MEANS AND METHODS FOR TREATING BACTERIAL INFECTIONS

Abstract

The present invention relates to a pharmaceutical composition comprising or consisting of a combination of (a) two or more peptides, each peptide consisting of or comprising 17 to 23 amino acids, wherein the amino acids in positions 1 to 23, counted from the N-terminus, are as follows (1) G, S or lacking; (2) C or lacking; (3) K or R; (4) K or R; (5) Y, W or F; (6) K or R; (7) K or R; (8) F, W or L; (9) K or R; (10) K or L or lacking; (11) W, L or F; (12) K or R; (13) F, Y or C; (14) K or R; (15) G or Q; (16) K or R; (17) F, L or W; (18) F or W; (19) F, L or W; (20) W or F; (21) C or lacking; (22) F or G or lacking; (23) G or lacking; or (b) one or more peptides, each peptide consisting of or comprising 17 to 23 amino acids, wherein the amino acids in positions 1 to 23, counted from the N-terminus, are as follows (1) G, S or lacking; (2) C or lacking; (3) K or R; (4) K or R; (5) Y, W or F; (6) K or R; (7) K or R; (8) F, W or L; (9) K or R; (10) K or L or lacking; (11) W, L or F; (12) K or R; (13) F, Y or C; (14) K or R; (15) G or Q; (16) K or R; (17) F, L or W; (18) F or W; (19) F, L or W; (20) W or F; (21) C or lacking; (22) F or G or lacking; (23) G or lacking, and one or more antibiotics selected from small organic molecule antibiotics such as ceftriaxone, oxacillin, amoxicillin, amikacin, ciprofloxacin, erythromycin, imipenem and tetracycline, and peptidic antibiotics such as daptomycin and vancomycin.

Claims

1. A pharmaceutical composition comprising or consisting of a combination of (a) two or more peptides, each peptide consisting of or comprising 17 to 23 amino acids, wherein the amino acids in positions 1 to 23, counted from the N-terminus, are as follows (1) G, S or lacking; (2) C or lacking; (3) K or R; (4) K or R; (5) Y, W or F; (6) K or R; (7) K or R; (8) F, W or L; (9) K or R; (10) K or L or lacking; (11) W, L or F; (12) K or R; (13) F, Y or C; (14) K or R; (15) G or Q; (16) K or R; (17) F, L or W; (18) F or W; (19) F, L or W; (20) W or F; (21) C or lacking; (22) F or G or lacking; (23) G or lacking; or (b) one or more peptides, each peptide consisting of or comprising 17 to 23 amino acids, wherein the amino acids in positions 1 to 23, counted from the N-terminus, are as follows (1) G, S or lacking; (2) C or lacking; (3) K or R; (4) K or R; (5) Y, W or F; (6) K or R; (7) K or R; (8) F, W or L; (9) K or R; (10) K or L or lacking; (11) W, L or F; (12) K or R; (13) F, Y or C; (14) K or R; (15) G or Q; (16) K or R; (17) F, L or W; (18) F or W; (19) F, L or W; (20) W or F; (21) C or lacking; (22) F or G or lacking; (23) G or lacking, and one or more antibiotic.

2. The pharmaceutical composition of claim 1, wherein the one or more antibiotics are small organic molecule antibiotics or peptidic antibiotics.

3. The pharmaceutical composition of claim 2, wherein the small organic molecule antibiotics are selected from the group consisting of ceftriaxone, oxacillin, amoxicillin, amikacin, ciprofloxacin, erythromycin, imipenem, and tetracycline.

4. The pharmaceutical composition of claim 2, wherein the peptidic antibiotics are selected from the group consisting of daptomycin and vancomycin.

5. The pharmaceutical composition of claim 1, wherein (a) the combination is synergistic, and wherein synergism preferably occurs with regard to antibacterial activity; and/or (b) the pharmaceutical composition includes a broad-spectrum antibiotic.

6. The pharmaceutical composition of claim 1, wherein the combination is a combination of (i) a peptide comprising the sequence of SEQ ID NO: 1 and a peptide comprising the sequence of SEQ ID NO: 2; (ii) a peptide comprising the sequence of SEQ ID NO: 1 and an antibiotic, wherein the antibiotic is a broad-spectrum antibiotic; or (iii) a peptide comprising the sequence of SEQ ID NO: 2 and an antibiotic, wherein the antibiotic is a broad-spectrum antibiotic.

7. The pharmaceutical composition of claim 1, wherein the combination is a combination of a peptide comprising the sequence of SEQ ID NO: 1, a peptide comprising the sequence of SEQ ID NO: 2 and a broad-spectrum antibiotic.

8. A method for treating or ameliorating one or more conditions selected from sepsis, bacterial infections of the respiratory tract, bacterial infections of the gastrointestinal tract, bacterial infections of the urogenital tract, necrotizing fasciitis, bacterial infections of burns, bacterial wound infections, and bacterial infections of the skin, comprising administering the pharmaceutical composition of claim 1 to a patient in thereof.

9. A method for promoting wound healing comprising administering the pharmaceutical composition of claim 1 to a patient in need thereof.

10. The method of claim 8, wherein the bacterial infection of the respiratory tract causes tuberculosis, cystic fibrosis or chronic obstructive pulmonary disease (COPD).

11. The method of claim 8, wherein the bacterial infection of the gastrointestinal tract causes Crohn's disease.

12. The method of claim 8, wherein the condition is caused by Gram positive and/or Gram negative bacteria, wherein the Gram positive and/or Gram negative bacteria are selected from the group consisting of Staphylococcus such as Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium such as Mycobacterium tuberculosis such as multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, Pseudomonas such as Pseudomonas aeruginosa and multidrug-resistant Pseudomonas aeruginosa (MDRPA), Enterococcus such as vancomycin-resistant Enterococcus (VRE), Haemophilus such as Haemophilus influenzae, E. coli such as extended-spectrum beta-lactamase (ESBL) producing E. coli, Klebsiella such as Klebsiella pneumonia, β-hemolytic Streptococcus such as group A Streptococcus such as Streptococcus pyogenes, and Acinetobacter such as Acinetobacter baumannii.

Description

[0085] FIG. 1: Bacterial growth in presence and absence of agents of the invention.

[0086] FIG. 2: Inactivation of a biofilm from Pseudomonas aeruginosa with GFP-labelled bacteria (GFP: Green-Fluorescent Protein). Living bacteria: white, inactivated bacteria: dark.

[0087] FIGS. 3A-3C: Peptide 19-2.5/Peptide 9-4LF/levofloxacin (3A). Peptide 19-2.5/Peptide 9-4LF/levofloxacin (3B). The area under the curve (AUC) is a measure of the antimicrobial effectiveness of the drugs, with lowest values exhibiting the strongest effects (3C).

[0088] FIG. 4: Wound before and after daily treatment at t=0, 3 months and 6 months.

[0089] FIG. 5: Does dependent inhibition of M. tuberculosis-induced TNF formation of human peripheral blood mononuclear cells by Peptide 19.2.5. Supernatants of Isoniazid-treated M. tuberculosis bacteria (0,1 μg/ml; 72 h) were left untreated or incubated for 30 min with the peptides X, Y, Z at the concentrations indicated. Equal amounts were subsequently added to human PBMC (1×10.sup.6/ml) and incubated for further 24 h. The TNF formation was measured by ELISA (R&D Systems).

[0090] FIG. 6: Aspidasept® inhibits maturation and migration of MoDCs.

[0091] FIGS. 7A-7B: Aspidasept® (FIG. 7A, Pep19-2.5) and Aspisasept II (FIG. 7A, Pep 19-4LF) reduce IL-8 release in TLR2/6-activated keratinocytes, whereas the control peptide Pep19-2.5gek was completely inactive (FIG. 7B).

[0092] FIG. 8: Inhibition of biofilm formation by Aspisasept II (Pep 19-4LF) with and without levofloxacin.

[0093] FIG. 9: Synergistic effect of the combination of levofloxacin with a peptide of the invention. Data were obtained from growth experiments in Mueller-Hinton (cation adjusted) with continuous shaking at 37° C. using Bioscreen C, Labsystem, Helsinki, Finland. Concentrations were adjusted after checkerboard analysis, once Fractional Inhibitory Concentrations (FIC) were calculated. All cases resulted in a FIC index <0,5, indicating synergistic effect. Results show the average of three independent experiments.

[0094] FIGS. 10A-10B: Synergistic effect of the combination of gentamycin with Aspidasept® (Pep19-2.5) (10A) and the combination of oxacillin with Aspisasept II (Pep 19-4LF) (10B), respectively.

[0095] FIGS. 11A-11B: Synergistic effect of the combination of two peptides of the invention (Aspidasept® and Aspidasept II) against Acinetobacter baumannii (FIG. 11A) and Moraxella catarrhalis (FIG. 11B).

[0096] The Examples illustrate the invention.

Example 1

Growth of Escherichia coli ESBL (CUN E20) in the Presence of Combinations of Ceftriaxon and Peptides of the Invention

[0097] The ability of the peptides to induce bacterial sensitization to antibiotics was determined by a standard checkerboard titration method in 96-well polystyrene microtiter plates [Eliopoulos GM, Moellering, RC: Antimicrobial combinations. In Antibiotics in Laboratory Medicine 4th edition. Edited by: Lorian V. Baltimore: The Williams and Wilkins Co; 1996:330-396]. For this purpose, serial dilutions of the two antimicrobial agents were mixed together in a microtiter plate so that each row contained a fixed amount of one agent and increasing amounts of the other. Inocula consisted of 1×10.sup.5 CFU/mL, approximately in Mueller-Hinton (MH) medium (Difco Laboratories, Sparks, MD, USA). To assess the synergy between peptides, the Fractional Inhibitory Concentration (FIC) index of each combination was calculated according to the following formula: [(A)/MICA]+[(P)/MICP]=FICA+FICP=FIC index, where MICA and MICP are the MICs of the two agents determined separately, and (A) and (P) are the MICs of the agents when determined in combination. A given peptide-peptide combination was considered as synergistic if its FIC index was 0.5. Peptides with a MIC higher than the maximum concentration tested (250 μg/mL) were arbitrarily assigned a MIC value of 500 μg/mL.

TABLE-US-00001 TABLE 1 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 4LF 8 Positive Control P19-2.5 16 P19-2.5 8 P19-2.5 4 P19-2.5 2 P19-2.5 1 P19-2.5 0.5 19-2.5 0.25 19-2.5 0.12 19-2.5 0.06 19-2.5 0.03 of Growth (no 4LF 8 4LF 8 4LF 8 4LF 8 4LF 8 4LF 8 4LF 8 4LF 8 4LF 8 4LF 8 Antimicrob.) CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 4LF 4 Positive P19-2.5 16 P19-2.5 8 P19-2.5 4 P19-2.5 2 P19-2.5 1 P19-2.5 0.5 19-2.5 0.25 19-2.5 0.12 19-2.5 0.06 19-2.5 0.03 Control of 4LF 4 4LF 4 4LF 4 4LF 4 4LF 4 4LF 4 4LF 4 4LF 4 4LF 4 4LF 4 Growth (no Antimicrob.) CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 4LF 2 Positive Control P19-2.5 16 P19-2.5 8 P19-2.5 4 P19-2.5 2 P19-2.5 1 P19-2.5 0.5 19-2.5 0.25 19-2.5 0.12 19-2.5 0.06 19-2.5 0.03 of Growth (no 4LF 2 4LF 2 4LF 2 4LF 2 4LF 2 4LF 2 4LF 2 4LF 2 4LF 2 4LF 2 Antimicrob.) CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 4LF 1 Positive Control P19-2.5 16 P19-2.5 8 P19-2.5 4 P19-2.5 2 P19-2.5 1 P19-2.5 0.5 19-2.5 0.25 19-2.5 0.12 19-2.5 0.06 19-2.5 0.03 of Growth (no 4LF 1 4LF 1 4LF 1 4LF 1 4LF 1 4LF 1 4LF 1 4LF 1 4LF 1 4LF 1 Antimicrob.) CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 4LF 0.5 Positive Control P19-2.5 16 P19-2.5 8 P19-2.5 4 P19-2.5 2 P19-2.5 1 P19-2.5 0.5 19-2.5 0.25 19-2.5 0.12 19-2.5 0.06 19-2.5 0.03 of Growth (no 4LF 0.5 4LF 0.5 4LF 0.5 4LF 0.5 4LF 0.5 4LF 0.5 4LF 0.5 4LF 0.5 4LF 0.5 4LF 0.5 Antimicrob.) P19-2.5 16 P19-2.5 8 P19-2.5 4 P19-2.5 2 P19-2.5 1 P19-2.5 0.5 19-2.5 0.25 19-2.5 0.12 19-2.5 0.06 19-2.5 0.03 Sterility Positive Control 4LF 8 4LF 8 4LF 8 4LF 8 4LF 8 4LF 8 4LF 8 4LF 8 4LF 8 4LF 8 control of Growth (no (No Antimicrob.) inoculum) P19-2.5 16 P19-2.5 8 P19-2.5 4 P19-2.5 2 P19-2.5 1 P19-2.5 0.5 19-2.5 0.25 19-2.5 0.12 19-2.5 0.06 19-2.5 0.03 Sterility Positive Control control of Growth (no (No Antimicrob.) inoculum) CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 CFX 2 Sterility Positive Control P19-2.5 16 P19-2.5 8 P19-2.5 4 P19-2.5 2 P19-2.5 1 P19-2.5 0.5 19-2.5 0.25 19-2.5 0.12 19-2.5 0.06 19-2.5 0.03 control of Growth (no (No Antimicrob.) inoculum) CFX: Ceftriaxone; P19-2.5: Peptide 19-2.5; 4LF: Peptide 19-4LF; Numbers are expressed in μg/mL. Squares in grey and white correspond to microplate wells with and without growth, respectively.

[0098] The MIC values for the individual agents are as follows: Peptide 19-4LF: 16 μg/ml; Peptide 19-2.5: 128 μg/ml; Ceftriaxon: 16 μg/ml.

[0099] The index of Fractioned Inhibitory Concentration (FIC) is used as a measure of synergy. Double and triple synergy, respectively, were found for the following combinations:

[0100] Binary combination Cef+Peptide 19-2.5: FIC 0,375; binary combination Cef+Peptide 19-4LF: FIC 0.5; binary combination Peptide 19-4LF+Peptide 19-2.5: FIC 0.5; and ternary combination Cef+Peptide 19-2.5+Peptide 19-4LF: FIC 0.375.

Example 2

Synergistic Effects on Growth of MRSA

[0101] Growth curves of Methicillin Resistant Staphylococcus aureus ATCC 43300 (MRSA) exposed at time 0 to combinations of Pep 19-2.5 (8 μg/mL), Pep 19-4LF (2 μg/mL) and oxacillin (4 μg/mL) are shown in FIG. 1.

[0102] The inhibitory activity of combinations were determined by an automated turbidimetric-based system (Bioscreen C, Labsystem, Helsinki, Finland), which measures absorbance of the culture at regular intervals. Assays were performed in MH broth using Bioscreen polystyrene honeycomb 100-well plates. Inocula consisted of 1×10.sup.5 CFU/mL, approximately in Mueller-Hinton (MH) medium (Difco Laboratories, Sparks, MD, USA). Cell suspensions were grown at 37° C. with shaking (control set at “medium r.p.m.” position) and the absorbance was determined every 15 min for at least 48 h.

[0103] The absorbance of the cultures was measured every 15 minutes using an automated Bioscreen C system.

Example 3

Inactivation of Biofilm

[0104] The data shown in FIG. 2 indicate that already after short-time treatment (1 h) most bacteria are inactivated. The representative data shown in FIG. 2 indicated that after short-time of Peptide 19-4LF addition (1h) the most bacteria are inactivated. The micrographics shown that only a small fraction of the surface was covered by live bacteria forming a biofilm after 1 h (B) compared with the untreated one (A). The degree of reduction in life bacteria was very obvious, suggesting the Peptide 19-4LF can penetrate the extracellular polymeric substance (EPS) matrix and kill the bacteria after a short time period.

[0105] The data shown in FIG. 8 were obtained in experiments carried out using the Center for Disease Control (CDC) Biofilm Reactor (CBR). In this case, clinical strain Pseudomonas aeruginosa PS4 was incubated in TSB under continuous shaking for 24 hours, followed by additional 24 hours growth with a flow of diluted TSB. Samples received treatments during another 24 hours dissolved at Phosphate Buffer at 37° C. Biofilms were scraped and serially diluted prior to plating and counting. For confocal microscopy, Biofilms were stained using Live/Death BacLight (Life technologies, Carlsbad, California, USA). Results show the average of two independent experiments.

Example 4

Kinetics of Inhibitory Synergistic Action: Antibiotic Peptides of the Invention in Combination with Levofloxacin

[0106] Combinations of Peptide 19-2.5 and Peptide 19-4LF with the antibiotic levofloxacin (third generation drug from the group of fluorochinolones) and combinations of Peptide 19-2.5 and Peptide 19-4LF alone have been tested on multiresistant bacteria from Pseudomonas aeruginosa PS4.

[0107] In particular, the inhibitory activity of combinations were determined by an automated turbidimetric-based system (Bioscreen C, Labsystem, Helsinki, Finland), which measures absorbance of the culture at regular intervals. Assays were performed in MH broth using Bioscreen polystyrene honeycomb 100-well plates. Inocula consisted of 1×10.sup.5 CFU/mL, approximately in Mueller-Hinton (MH) medium (Difco Laboratories, Sparks, MD, USA). Cell suspensions were grown at 37° C. with shaking (control set at “medium r.p.m.” position) and the absorbance was determined every 15 min for at least 48 h. Each experiment was repeated three times independently and the results were analyzed with the Prism program. For this purpose, first the area under the curve was obtained for each triplicate and the average result was statistically analyzed using the nonparametric Mann-Whitney U supplemented with Kruskal Wallis test for pairwise comparisons.

[0108] In FIGS. 3 and 9, the growth of the bacteria (measured optically: optical density) is plotted versus time (in hours). Both combinations, the peptides with the antibiotic as well as the peptides alone are potent synergistic combinations, evidenced by FIC values below 0.5 (FIC=0.31 in FIG. 9).

[0109] The peptides alone as well as with antibiotics (beside levofloxacin also gentamycin) act synergistically against multi-resistant strains from Pseudomonas aeruginosa as well as from Acinetobacter baumanii.

[0110] Kinetics of inhibitory synergistic action: antibiotic peptides of the invention in combination with gentamycin and oxacillin, respectively.

[0111] The data shown in FIGS. 10A-10B were obtained in growth experiments in Mueller-Hinton (cation adjusted) with continuous shaking at 37° C. using Bioscreen C, Labsystem, Helsinki, Finland. Concentrations were adjusted after checkerboard analysis, once Fractional Inhibitory Concentrations (FIC) were calculated. All cases resulted in a FIC index <0,5, indicating synergistic effect. Results show the average of three independent experiments.

Example 5

Healing Attempt According to the German Arzneimittelgesetz § 4b with a Non-Approved Drug

[0112] A male patient (78 years old) had—due to a cured tumor in the back—an open wound (see picture at t=0). Because of the bad soft tissue conditions after radiotherapy, it was decided to perform an operative rehabilitation which, however, did not succeed. Therefore, a conservative wound treatment was initiated. The wound's localization required the involvement of an ambulant nursing service who took over the daily care. Nevertheless, in sporadic intervals, wound infections occurred which inhibited the healing process. A microbiological analysis showed the occurrence of Staphylococcus aureus, Parvimonas micra, β-hemolysing Streptococcus, and Pseudomonas aeruginosa. Over 6 years, all therapeutical approaches with different antibiotics and topically applied salve formulations failed. In November 2014 the patient was informed about the possibility of a, healing attempt′, to which he agreed. The therapy was started with 0.1% Pep19-2.5 (Aspidasept®) in salve (BACHEM Lot. 1053821 in DAC-base cream from pharmacist), which showed no effect. Only after increase of the concentration to 1% a significant effect was observed (see picture below at t=3 months in February 2015), connected with an increasing healing of the wound. Already after 2 months the diameter of the wound was reduced by 50%, and completely healed after 6 months; see FIG. 4. This therapeutically effect can be explained only from the use of the Aspidasept® salve, since all other parameters were not changed. The wound is now completely closed.

Example 6

Inhibition of the Inflammatory Response Induced by Cell-Wall Compounds of Mycobacterium tuberculosis

[0113] M. tuberculosis bacteria were treated with the anti-Mtb first line antibiotics isoniazid (INH) or rifampicin (RIF) for 3 days at 37° C. Subsequently, the supernatant of the bacterial cells was added to human mononuclear cells (5×10.sup.5 cells/a) in the absence or presence of the peptides Pep19-2.5, Pep19-12 and Pep19-2.5 Acyl (Hexanoic residue). The inflammatory response was monitored by measuring tumor-necrosis-factor α (TNFα) formation in an ELISA. It was observed that compound Pep19-2.5 exhibits the strongest anti-TNFα activity, already at a rather low concentration of 10 μg/ml the TNFα formation was inhibited (Figure on the left) by more than 50%. Other peptides with sequence variations showed a weaker inhibitory activity. As control, the inactivation of the LPS-induced TNFα production is presented for the three investigated peptides on the right side of the figure, with a very efficient inhibition as previously described by T. Gutsmann et al. (Gutsmann et al., New antiseptic peptides to protect against endotoxin-mediated shock, AAC 54, 3817-3824 (2010)). See FIG. 5.

Example 7

Aspidasept® Inhibits Maturation and Migration of MoDCs

[0114] Maturation and migration of immature dendritic cells are key steps in the initiation of adaptive immunity against pathogens. However, sustained and excessive inflammatory responses mediated by activated T cells may contribute to chronic inflammation and delayed wound healing.

[0115] In monocyte-derived dendritic cells (MoDCs), Pep19-2.5 inhibited LPS-mediated upregulation of the maturation marker CD83 and the co-stimulatory molecule CD80 at a peptide:LPS weight ratio of 1000:1. In addition, LPS-induced migration of MoDCs and CCR7 gene expression was completely blocked by Pep19-2.5; see FIG. 6.

Example 8

Aspidasept® and Aspidasept II Reduce IL-8 Release in TLR2/6-Activated Keratinocytes

[0116] It can be shown that the keratinocytes from human skin do not react to Gram-negative endotoxin (LPS), apparently due to the lack of the TLR4-receptor and the fact that most bacteria from the skin are of Gram-positive origin. Thus, the effect of Pep19-2.5 and Pep19-4LF on the toxin (pathogenicity factor) FSL-1 (fibroblast-stimulating lipopeptide), a TLR-2/6 activating compound, was checked.

[0117] It could be shown that the IL-8 inducing activity of FSL-1 was considerably reduced by the addition of the peptides already at a 10:1 weight ratio, whereas the control peptide Pep19-2.5gek, lacking the C-terminal end of the two peptides, was completely inactive; see FIGS. 7A-7B.

Example 9

Suppression of Inflammatory Responses in Skin Cells and Promotion of Keratinocyte Migration

[0118] The potential of Peptide 19-2.5 and the structurally related compound Peptide 19-4LF has been investigated for their therapeutic application in bacterial skin infections. Primary human keratinocytes responded to TLR2 (FSL-1) but not TLR4 (LPS) activation by increased IL-8 production which was determined with ELISA. Both SALPs inhibited FSL-1-induced phosphorylation of NF-κB p65 and p38 MAPK and significantly reduced IL-8 release and gene expression of IL-1β, CCL2 (MCP-1) and hBD-2. To detect phosphorylation of the intracellular proteins Western Blot was performed. Gene expression was evaluated by quantitative real-time PCR. In the MTT test cytotoxicity was observed at SALP concentrations below 10 μg/ml. In LPS-stimulated monocyte-derived dendritic cells, the peptides blocked IL-6 secretion, downregulated expression of the maturation markers CD83 and CD86— detected with flow cytometry—and inhibited CCR7-dependent migration capacity. Similarly, monocyte-derived Langerhans-like cells activated with LPS and pro-inflammatory cytokines showed reduced IL-6 levels and CD83/CD86 expression in the presence of SALPs. In addition to acute inflammation, bacterial infections often result in impaired wound healing. Since re-epithelialization is a critical step in wound repair, we tested whether Peptide 19-2.5 affects keratinocyte migration. In a scratch assay the peptide markedly promoted cell migration and accelerated artificial wound closure at concentrations as low as 1 ng/ml and was equipotent to TGF-β.

Example 10

Synergistic Action of Two Peptides of the Invention in Further Bacteria

[0119] FIGS. 11A-11B show data obtained in growth experiments in Mueller-Hinton (cation adjusted) with continuous shaking at 37° C. using Bioscreen C, Labsystem, Helsinki, Finland. Concentrations were adjusted after checkerboard analysis, once Fractional Inhibitory Concentrations (FIC) were calculated. All cases resulted in a FIC index <0,5, indicating synergistic effect. Results show the average of three independent experiments.