisms (Oppenheim et al. includes adrenomedullin, a-defensins
lactoferrin content is normal (Putsep 2007, Whitelegge et al. 2007). This (HNP), b-defensins, cathelicidin, hista-
et al. 2002). In addition, treatment diversity presumably protects the oral tins 1 and 3, statherin, C–C motif che-
with granulocyte-colony-stimulating factor tissues from invasion or infection by the mokine 28 (CCL28), azurocidin and the
restores the number of neutrophils to large variety of microorganisms that neuropeptides CGRP, substance P neu-
normal but patients continue to lack enter the mouth and airways. As noted ropeptide Y and vasoactive intestinal
LL-37 and exhibit periodontal disease above, the resident flora is maintained in peptide (Table 1) (Gorr 2009).
(Putsep et al. 2002, Carlsson et al. a balance between pathogenic and com- As an example of this functional
2006). A bone marrow transplant in a mensal bacteria. Interestingly, the mini- family, LL-37 is a cationic peptide that
single patient restored both neutrophils mal inhibitory concentrations of most is derived from the 18 kDa precursor
numbers and the levels of LL-37 and no AMPs to oral bacteria are higher than protein cathelicidin by proteolytic clea-
further dental problems were noted. their concentrations in the gingival cre- vage. Cathelicidin is expressed in neu-
Similarly, patients with Papillon-Lefèvre vicular fluid. Thus it is not clear if the trophils and epithelial cells and LL-37 is
syndrome and Haim-Munk syndrome AMPs exert direct antibacterial activity, found in saliva and gingival crevicular
also exhibit low levels of LL-37 and act as a group or if these peptides are fluid (Murakami et al. 2002a, Puklo et
develop periodontitis (de Haar et al. acting as sentinels of bacterial status that al. 2008). LL-37 exhibits dual function
2006). In these patients, the LL-37 pre- stimulate other aspects of the immune by both killing bacteria and neutralizing
cursor cathelicidin is present at normal system (Diamond et al. 2008). The rapid the lipopolysaccharide from Gram-
levels but little is processed to the active growth of bacterial biofilms in the negative bacteria. As is the case for
LL-37 peptide due to allelic mutations absence of oral hygiene supports the several AMPs, the activity of LL-37 is
of the cathepsin C gene CTSC (Hart view that the AMPs do not serve pri- partially inhibited by saliva. On the
et al. 2000). marily to kill and eliminate oral bacteria other hand, saliva protects the peptide
but may serve to maintain the balance from proteolytic inactivation by gingi-
between resident pathogens and com- pain proteases secreted by the perio-
mensals and as sentinels for invading dontal pathogen P. gingivalis (Gutner
Functional Families of Antimicrobial microorganisms. et al. 2009).
Proteins in the Oral Cavity, See Individual testing of biological activ-
Tables 1 and 2 for details ity of AMPs in vitro has revealed func- Bacterial agglutination and adhesion
Oral tissues express a large variety of tional families that cover a broad range
AMPs, which may contribute to the of biological activities against oral bac- Several antibacterial proteins are active
host-defense of the oral cavity, although teria. However, it is not yet clear why in bacterial agglutination or adhesion.
their exact mode of action remains to be the oral complement of AMPs leads to These include the small salivary
determined (Chung et al. 2007, Dia- maintenance of bacterial colonization mucin-7 (MUC7) (MG2), which pro-
mond et al. 2008). At least 45 AMPs by commensals and pathogens, which motes bacterial agglutination, surfactant
are secreted by oral epithelial cells, can increase to biofilm formation in the protein-A, proline-rich proteins, prolac-
neutrophils and salivary glands. All are absence of oral hygiene, while the simi- tin-inducible protein and b-2-microglo-
found in saliva and a subset are also lar complement of AMPs in the airways bulin, which is notably present in most
found in gingival crevicular fluid (Gorr maintain a near sterile environment (82%) biopsies from aggressive perio-
2009). Several antimicrobial peptides (Diamond et al. 2008). The promise of dontitis patients but largely absent from
are highly concentrated in gingival cre- antimicrobial peptide therapy may be normal controls and chronic severe
vicular fluid compared with saliva: realized by over-expressing or supple- periodontitis specimens (Syrjanen et al.
Adrenomedulin and b-2-microglobulin menting individual antimicrobial pep- 1985). Saliva from prolactin-inducible
are enriched about 30-fold in gingival tides for oral therapy or by devising protein-knock-out mice exhibit signifi-
crevicular fluid while the concentrations ‘‘cocktails’’ of antimicrobial peptides cantly lower agglutination of oral bac-
of calgranulins, fibronectin, substance P to combat a subset of oral pathogens. teria than saliva from wild-type control
mice, suggesting that prolactin-induci- teins, including activation of coagula- Peroxidases

ble protein contributes to host-defense tion factors, cleavage of fibrinogen
of the oral cavity by agglutinating oral (Imamura 2003) and cleavage of IL-8. Lactoperoxidase and myeloperoxidase
bacteria (Nistor et al. 2009). The sali- The IL-8 cleavage products differ by are found in saliva where they form
vary agglutinin/GP340/Deleted in Mali- cellular origin of IL-8 and differentially the principal components of the perox-
gnant Brain Tumors-1 (DMBT1) is affect chemotaxis and activation of idase system of saliva (Ihalin et al.
a large glycoprotein that contains multi- neutrophils in response to IL-8 (Dias 2006). Both enzymes catalyse the oxi-
ple scavenger receptor cysteine-rich et al. 2008). Gingipains also activate dation of thiocyanate ions (SCN ) by
repeats. The protein is expressed in protease-activated receptors (e.g., hydrogen peroxide to form the bacter-
mucosal tissues, including salivary PAR2), which mediates the expression icidal reaction product hypothiocyanite
glands and is found in saliva (Wilmarth of the AMPs hBD-2 and CCL20 in (OSCN ) (Ashby 2008). Further bac-
et al. 2004, Xie et al. 2005, Denny et al. gingival epithelial cells (Dommisch et tericidal products are produced by the
2008) DMBT1 has not been linked al. 2007). Several protease inhibitors oxidation of chloride and iodide (Miya-
directly to periodontitis but DMBT1 are found in saliva and gingival crevi- saki et al. 1986, Ihalin et al. 2001,
polymorphisms have been associated cular fluid to inactivate these and other Ashby 2008). The reaction products
with a high incidence of caries (Jonas- proteases. These include the cystatins, produced by both peroxidases are active
son et al. 2007). a family of 14 human genes and two against A. actinomycetemcomitans, P.
Fibronectin is a 2386 amino acid pseudogenes. Seven of these genes are gingivalis and oral streptococci (Miya-
glycoprotein that is expressed in hepa- expressed in saliva and act by blocking saki et al. 1986) (Ihalin et al. 2001). The
tocytes and epithelial cells and is present the action of bacterial proteases (Dick- concentration of myeloperoxidase in
in saliva (Llena-Puy et al. 2004). The inson 2002). gingival crevicular fluid is about 5 mg/
protein induces bacterial agglutination Secretory leucocyte protease inhibitor ml with no significant differences
and plays a role in reducing bacterial and SKALP (skin-derived anti-leuco- between chronic periodontitis, aggres-
adhesion to oral surfaces (Llena-Puy et protease)/Elafin, also known as ESI sive periodontitis and healthy controls,
al. 2000). Fibronectin also binds directly (elastase-specific inhibitor). The latter respectively (Puklo et al. 2008). On the
to fimbrillin from P. gingivalis and is expressed in human submandibular other hand, antibiotic treatment of perio-
thereby inhibits the fimbrillin-induced gland (Lee et al. 2002) and saliva (Tjab- dontal patients for 3 months resulted in
expression of inflammatory cytokines ringa et al. 2005, Lee et al. 2002). The reduced levels of myeloperoxidase in
in macrophages (Murakami et al. protein has an N-terminal domain that gingival crevicular fluid (Kaner et al.
1998). Low levels of fibronectin are acts as a transglutaminase substrate and 2006).
correlated with high levels of Strepto- a C-terminal domain that exhibits anti-
coccus mutans in children (Llena-Puy elastase activity. In addition, the protein Activity against bacterial cell walls
et al. 2000) and periodontitis is asso- kills both Gram-negative and Gram-
ciated with a relative lack of fibronectin positive bacteria. This activity depends Two types of proteins show activity
in adults (Murakami et al. 1998). on the presence of both peptide domains against bacterial cell walls. Lysozyme
(Simpson et al. 1999). Elafin consists of (1,4-b-N-acetylmuramidase) is a 14 kDa
a single four-disulphide core protein protein that is expressed widely in
Metal ion chelators mucosal epithelia and found in saliva
domain, with the reactive site loop
These proteins inhibit bacterial growth expanding to the outside. The rigid, and gingival crevicular fluid. The
by acting as divalent cation scavengers. strongly stabilized core renders elafin enzyme is mainly active against the
The 80 kDa iron-binding glycoprotein unusually stable and resistant to proteo- cell wall of Gram-positive bacteria by
lactoferrin/lactotransferrin, which acts lysis (Guyot et al. 2005). Elafin expres- hydrolysing peptidoglycans. The other
as a scavenger of Fe31 ions, exhibits sion is induced in inflamed epithelial protein type with activity against cell
gene polymorphisms that have been tissues and P. gingivalis up-regulates wall peptidoglycans are peptidoglycan
associated with aggressive periodontitis Elafin expression in gingival epithelial recognition proteins 3 and 4, which are
(Wu et al. 2009a). The other members of cells. While the protein is highly resis- expressed in mucosal epithelia, includ-
this functional family, Calgranulin A tant to most proteases, elafin is degraded ing salivary glands. These large proteins
(S100A8) and calgranulin B (S100A9) by gingipains from P. gingivalis (Kan- (89–115 kDa disulphide linked homo- or
form a dimer named calprotectin, which tyka et al. 2009). The ability to disturb hetero-dimers) bind to cell wall pepti-
is up-regulated in periodontitis and the balance between proteases and pro- doglycans but do not permeabilize bac-
detected in increased levels in gingival tease inhibitor in infected gingival tissue terial membranes (Lu et al. 2006). The
crevicular fluid of periodontal patients contributes to the degradation of host proteins are bacteriostatic for most
(Kido et al. 1999). Calprotectin protects proteins. Indeed, the protease inhibitors Gram-positive and Gram-negative bac-
cells from bacterial invasion, including SLPI and elafin are often inactivated at teria but not for non-pathogenic bacteria
the periodontal pathogen P. gingivalis sites of inflammation. Inactivation may or C. albicans (Lu et al. 2006).
(Nisapakultorn et al. 2001). be due to microbial proteases, e.g. gin-
gipains, or host proteases secreted by
neutrophils at the site of inflammation Peptides Derived from Host-Defense
Protease inhibitors Proteins
(Sallenave 2010). Protease inhibitors
Proteases are important virulence fac- based on the sequence of SKALP/Elafin In addition to the already identified
tors for several bacteria. As an exam- may prevent the tissue destruction AMPs, new peptides are continually
ple, P. gingivalis secrete gingipains caused by inflammatory and bacterial discovered or developed from existing
that bind and cleave multiple host-pro- proteases. proteins. Hundreds of existing AMPs
are accessible in on-line databases, the predicted structure of the PLUNC block approach additional targeting
including CAMP: collection of anti-- protein Parotid Secretory Protein, led to domains were combined with antimicro-
microbial peptides http://www.bicnirrh. the design of a series of antimicrobial bial domains to generate peptides that
res.in/antimicrobial/index.php (Thomas peptides that exhibit anti-endotoxin specifically targeted and killed S.
et al. 2010), AMSDb: anti-microbial activity (Geetha et al. 2005), bacterial mutans (He et al. 2010).
sequence database (http://www.bbcm. agglutinating activity and act to increase
units.it/ tossi/pag1.htm) (A. Tossi, bacterial clearance by macrophages in
University of Trieste), APD: antimicro- cell culture (Gorr et al. 2008). Anti-Microbial Peptide Mimetics
bial peptide database (http://aps.unmc. As a further example of antimicrobial
As outlined above, the clinical use of
edu/AP/main.php) (Wang and Wang peptides derived from human proteins,
AMPs is associated with significant chal-
2004) and PepBank http://pepbank.mgh. hemoglobin gives rise to the antibacter-
lenges. In some cases the natural peptides
harvard.edu/ (Shtatland et al. 2007). These ial peptides hemocidins. These peptides
have been modified to generate peptides
peptides and the numerous possible are active at low pH and potentiate the
with more favourable efficacy/toxicity
modifications represent a rich source activity of other AMPs, including LL-
profiles (Zasloff 2002a). An alternate
for the identification and testing of anti- 37, lysozyme and defensins (Mak et al.
approach is the design and synthesis of
microbials with activity/toxicity profiles 2007). While hemoglobin is found in
peptide mimetics that retain the biologi-
that are beneficial against periodontal both saliva and gingival crevicular fluid,
cal activity of AMPs but are more readily
pathogens. the hemocidins have not yet been
produced, exhibit favourable therapeutic
Peptides of human origin have parti- described in the oral cavity. Their func-
index and are stable under physiological
cular promise as therapeutic agents with tion in conjunction with other AMPs at
conditions (Tew et al. 2006). One such
low host toxicity. In addition, the co- acidic pH may make them attractive
non-peptide compound mPE shows low
evolution of these peptides with the oral agents for the treatment of dental bio-
toxicity, is active against clinical isolates,
microflora suggests that they may result films.
including antibiotic-resistant bacteria and
in lower rates of bacterial resistance Anti-microbial peptides constitute a
did not cause resistance in Staphylococ-
(Peschel and Sahl 2006). It is important relatively new class of compounds that
cus aureus over 17 passages. mPE is
to note that bacterial resistance has been has shown promise as effective antibio-
active against both Gram-negative and
observed in vitro and the development tics to many bacterial species and fungi
Gram-positive oral pathogens in both the
of resistance could potentially result in in vitro. A recent review of the patent
planktonic and biofilm culture (Tew
severe consequences for the effective- literature shows the broad range of pep-
et al. 2006). Similar mimetics based on
ness of the endogenous human peptide tides in development (Pathan et al.
the structure of defensin have shown a
(Bell and Gouyon 2003). This concern is 2010). It is hoped that this class of
high therapeutic index in pre-clinical
somewhat mitigated, however, by the antibiotics will include clinically useful
studies (Beckloff et al. 2007). The func-
alternate host-defense mechanisms that peptides that could exhibit both high in
tional domain of BPI protein has been
function in the human body such that we vivo efficacy and low host toxicity.
used to design a modified D-enantiomer
do not rely on a single peptide for However, a 2005 review noted the con-
(XOMA 629, Xoma, Berkeley, CA,
protection (Hancock 2003). tinuing challenges in obtaining approval
USA), which is highly active against a
Human saliva may be a rich source of from the U.S. Food and Drug Adminis-
wide variety of bacteria and fungi (Lim
new AMPs, in addition to the existing tration for these peptides (Gordon et al.
et al. 2001). Structure function analysis
proteins described above. The human 2005). Thus, continued peptide selection
of naturally occurring peptides will pro-
salivary proteome contains over 1100 and optimization for in vivo conditions
vide additional sources for the design and
proteins (Xie et al. 2005, Denny et al. is needed to further develop these pep-
tuning of peptide mimetics that take
2008), many of which have not yet been tides for therapeutic use.
advantage of the biological activity of
functionally identified. One approach
AMPs but avoid some of the challenges
for the identification of new peptides is
associated with their synthesis and ther-
the analysis for antimicrobial consensus
Targeting of Antimicrobial Peptides apeutic use. In the oral cavity, it may be
motifs in peptide sequences (Yount and
of particular importance to develop anti-
Yeaman 2004). Structural similarities of Broad-spectrum antibiotics and AMPs
biotics that control harmful pathogens
new proteins and existing proteins also can reduce beneficial commensal bac-
without eliminating beneficial commen-
provide functional clues. Thus, the teria in the oral cavity and broad appli-
sals that are needed for microbiological
PLUNC family was recently identified cation of AMPs may be associated with
balance.
in the oral cavity and airway epithelia patient toxicity. As an approach to over-
(Bingle and Craven 2002). Based on the come these concerns, systems are being
sequence of the PLUNC proteins and a developed to more precisely deliver the
predicted similarity to the known anti- AMPs to the target bacteria. Specifically Regulation of Antimicrobial Peptide
bacterial and endotoxin-binding proteins targeted antimicrobial peptides consist Expression
bactericidal/permeability-increasing pro- of a targeting peptide, linker region and Rather than use AMPs as exogenous
tein (BPI) and lipopolysaccharide-bind- antimicrobial peptide component. The therapeutic agents, the stimulation of
ing protein (LBP), it was predicted that targeted peptides retained antimicrobial endogenous peptide expression is a pos-
these proteins contribute to host-defense activity and selectively killed targeted sible approach to antimicrobial therapy.
in the oral cavity and airways (Bingle bacteria in mixed cultures of Pseudo- Although many AMPs are regulated by
and Gorr 2004). Comparative analysis monas aeruginosa, S. mutans, Escher- bacteria and bacterial toxins (Diamond
of known anti-endotoxin peptides in BPI ichia coli and Staphylococcus epidermis et al. 2008, Gorr 2009, Dommisch et al.
and LBP (Dankesreiter et al. 2000) with (He et al. 2009). Using this building 2010) this is not an attractive option for
therapy. However, alternative regulatory resistance, and concomitant broad anti- Conclusions
mechanisms have been described. Thus, inflammatory activities. On the other While treatment of periodontitis with
LL-37 and hBD-2 are up-regulated by hand a number of disadvantages must conventional antibiotics has had mixed
1,25-dihydroxy vitamin D3 in several be overcome, including the systemic success and does not appear to be effec-
human cell types (Wang et al. 2004) and and local toxicity, reduced activity based tive in the absence of mechanical deb-
PSP expression is up-regulated by 17-b on salt, serum, and pH sensitivity, sus- ridement (Herrera et al. 2008), AMPs
estradiol in human gingival epithelial ceptibility to proteolysis, pharmacoki- have unique properties that may make
cells (Shiba et al. 2005). netic and pharmacodynamic issues, them suitable for the prevention or
An interesting regulatory system for sensitization and allergy after repeated elimination of oral biofilms and the
antimicrobial peptides has been des- application, natural resistance, confound- associated inflammation of gingival tis-
cribed in the intestine (Gudmundsson ing biological functions (e.g., angiogen- sue. Many AMPs are both bactericidal
et al. 2010). Shigellosis is associated esis) and high manufacturing costs and anti-inflammatory and can block the
with reduced intestinal levels of LL-37 (Gordon et al. 2005). Despite the discov- inflammatory effects of bacterial toxins.
and hBD-1. The rabbit homologue of LL- ery of hundreds of AMPs in the past 25 The peptides have co-evolved with oral
37, CAP-18 is induced by sodium buty- years, only few are in current clinical use. bacteria, which have not developed sig-
rate in a rabbit model of the disease. This One such peptide is polymyxin B, which nificant resistance to these peptides.
treatment reduced clinical illness and the is in clinical use for ophthalmic infec- Although these peptides do not appear
bacterial load in the stool (Raqib et al. tions, often in formulations that include to prevent biofilm formation on their
2006). A clinical trial is underway to Neosporin. The peptide shows high anti- own, they are often found in saliva in
determine if butyrate is an effective treat- bacterial activity but is also associated less than effective concentrations. Thus,
ment in human shigellosis patients (Clin- with significant toxicity. Thus, polymyx- they may prove effective when adminis-
icalTrials.gov Identifier: NCT00800930). in use was discontinued for many years tered in higher doses or as an adjunct to
It is not clear if this approach can be but has recently resumed in lower doses. other therapy. Peptides of human origin
directly applied to periodontal disease Polymyxin E (colistin) is also in clinical are unlikely to exhibit toxicity in near
since gingival epithelial cells undergo use but is associated with similar nephro- physiological concentrations. A key to
apoptosis and autophagy in the presence toxicity and neurotoxicity at high doses. successful antimicrobial peptide therapy
of butyrate (Tsuda et al. 2010). Despite these drawbacks, the rise in may be the use of multiple AMPs to
A current clinical trial is examining bacterial resistance to other antibiotics mimic the in vivo mix of antibacterial
the expression of chromogranin A in has led to a re-evaluation of these ‘‘old- activities.
periodontitis. The endocrine protein er’’ AMPs (Stein and Raoult 2002). Forty-five antibacterial proteins are
chromogranin A has been detected in A recent review noted that no new found in human saliva and many of
saliva (Kanno et al. 2000) and is the peptide antibiotics have been approved these are also found in gingival crevi-
precursor for potential antimicrobial pep- by the US Food and Drug Administration cular fluid. Careful mining of the
tides (Shooshtarizadeh et al. 2009). The in recent years (Gordon et al. 2005), increasing number of proteins identified
goal is to determine if chromogranin although research and clinical trials are in saliva, gingival crevicular fluid and
peptides exhibit antimicrobial activity in ongoing for several promising peptides oral epithelial cells by proteomic
gingival crevicular fluid samples from and peptide mimetics (Zhang and Falla approaches, promises to reveal addi-
diabetic patients with and without perio- 2009). These include the Histatin 5 tional AMPs. Much work remains to
dontitis (ClinicalTrials.gov Identifier: derived 12-mer (PAC 113) (PacGen be performed to determine how these
NCT00399620). This trial is diagnostic Biopharmaceuticals, Vancouver, British peptides interact to achieve the antibac-
and does not include treatment or pre- Columbia, Canada), which appeared to terial properties of healthy oral tissues.
vention using the chromogranin peptides. prevent the development of experimental
gingivitis in healthy subjects (Paquette
et al. 2002). PAC-113 has completed
phase IIb clinical trials as a mouth rinse Acknowledgements
Clinical Applications for the treatment of oral candidiasis in The author’s work on Parotid Secretory
The limits of conventional antibiotic/anti- HIV patients. Other AMPs include the Protein and antimicrobial peptides was
microbial approaches in the treatment of magainin mimetic mPE (Polymedix Inc., supported by PHS Grant numbers 2R01
periodontitis are well recognized (Her- Radnor, PA, USA); a synthetic decapep- DE012205 and 1R01 DE017989 from
rera et al. 2008, Sanz and Teughels 2008, tide KSL-W and a mimetic based on the National Institute for Dental and
Angaji et al. 2010). Thus, new defensins (PMX-30063, Polymedix Inc.) Craniofacial Research at the National
approaches for non-mechanical perio- (Zhang and Falla 2009). The latter has Institutes of Health. Additional support
dontal therapy are desirable. An attractive passed Phase I safety evaluation in from the University of Louisville and
option is to mine the innate host-defense healthy subjects and Phase II trials are University of Minnesota Schools of
system for potential therapeutic com- planned for 2010. The functional families Dentistry is gratefully acknowledged.
pounds that would be effective against of AMPs are large and diverse. Thus,
periodontal pathogens with limited side while the development of antimicrobial
effects and host toxicity. The clinical use peptides has not yet resulted in new
of AMPs is associated with several per- approved therapeutics, the continued
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18-208 Moos Tower
trometry 268, 190–197. proteins identified by free flow electrophoresis-
Wilde, C., Griffith, J., Marra, M., Snable, J. & Scott, R. based peptide separation and Tandem mass spectro-
515 Delaware Street SE
(1989) Purification and characterization of human metry. Molecular and Cellular Proteomics 4, 1826– Minneapolis
neutrophil peptide 4, a novel member of the defen- 1830. MN 55455
sin family. Journal of Biological Chemistry 264, Yount, N. Y. & Yeaman, M. R. (2004) Multidimen- USA
11200–11203. sional signatures in antimicrobial peptides. Pro- E-mail: sugorr@umn.edu
Clinical Relevance 45 different AMPs that belong to Practical Implications: Antimicro-

Scientific rationale for study: Human different functional families. These bial peptide deficiency is linked to
antibiotic peptides and proteins have proteins and peptides may serve as a the development of periodontitis.
promise as novel antibiotic reagents source of novel antimicrobial agents Research on antimicrobial peptides
for the treatment of periodontal dis- that are developed to combat perio- and proteins will provide lead com-
ease. dontal pathogens with low host-toxi- pounds that could be developed into
Principal Findings: Saliva and gin- city or bacterial resistance. new treatments for periodontal dis-
gival crevicular fluid contains at least ease.

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J Clin Periodontol 2011; 38 (Suppl. 11): 126–141 doi: 10.1111/j.1600-051X.2010.01664.

Antimicrobial peptides and Sven-Ulrik Gorr and Mahsa

periodontal disease Sciences, University of Minnesota School of

Gorr S-U, Abdolhosseini M. Antimicrobial peptides and periodontal disease. J Clin

Table 1. Functional classes of antimicrobial proteins

1 Adrenomedullin b-2-microglobulin Calgranulin A Lactoperoxidase Cystatin A Lysozyme C

See Table 2 for additional details for individual proteins.

r 2011 John Wiley & Sons A/S

et al. (1997) et al. (1997)

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recognition protein 4 Gram-negative bacteria LD99 200 mg/ml (2007)

Prolatin-inducible PIP MS Streptococci Nistor et al.

Psoriasin S100A7 MS E. coli MBC 100 mg/ml Michalek et al.

Salivary agglutinin DMBT1 MS Oral streptococci Ligtenberg et

1, present; *, HNP 1–3 (neutrophil defensins).

r 2011 John Wiley & Sons A/S

mice, suggesting that prolactin-induci- teins, including activation of coagula- Peroxidases

r 2011 John Wiley & Sons A/S

r 2011 John Wiley & Sons A/S

r 2011 John Wiley & Sons A/S

r 2011 John Wiley & Sons A/S

r 2011 John Wiley & Sons A/S

Clinical Relevance 45 different AMPs that belong to Practical Implications: Antimicro-

r 2011 John Wiley & Sons A/S

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