AU2021101008A4 - Use of capsaicin and colistin in preparing a medicament for inhibiting acinetobacter baumannii infection - Google Patents
Use of capsaicin and colistin in preparing a medicament for inhibiting acinetobacter baumannii infection Download PDFInfo
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- AU2021101008A4 AU2021101008A4 AU2021101008A AU2021101008A AU2021101008A4 AU 2021101008 A4 AU2021101008 A4 AU 2021101008A4 AU 2021101008 A AU2021101008 A AU 2021101008A AU 2021101008 A AU2021101008 A AU 2021101008A AU 2021101008 A4 AU2021101008 A4 AU 2021101008A4
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- colistin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention discloses a use of capsaicin and colistin in preparing a medicament for
inhibiting Acinetobacter baumannii infection, belongs to the technical field of biomedicine,
in which the Acinetobacter baumannii includes colistin-resistant Acinetobacter baumannii.
The synergistic effects of capsaicin on colistin can recover or enhance its Anti-Acinetobacter
baumannii function, so that the infections caused by colistin-resistant Acinetobacter
baumannii can be treated. Under the combination of capsaicin and colistin, more than 50%
of colistin-resistant Acinetobacter baumannii can be killed within 12 h and the CFU per
milliliter can be decreased by more than 2log10 after 12 h, which proves that capsaicin and
colistin have a synergistic effect.
1/2
AhI3- AbIW6R
A i-9- A:DMM) B .- AffMS
-U- CoI U f:CoI
-*- C:Csp -. (:(aP
D:Cap+9o D:Cap+C 2a
6 it
C ATCC19606-R
-0-A:DMSOA
H :CoI
-4 f:CSP+C.I
41
0 i 4; 5 10 I
Fig. 1
Description
1/2
AhI3- AbIW6R
A i-9- A:DMM) B .- AffMS -U- CoI U f:CoI -*- C:Csp -. (:(aP 2a D:Cap+9o D:Cap+C
6 it
C ATCC19606-R
-0-A:DMSOA H :CoI
-4 f:CSP+C.I
41
0 i4; 510 I
Fig. 1
FIELD OF THE INVENTION The present invention relates to a technical field of biomedicine, in particular to a use of capsaicin and colistin in preparing a medicament for inhibiting Acinetobacter baumannii infection.
BACKGROUND OF THE INVENTION Acinetobacter baumannii (Ab) is an obligate aerobic non-fermenting Gram-negative bacterium. This bacterium causes a variety of infections in patients with severe underlying disease or low immunity, including ventilator-associated pneumonia, bacteremia, skin and soft tissue infections, endocarditis, urinary tract infections and meningitis. Therefore, it is particularly important to develop new strategies to treat Acinetobacterbaumanniiinfections. As a result of the lack of effective therapeutic drugs and new antibiotics, some traditional drugs such as polymyxin (colistin, polymyxin B), whose use has been discontinued, have had to be reinstated in the treatment of severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria. Colistin is highly sensitive to resistant Gram-negative bacteria and is the last resort for the treatment of severe infections by MDR Gram-negative pathogens. Unfortunately, with the increased use frequence and dosage of colistin, colistin-resistant (heterogeneous drug resistance) strains have been detected. To ensure that this last barrier against MDR Gram-negative pathogens remains effective, appropriate treatment ways to delay the emergence of colistin resistance and restore its antibacterial activity are urgently needed.
SUMMARY OF THE INVENTION In order to solve the problems existing in the prior art, the present invention provides a use of capsaicin and colistin in preparing a medicament for inhibiting Acinetobacter baumannii infection. Capsaicin and colistin can inhibit the infections caused by colistin resistant Acinetobacter baumannii.
Detailed technical solutions are as follows:
A first aspect of the present invention provides a use of capsaicin and colistin in
preparing a medicament for inhibiting Acinetobacter baumannii infection.
Preferably, the Acinetobacter baumannii includes colistin-resistant Acinetobacter
baumannii.
A second aspect of the present invention provides a medicament for inhibiting
Acinetobacter baumannii infection, wherein the medicament comprises capsaicin and
colistin which are individually packaged.
Preferably, the mass concentration of capsaicin in the medicament is 8-256 mg/L,
and the mass concentration of colistin in the medicament is 0.5-16 mg/L.
Preferably, the dosage form of the medicament includes injection form.
The foregoing technical solutions in the present invention have the following
advantages or beneficial effects:
The present invention provides the use of capsaicin and colistin in preparing a
medicament for inhibiting infections caused by Acinetobacter baumannii, especially caused
by colistin-resistant Acinetobacter baumannii. The synergistic effects of capsaicin on
colistin can recover or enhance its Anti-Acinetobacter baumannii function, so that the
infections caused by colistin-resistant Acinetobacter baumannii can be treated. Under the
combination of capsaicin and colistin, more than 50% of colistin-resistant Acinetobacter
baumannii can be killed within 12h and the CFU per milliliter can be decreased by more
than 2log10 after 12h, which proves that capsaicin and colistin have a synergistic effect.
The accompanying drawings, together with the specification, illustrate exemplary
embodiments of the present disclosure, and, together with the description, serve to explain
the principles of the present invention.
Fig. 1 shows time-kill curves of Acinetobacter baumannii strains using capsaicin
and/or colistin, wherein 'A' indicates the trend in the number of Abl3-R strain within 12
hours, 'B' indicates the trend in the number of Abl56-R strain within 12 hours, and 'C'
indicates the trend in the number of ATCC19606-R strain within 12 hours.
Fig. 2 shows the effect of capsaicin and/or colistin on Acinetobacter baumannii burden in different target tissues of the mice infected by Acinetobacter baumannii, wherein 'A' indicates the Acinetobacter baumannii burden in liver under four different treatments, 'B' indicates Acinetobacter baumannii burden in lung under four different treatments, 'C' indicates Acinetobacterbaumanniiburden in kidney under four different treatments, and 'D' indicates Acinetobacter baumanniiburden in spleen under four different treatments. Fig. 3 shows the effect of capsaicin and/or colistin on the number of Acinetobacter baumannii contained within the blood of the mice infected by Acinetobacter baumannii. DETAILED DESCRIPTION OF THE INVENTION The present invention will now be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Like reference numerals refer to like elements throughout. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms "a","an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and/or ''comprising," or "includes" and/or "including" or "has" and/or "having" when used herein,
specify the presence of stated features, regions, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and/or groups thereof. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
As used herein, "around", "about" or "approximately" shall generally mean within
20 percent, preferably within 10 percent, and more preferably within 5 percent of a given
value or range. Numerical quantities given herein are approximate, meaning that the term
"around", "about" or "approximately" can be inferred if not expressly stated. As used herein,
the term "plurality" means a number greater than one.
The present invention provides a use of capsaicin and colistin in preparing a
medicament for inhibiting Acinetobacter baumanniiinfection.
In some embodiments, the Acinetobacter baumannii is preferably colistin-resistant
Acinetobacter baumannii. Colistin and capsaicin were obtained from Selleck. Based on the
study of the effect of capsaicin on the biofilm of Acinetobacter baumannii, it indicates that
capsaicin can significantly inhibit the formation of Acinetobacter baumanniibiofilm, which
weakens the aggregation of bacterial cells, alleviates the barrier of drug diffusion and
enhances the antibacterial effect of colistin.
The present invention provides a medicament for inhibiting Acinetobacter
baumannii infection, wherein the medicament comprises capsaicin and colistin which are
individually packaged. Capsaicin can significantly decrease the colistin MICs of colistin
resistant Acinetobacter baumannii, especially decrease the colistin MICs to values lower
than the susceptibility breakpoint in most strains. The synergistic effect of capsaicin on
colistin can enhance Anti-Acinetobacter baumannii effect, so that the infections caused by
colistin-resistant Acinetobacter baumanniican be treated.
In some embodiments, the mass concentration of capsaicin in the medicament is
preferably 8-256 mg/L, more preferably 32~128 mg/L, most preferably 6490mg/L; and,
the mass concentration of colistin in the medicament is preferably 0.5-16 mg/L, more
preferably 2 mg/L in clinical practice considering the neurotoxicity and nephrotoxicity of
colistin.
In some embodiments, the solvent of capsaicin is preferably dimethyl sulfoxide
(DMSO), and the solvent of colistin is preferably ddH 20.
In some embodiments, the dosage form of the medicament includes injection form.
Hereinafter, certain exemplary examples according to the present disclosure will be
described with reference to the accompanying drawings.
Example 1 - Synergistic Effects of Colistin in Combination with Capsaicin in a
Checkerboard Assay
Isolated Acinetobacter baumannii strains Ab13 and Ab156 from different clinical
sources and the type strain ATCC 19606 were used in this study and were induced of colistin
resistance. The obtained colistin-resistant Acinetobacter baumannii were respectively
designated Ab13-R, Ab156-R, andATCC 19606-R. Acinetobacter baumannii strainsAb13,
Ab156, Ab13-R, Ab156-R and ATCC19606-R were preserved in the pathogenic
microbiology laboratory of Yangzhou University. Capsaicin was dissolved in DMSO, and
colistin was dissolved in ddH 20. The mother liquor of capsaicin or colistin was diluted with
MH broth medium to the desired concentration (27g/1000mL distilled water).
Colistin-resistant and non-resistant Acinetobacter baumannii strains were treated
with capsaicin alone at concentrations of 256 mg/L, 128 mg/L, 64 mg/L, 32 mg/L and 16
mg/L. The MICs of capsaicin were >512 mg/L for all of the strains tested, revealing the lack
of antimicrobial activity of capsaicin alone.
Checkboard assays were carried out to test the synergistic effects of the combination
of colistin and capsaicin. In brief, increasing concentrations of capsaicin (0-256 mg/L) in
each column and increasing concentrations of colistin (0-64 mg/L) in each row were set up
in 96-well microtiter plates. Each well was inoculated with 100 L of suspension containing
5x105 CFU/mL of the test strain, and then the required concentration of drugs was added to
a final volume of 200 [L. The plates were incubated at 37 °C for 24 h. As shown in Table 1,
capsaicin could decrease the colistin MICs values of the strains Ab13-R, Ab156-R and
ATCC19606-R by 8-128 times, 16~128 times and 128-2048 times, respectively.
Checkerboard assays revealed capsaicin at different concentrations all could significantly
decrease the colistin MICs of colistin-resistant Acinetobacterbaumannii, especially decrease
the colistin MICs to values lower than the susceptibility breakpoint (2 mg/L) in most cases.
These results suggested that the synergistic effect of capsaicin on colistin had recovered or
enhanced its Anti-Acinetobacter baumannii effect, so that the infections caused by colistin
resistant Acinetobacter baumannii could be treated.
Table 1 - Colistin MICs of colistin-resistant Acinetobacterbaumannii strains when treated with capsaicin at different concentrations
Colistin MIC (mg/L) at different Capsaicin concentrations (mg/L)
Capsaicin concentrations (mg/L) Strain Only colostin 256 128 64 32 16
Abl3 1 - - - -
Abl3-R 128 1 4 4 4 16 Ab156 2 - - - -
Abl56-R 64 0.5 0.5 0.5 0.5 0.5
ATCC19606 0.5 - -
ATCC19606-R 1024 0.5 0.5 0.5 0.5 0.5
Example 2 - Synergistic Effects of Capsaicin and Colistin in Time-kill Assays To further confirm the synergism of capsaicin with colistin, time-kill assays were carried out with the three colistin-resistant Acinetobacter baumannii strains. The 5x109 CFU/mL Ab13-R, 5x106 CFU/mL Ab156-R and 5x106 CFU/mL ATCC19606-R inoculums were subjected to time-kill assays using different drugs, i.e. colistin alone or in combination with capsaicin, then were cultured on a shaker at 37 °C and sampled every 2 h for plate count. The colistin concentration used was the clinical breakpoint for susceptibility (2 mg/L), the capsaicin concentration used for Abl3-R was 256 mg/L, while that used for Abl56-R and ATCC19606-R was 32 mg/L. As shown in Fig. 1, there is no significant difference in bacterial growth within 12 hours between the three colistin-resistant strains using the drug alone and the control group. However, under the combination of capsaicin and colistin, more than 50% of colistin-resistant Acinetobacter baumannii could be killed within 12h and the CFU per milliliter was decreased by more than 2log10 after 12h, which proved that capsaicin and colistin had a synergistic effect. Example 3 - Synergistic Effects of Capsaicin and Colistin in vivo experiments For the in vivo experiments, mice were injected intraperitoneally with Abl3-R suspension (2x1o7 CFU/mouse). No deaths were recorded at 24h after infection. This indicated that the pathogenicity of Ab13-R, which was isolated and induced to be resistant to colistin, was weak. Then, mice were infected intraperitoneally with Ab13-R suspension and were divided into four groups. The control group received sterile PBS, and the drug treatment groups were treated 24 hours after the mice were infected and were administrated with two divided doses with an interval of 2 hours, in which the colistin group received 5 mg/kg colistin, the capsaicin group received 200 pmol/L capsaicin solution, and the combination group received 1 mg/kg colistin and 100pmol/L capsaicin solution. 3 days after the treatment, bacterial burden in blood (from the mice eyeball), lung, kidney, spleen and liver were detected. As shown in Table 2, Fig. 2 and Fig. 3, blood and all organs in the mice were infected with Acinetobacter baumannii. Furthermore, the combination group (colistin and capsaicin) showed reduced Acinetobacter baumannii densities in the target tissues
(blood, lung, liver, spleen, and kidney). Table 2 - Capsaicin and/or colistin on bacterial burden in different target tissues of the mice infected by Acinetobacterbaumannii (**P<0.01).
Log10 Drug treatment groups (4 mice/group)
CFU/(mL/g) Control Colostin Capsaicin Combination
Blood 4.60±0.16 4.67i0.27 4.36k0.28 2.73±0.32**
Liver 4.74£0.31 4.5510.25 4.7010.29 3.38i0.21**
Spleen 4.24±0.22 4.56±0.16 4.46+0.45 3.18±0.22**
Kidney 4.6540.16 4.5910.31 4.59±0.45 3.32±0.47**
Lung 4.26A0.19 4.15-0.25 4.18+0.41 3.49+0.24**
Once the nature of the invention has been sufficiently described, as well as preferred
embodiment, it is stated to the appropriate effects that the described elements may be
modified, provided that this does not imply an alteration of the essential characteristics of
the invention, which are claimed below.
Claims (5)
1. A use of capsaicin and colistin in preparing a medicament for inhibiting Acinetobacter baumanniiinfection.
2. The use as claimed in Claim 1, wherein the Acinetobacter baumannii includes colistin-resistant Acinetobacter baumannii.
3. A medicament for inhibiting Acinetobacter baumannii infection, wherein the medicament comprises capsaicin and colistin which are individually packaged.
4. The medicament as claimed in Claim 3, wherein the mass concentration of capsaicin in the medicament is 8-256 mg/L, and the mass concentration of colistin in the medicament is 0.5~16 mg/L.
5. The medicament as claimed in Claim 3 or Claim 4, wherein the dosage form of the medicament includes injection form.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010466197.3A CN111420026B (en) | 2020-05-28 | 2020-05-28 | Application of capsaicin and colistin in preparation of medicines for inhibiting acinetobacter baumannii infection |
| CN2020104661973 | 2020-05-28 |
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| AU2021101008A4 true AU2021101008A4 (en) | 2021-04-29 |
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| CN (1) | CN111420026B (en) |
| AU (1) | AU2021101008A4 (en) |
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| CN111420026A (en) | 2020-07-17 |
| CN111420026B (en) | 2022-08-05 |
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