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Antimicrobial Agents and Chemotherapy, November 2006, p. 3856-3860, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00082-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Hyaluronic Acid Binding Peptides Prevent Experimental Staphylococcal Wound Infection

Kathleen J. Zaleski,1* Tadeusz Kolodka,2 Colette Cywes-Bentley,1 Rachel M. McLoughlin,1 Mary L. Delaney,3 Bernard T. Charlton,2 Wendy Johnson,2 and Arthur O. Tzianabos1,4

Department of Medicine, Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,1 Cangene Corporation, Winnipeg, Manitoba R3T 5Y3, Canada,2 Department of Pathology, Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,3 Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 021154

Received 19 January 2006/ Returned for modification 22 February 2006/ Accepted 6 August 2006


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Staphylococcus aureus is a major cause of surgical wound infections. The development of mechanisms of antimicrobial resistance by this and other bacterial pathogens has prompted the search for new approaches to treat infectious diseases. Hyaluronic acid binding peptides have been shown to modulate cellular trafficking during host responses and were assessed for their ability to treat and possibly prevent experimental surgical wound infections caused by S. aureus. Treatment with these peptides was highly efficacious in reducing the number of S. aureus cells at the wound site and ameliorated the inflammatory host response associated with these infections. These data suggest a novel approach for the treatment and prophylaxis of staphylococcal wound infections in the clinical setting.


   INTRODUCTION
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Staphylococcus aureus causes severe systemic human infections, such as pneumonia and sepsis, and is a major cause of localized infections, such as surgical wound infections (6). Treatment of these infections is complicated by the evolution of multiple mechanisms of antimicrobial resistance by this organism (3). The increase in the number of methicillin- and vancomycin-resistant strains of S. aureus isolated from clinical cases worldwide is alarming (11). Community-acquired infection with antibiotic-resistant strains of S. aureus has become a major public health concern and has led to the investigation of alternative or adjunct approaches for treatment of staphylococcal diseases.

Hyaluronic acid (HA) is a glucosaminoglycan found in tissue spaces. Several proteins and peptides, known as hyaladherins, bind to hyaluronic acid through a variety of binding motifs. Proteins such as CD44 and TSG-6 and proteoglycans such as link protein, aggrecan, brevican, neurocan, and versican possess conserved HA binding regions of approximately 100 amino acids, known as link domains (for more information and consensus sequences, see http://www.expasy.org/prosite/PDOC00955).

Proteins such as RHAMM, cdc37, SPACR, and others bind to HA via a 9- to 11-amino-acid motif of the form B-X7-B, with B being the basic amino acid lysine or arginine and X representing nonacidic amino acids. HABP35 is the mouse RHAMM HA binding domain I sequence followed by the mouse RHAMM HA binding domain II sequence (5). HABP35 was synthesized to include both domains I and II separated by a linker (13), and it contains four B-X7-B motifs.

Another peptide isolated by phage display, Pep-1 (HABP52 in this paper), has been shown to bind to hyaluronic acid (HA) with high affinity and to inhibit leukocyte adhesion to HA. This peptide lacks similarity to the HA binding motifs discussed above, in that 2 of 16 amino acids are basic. In contrast, HABP35 possesses 11 of 27 basic residues, which may help contribute to ionic binding of this peptide to negatively charged HA. Pep-1/HABP52 inhibits contact hypersensitivity responses in mice by blocking skin-directed trafficking of inflammatory leukocytes (8, 9, 12).

Despite the ability of certain HABPs to mitigate inflammatory host responses, the activity of these peptides in animal models of bacterial infection has not been studied to date. This led us to examine if these HABPs could ameliorate surgical wound infections in a low-inoculum, clinically relevant model of S. aureus infection.


   MATERIALS AND METHODS
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Bacterial strains. S. aureus strain PS80 (serotype 8) was obtained from the American Type Culture Collection (no. 27700) and is a potent inducer of intraabdominal abscess formation (12). S. aureus COL is a methicillin-resistant strain that produces a serotype 5 capsule, as described previously (12). Staphylococci were cultivated for 24 h at 37°C on Columbia agar (Difco Laboratories, Detroit, MI) supplemented with 2% NaCl.

Peptides. HABPs are synthetic molecules 15 to 27 amino acid residues in length. HABP35 is the mouse RHAMM HA binding domain I sequence followed by the mouse RHAMM HA binding domain II sequence (13). HABP35 contains four B-X7-B motifs.

HABP42 is synthesized from D-amino acid stereoisomers, and the original sequence was isolated from a phage library based on high-affinity binding to hyaluronic acid. HABP52 was also isolated by phage display and has been shown to bind to HA with high affinity and inhibit leukocyte adhesion to HA. HABPs were synthesized with L-amino acids (except HABP42, which is all D-amino acids), and the C terminus is amidated. The peptides were synthesized by SynPep Corporation (Dublin, CA) using standard 9-fluorenylmethoxy carbonyl chemistry and purified to >95% purity. Each synthetic peptide was analyzed by reverse-phase high-performance liquid chromatography to assure the purity. The peptides (and sequences) used in this study were SCRM (HKSVSRHTSMRHSTM), HABP35 (LKQKIKHVVKLKVVVKLRSQLVKRKQN), HABP42 (all D-amino acids; STMMSRSHKTRSHHV), and HABP52 (GAHWQFNALTVRGGGS). SCRM represents a control peptide with a random sequence of amino acids.

Antimicrobial activity testing. The antimicrobial activity of HABP35 and HABP52 was determined by using a modified CLSI (formerly NCCLS) macrodilution broth method (10). S. aureus PS80 was grown overnight on tryptic soy agar plates containing 5% sheep blood. Colonies were suspended in sterile saline and diluted to achieve final concentrations of 5 x 102, 5 x 103, 5 x 104, and 5 x 105 CFU/ml in each tube containing 5 ml of Mueller-Hinton and HABP35 or HABP52. The HABPs were tested at 1-, 10-, or 100-µg/ml concentrations, with a bacterial concentration of 5 x 105 CFU/ml. In addition, HABPs were tested at 100 µg/ml with bacterial concentrations of 5 x 102, 5 x 103, and 5 x 105 CFU/ml. Once inoculated, the tubes were incubated in ambient air at 37°C, and bacterial concentrations were determined at 4, 8, and 24 h. Modification of testing parameters included the 10-fold dilution of the HABPs and the determination of bacterial counts at 4, 8, and 24 h rather than the visual determination of growth or inhibition.

Mouse model of S. aureus wound infection. The mouse model of S. aureus surgical wound infection was first described by McLoughlin et al. (7). Mice (C57BL6; male, 6 to 8 weeks old) were obtained from Charles River Laboratories (Wilmington, MA). All animal experiments were performed in accordance with the guidelines set forth by the Harvard Medical School Standing Committee on Animals. Briefly, groups of mice (n = 4/group/experiment) were anesthetized and their right thighs were shaved, and the surgical area was disinfected with iodine and 70% ethanol. A 1-cm incision was made in the right thigh muscle and then closed with one 4-0 silk suture. Ten microliters of an S. aureus suspension ranging in dose from 102 to 104 CFU was introduced into the incision under the suture. The skin was closed with four additional Prolene sutures. The mice were euthanized at 3 days postsurgery, and the wounded muscle tissue was excised, weighed, and homogenized in 1 ml of tryptic soy broth. Serial dilutions of the homogenates were plated in duplicate on tryptic soy agar plates supplemented with 500 mg/ml streptomycin (Sigma, St. Louis, MO), and results were expressed as CFU/gram of tissue. Peptides were administered to animals in four ways. For most experiments, peptides were solubilized in phosphate-buffered saline (PBS) containing the appropriate concentration of bacteria and were simultaneously injected into the wound in a 10-µl volume. For other experiments, peptides were solubilized in PBS and administered with a pipette into the wound in a 10-µl volume following challenge with bacteria. A 100-µg dose was used for most experiments, and no differences were observed between these two methods of administration. For therapeutic and systemic studies, peptide was administered via a 1-ml tuberculin syringe fitted with a 25-gauge needle in a 0.25-ml volume. Therapeutically, the peptide was injected into the thigh muscle containing the wound, 2 cm away from the incision site. For systemic experiments, peptide or a PBS control was given intraperitoneally immediately following the wound infection procedure.

Histologic analysis of wounds. Muscle tissue was harvested from mice at designated intervals postsurgery, fixed in 10% buffered formalin, and mounted in paraffin; 5- to 6-µm sections were cut and stained with hematoxylin and eosin for microscopic examination.

Statistical analyses. All animal experiments were performed at least twice, and the data were pooled. Comparison of S. aureus CFU/gram of tissue was made by the Welch modification of the unpaired Student t test (InStat; GraphPad Software, San Diego, CA).


   RESULTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
HABPs do not exhibit antimicrobial activity for S. aureus. The antimicrobial activity of the different HABPs was assessed in a modified CLSI broth macrodilution antimicrobial assay. Peptides were assessed at concentrations of 1 to 100 µg/ml for their ability to inhibit the growth of S. aureus PS80. Cultures were seeded at 5 x 105 CFU/ml and allowed to grow overnight. Quantitative cultures performed at 4, 8, and 24 h demonstrated that growth of S. aureus was not inhibited by HABP35 or HABP52 compared with controls that did not contain the HABPs (Fig. 1). In additional experiments, addition of 100 µg/ml of HABP35 or HABP52 did not inhibit cultures seeded with lower inocula (5 x 102, 5 x 103, or 5 x 104 CFU/ml) (data not shown).


Figure 1
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  		FIG. 1. HABPs do not possess antimicrobial activity for S. aureus PS80. The antimicrobial activity of two HABPs was tested according to the CLSI broth macrodilution method. Five-milliliter cultures of Mueller-Hinton broth were seeded with 5 x 105 CFU/ml of S. aureus PS80 and incubated with increasing 10-fold concentrations of HABP35 (A), HABP52 (B), or PBS. Quantitative cultures were performed at 4, 8, and 24 h. Incubation of either peptide with concentrations as high as 100 mg/ml did not inhibit bacterial growth.

 
Effect of HABP treatment on the pathogenesis of staphylococcal wound infections. A surgical wound infection model was employed to evaluate the in vivo activity of the HABPs. This model was developed as a low-inoculum model of S. aureus infection, where inocula as low as 10 CFU result in bacterial loads of 106 to 107 CFU/g tissue (7). Therefore, this model more closely approximates the clinical progression of staphylococcal infections than models requiring inocula of 106 to 108 CFU (3, 6).

Administration of HABP35, HABP52, or HABP42 (100 µg) to the wounds of mice at the time of challenge with 102 CFU resulted in a decrease in bacterial burden at the wound site 3 days later compared with treatment with PBS (Fig. 2A). Treatment with HABP35 or HABP52 resulted in a significant decrease (P < 0.0001 and P < 0.01, respectively, compared with the PBS control). Treatment with the SCRM control peptide did not have this effect.


Figure 2
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  		FIG. 2. Effect of HABP treatment on surgical wound infection caused by S. aureus. The ability of HABPs to ameliorate surgical wound infections caused by S. aureus was assessed. Different HABPs and a control scrambled peptide (SCRM) were used to treat wounds at the time of infection with 102, 103, or 104 CFU of S. aureus PS80. (A) Treatment with 100 µg of HABP35 or HABP52 significantly reduced the bacterial burden in wounds infected with 102 CFU of S. aureus PS80 compared with PBS treatment or a control SCRM peptide (*, P < 0.0001 versus PBS; **, P < 0.01 versus PBS). (B) Treatment with 100 mg of HABP35 or HABP52 reduced the bacterial burden in wounds infected with 103 CFU of S. aureus (*, P < 0.0001 compared with PBS). (C) Treatment with HABP35 does not reduce bacterial load in wounds infected with 104 CFU of S. aureus.

 
Treatment of mice with HABP35 or HABP52 was also effective against challenge with a 10-fold higher inoculum (103 CFU) compared with the PBS control (Fig. 2B). Quantitative culture of mice challenged with this inoculum and with PBS resulted in ~107 CFU/g tissue, whereas treatment with HABP35 or HABP52 yielded an ~3-log reduction in bacterial numbers. In contrast, treatment with HABP35 did not have this effect when an inoculum of 104 CFU was employed. Treatment with this peptide did not reduce bacterial counts in wounds compared with PBS treatment of these animals (Fig. 2C).

Dose response of HABP treatment. The effect of HABP dose was determined in the next series of experiments. Mice were treated with 10, 50, or 100 µg of HABP35 at the time of challenge with 102 CFU of S. aureus (Fig. 3). Treatment with 50 or 100 µg was the most effective in reducing bacterial burden (50-µg dose versus PBS, P < 0.005; 100-µg dose versus PBS, P < 0.0001). However, this activity waned when a 10-µg dose was used.


Figure 3
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  		FIG. 3. Dose response of HABP35 treatment of surgical wounds. The protective activity of HABP35 was assessed in a dose-response experiment in which decreasing concentrations of this HABP were evaluated in the surgical wound model. The challenge dose of S. aureus was 102 CFU (n = 4 mice/group). *, P < 0.005 (50-µg dose versus PBS); **, P < 0.0001 (100-µg dose versus PBS).

 
Gross pathology and histologic analysis of host response. Gross pathological examination of animals challenged with 102 CFU S. aureus and treated with PBS revealed a purulent inflammatory response localized around the suture site (Fig. 4A). In contrast, mice treated with HABP35 (100 µg) exhibited much less inflammation (Fig. 4B). Histologic examination of these wounds confirmed these findings. PBS-treated wounds exhibited a massive inflammatory cell infiltrate at the suture site that extended into the surrounding muscle (Fig. 4C) primarily comprised of polymorphonuclear leukocytes (PMNs) and fibrin. Treatment with HABP35 resulted in significantly fewer PMNs infiltrating to the wound site, with less fibrin deposition (Fig. 4D).


Figure 4
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  		FIG. 4. Gross pathology and histological analysis of HABP-treated wounds. Wounds were inoculated with 102 CFU of S. aureus PS80 and treated with 100 µg of HABP35 or PBS at the time of challenge. A) Wounds treated with PBS were inflamed, purulent, and fibrotic (arrow). B) Wounds treated with HABP35 were not inflamed and contained less pus and fibrosis. C) Histologic analysis revealed that wounds treated with PBS exhibited a severe cellular infiltrate comprised of PMNs, mononuclear cells, and macrophages (arrow). This infiltrate was accompanied by edema and early-stage necrosis. D) In contrast, wounds treated with HABP35 had a less severe cellular infiltrate and a mitigated inflammatory response. Pictures are representative of four mice examined per group.

 
Effect of therapeutic treatment with HABP35. The ability of HABP35 to reduce the extent of wound infection in mice when administered 2 or 6 h following challenge was determined. In these experiments, HABP35 (100 µg) was administered via a 25-gauge syringe (0.25 ml) into the thigh muscle containing the sutured incision but outside of the incision itself. The peptide or PBS was administered at the time of challenge (t = 0 h) or 2 or 6 h following challenge (t = 2 or 6 h). Administration of the peptide at the time of challenge resulted in a significant decrease in bacterial counts in the wound (Fig. 5A; P < 0.001 compared with PBS treatment), which demonstrated that administration of the peptide distal to the incision itself had a similar effect as placing the peptide directly into the wound with a pipette.


Figure 5
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  		FIG. 5. Effect of therapeutic treatment and activity against MRSA infection. A) Therapeutic effect of HABP35. Animals were challenged with 102 CFU of S. aureus and treated with 100 µg of HABP35 or PBS administered into the thigh muscle via syringe transverse to the wound site at the time of challenge (t = 0) or 2 h later (t = 2 h). Treatment with HABP35 at 0 or 2 h significantly reduced the bacterial burden at the wound site (*, P < 0.001). B) Treatment with HABP35 ameliorates wound infection by MRSA strain COL. The efficacy of HABP35 treatment to prevent infection by an MRSA strain was assessed. Animals were challenged with 102 CFU of S. aureus and were treated with 100 µg of HABP35 or PBS. Treatment with HABP35 significantly reduced the bacterial burden at the wound site (*, P < 0.001).

 
Treatment with HABP35 2 h after challenge also resulted in a significant reduction in bacterial burden in the wound (Fig. 5A; P < 0.001 compared with PBS). In contrast, treatment with HABP35 at 6 h did not result in reduced bacterial counts (data not shown). These data demonstrate that treatment with an HABP could be effective even when given in a therapeutic mode 2 h following challenge.

HABP treatment ameliorates wound infection caused by MRSA. The ability of HABP35 to ameliorate wound infection caused by an antibiotic-resistant strain of S. aureus, methicillin-resistant S. aureus (MRSA) strain COL, was assessed in the model. Mice were challenged with 102 CFU of this strain and treated at the time of challenge with HABP35 (100 µg). For these experiments, HABP35 was directly inoculated into the incision following challenge. Treatment with HABP35 significantly reduced the bacterial burden in the wound (Fig. 5B; P < 0.001) by approximately 2 logs compared with PBS-treated control animals.


   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Community-acquired antibiotic-resistant S. aureus is becoming an important public health problem. The appearance of new strains armed with an array of virulence factors and resistance mechanisms has been associated with high morbidity and mortality (3). The failure of standard chemotherapy in the treatment of S. aureus infections and the ability of HABPs to modulate the host response to inflammatory stimuli led us to consider their use in the treatment of experimental staphylococcal wound infection.

S. aureus is the most common cause of surgical wound infections in humans (4). A wound infection model that mimics S. aureus infection in a surgical setting was used. In this model, as few as 10 CFU initiates infection, and bacterial numbers increase in vivo by three to four orders of magnitude (7), mimicking the clinical setting where low inocula likely initiate infection. It should be noted that most models of staphylococcal disease require ≥106 CFU to establish infection (2, 3).

The data presented herein clearly demonstrate that treatment with HABPs significantly reduces bacterial burden in staphylococcal wound infections. This reduction was typified by a 2- to 3-log decrease in bacterial numbers compared with control groups. This is a striking effect, given the plethora of virulence factors elaborated by this organism. It is interesting to note that while HABP42 is a hyaluronic acid binding peptide, it was not as active as HABP35 or HABP52. It is possible that this difference is due to the fact that HABP42 is synthesized from D-amino acid stereoisomers, while the others were synthesized from L-stereoisomers.

The reduction in bacterial burden was associated with a concomitant amelioration of the inflammatory host response normally observed with this infection. Gross pathological and subsequent histologic examination showed a marked decrease in inflammation at the wound site, a finding consistent in all animals examined.

Treatment with the peptide was efficacious when administered directly into the wound following bacterial challenge at this site or when given via a syringe into the same thigh muscle containing the wound but approximately 2 cm away from the wound site. Interestingly, administration of HABP35 via a systemic (intraperitoneal) route at the time of challenge in the wound did not reduce the bacterial load (data not shown). Finally, treatment with the peptide in a therapeutic mode 2 h after challenge resulted in a significant reduction in bacterial counts.

The demonstration that HABP35 had similar activity against an MRSA in this model indicates that this approach may be useful in addressing infections by antibiotic-resistant strains of S. aureus. It is clear that a new approach is warranted in the treatment of staphylococcal disease, and it may be that an adjunct treatment that could enhance the activity of antimicrobial agents will be of clinical benefit. Further study of the activity of HABPs in vivo will address this question.

The mechanism by which the HABPs prevent surgical wound infections is not known. In broth dilution testing, these peptides demonstrated that they do not exhibit direct antimicrobial activity in vitro. The ability of HABP35 to ameliorate infection when administered into the thigh muscle (distal to the incision) as long as 2 h after bacterial challenge also indicated that there is not a direct antimicrobial effect in vivo.

An alternative explanation could be that the HABPs can modulate the development of host inflammatory responses in vivo to effectively minimize bacterial infection. The ability of HABPs to inhibit inflammatory host cell trafficking has been demonstrated in other models (8, 9), and this ability may be critical in controlling a localized S. aureus infection. Caver et al. as well as Gresham and coworkers have shown that by limiting an overwhelming PMN response to sites of staphylococcal infection the bacterial burden can be reduced, because S. aureus can survive inside of PMNs during the infectious process and contribute to the pathogenesis of infection (1, 5). Therefore, modulation of PMN trafficking to the wound site by HABPs may attenuate infection in a similar manner. This question is under further investigation.

In summary, treatment with HABPs can significantly reduce the bacterial burden and inflammation associated with staphylococcal wound infections in a clinically relevant animal model. This treatment was also effective against an antibiotic-resistant strain of S. aureus and when administered in a therapeutic mode 2 h after challenge. Given the magnitude of problems associated with the treatment of infectious diseases in this era of antibiotic resistance, it is clear that new approaches are required. The data presented in this study reveal a novel way to consider treating S. aureus infections in the clinical setting.


   ACKNOWLEDGMENTS
 
This work was supported by Cangene Corporation.

We thank John Warner for help in generating photographic images.


   FOOTNOTES
 
* Corresponding author. Present address: Shire Pharmaceuticals, 700 Main Street, Cambridge, MA 02139. Phone: (617) 613-4068. Fax: (617) 613-4022. E-mail: kzaleski{at}shire.com. Back


   REFERENCES
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Antimicrobial Agents and Chemotherapy, November 2006, p. 3856-3860, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00082-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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