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CN-121987761-A - Combination of lysin and aminoglycosides against diseases caused by gram-positive and gram-negative bacteria in non-human animals

CN121987761ACN 121987761 ACN121987761 ACN 121987761ACN-121987761-A

Abstract

The present invention relates to a combination of lysin and an aminoglycoside antibiotic for the treatment of diseases caused by gram-positive and gram-negative bacteria in non-human animals. The invention has proven to be particularly useful in relation to the treatment of mastitis in non-human animals. In particular bovine mastitis can be well addressed by the present invention.

Inventors

  • G. SCHIFFER
  • S. Falk
  • G. Dolby
  • W. Ville
  • J. Kobelin

Assignees

  • 礼蓝动物保健有限公司

Dates

Publication Date
20260508
Application Date
20180214
Priority Date
20170217

Claims (15)

  1. 1. A combination of lysin and at least one aminoglycoside antibiotic for the treatment of a non-human mammal against a disease caused by gram-negative bacteria and/or gram-positive bacteria.
  2. 2. The conjugate for use in therapy according to claim 1, wherein the non-human mammal is a female animal having a breast.
  3. 3. The combination for use in therapy according to claim 2, wherein the female non-human mammal having a breast is a cow and the disease is bovine mastitis.
  4. 4. A conjugate for use in therapy according to claim 2 or 3, wherein the conjugate is administered intramammary.
  5. 5. The conjugate for use in therapy according to claim 3 or 4, wherein bovine mastitis is clinically significant bovine mastitis.
  6. 6. The conjugate for use in therapy according to claim 3 or 4, wherein bovine mastitis is subclinical bovine mastitis.
  7. 7. The conjugate for use in therapy according to any one of claims 4 to 6, wherein the lysin is provided at a dose of 25 to 1000 mg per breast area.
  8. 8. The combination for use in therapy according to any one of claims 1 to 7, wherein at least one aminoglycoside antibiotic is kanamycin or neomycin, preferably at least one aminoglycoside antibiotic is neomycin.
  9. 9. The combination for use in therapy according to any one of claims 3 to 8, wherein bovine mastitis is caused by staphylococcus bacteria, streptococcus bacteria, stethoscopic suppurative bacteria, corynebacterium bacteria and/or escherichia bacteria.
  10. 10. The conjugate for use in therapy according to claim 9, wherein bovine mastitis is caused by staphylococcus aureus, coagulase-negative staphylococcus, streptococcus uberis, streptococcus branchi, streptococcus agalactiae and/or escherichia coli.
  11. 11. The conjugate for use in therapy according to claim 9, wherein bovine mastitis is caused by cryptococcus suppurative and/or escherichia coli.
  12. 12. The conjugate for use in therapy according to claim 9, wherein bovine mastitis is caused by corynebacterium bovis and/or escherichia coli.
  13. 13. Pharmaceutical composition formulated for intramammary administration to cattle, characterized in that the composition comprises lysin and at least one aminoglycoside antibiotic, preferably kanamycin or neomycin.
  14. 14. Use of a lysin and at least one aminoglycoside antibiotic for the manufacture of a medicament for the treatment of mastitis in a non-human animal.
  15. 15. A method of treating mastitis, comprising the step of administering to a female non-human animal in need thereof a therapeutically effective amount of a lysin and at least one aminoglycoside antibiotic.

Description

Combination of lysin and aminoglycosides against diseases caused by gram-positive and gram-negative bacteria in non-human animals The application is a divisional application of PCT/EP2018/053667 of the application patent application entitled "combination of lysin and aminoglycosides against diseases caused by gram-positive and gram-negative bacteria in non-human animals" filed on 2.14.2018, which originally was filed on 7.30.2019 in China with a national stage application number 201880009227.9. Technical Field The present invention relates to a combination of lysin and an aminoglycoside antibiotic for the treatment of diseases caused by gram-positive and gram-negative bacteria in non-human animals. The invention has proven to be particularly useful in relation to the treatment of mastitis in non-human animals. In particular bovine mastitis can be well addressed by the present invention. Background Mastitis is an inflammation of breast tissue and is still the most common and costly disease of cows. Economic losses caused by mastitis occur in sub-clinical and clinical stages of the disease. Losses caused by subclinical mastitis have been well documented. Each doubling of Somatic Cell Count (SCC) of over 50,000 cells/ml resulted in a daily loss of 0.4 kg and 0.6 kg milk （Hortet P, H. Seegers. 1998. Calculated milk production losses associated with elevated somatic cell counts in dairy cows: review and critical discussion. Vet Res. 29(6):497-510）., respectively, from clinical mastitis, including discarded milk, temporary decline in milk yield, and premature elimination (culling) of the first-time lactating cows and older cows. Mastitis should be treated against pathogenic bacteria whenever possible. PyInd ä l ä S in IRISH VETERINARY Journal, volume 62, pages 40-44 2009, has the following recommendations for the antimicrobial treatment of clinical mastitis caused by different pathogens: The most recent pharmaceutical composition for treating bovine mastitis is Ubrolexin, a broad-spectrum antibiotic against bacteria causing both gram-positive and gram-negative mastitis. Ubrolexin is a combination of Cefalexin and kanamycin, suitable for the treatment of clinical mastitis caused by Staphylococcus aureus, streptococcus branchis, streptococcus uberis and Escherichia coli. Cefalexin, an antibiotic of the cephalosporin class, acts in an irreversible manner by binding to D-alanine transpeptidase which disrupts bacterial cell wall synthesis. Kanamycin, which is an aminoglycoside antibiotic, acts by attaching to the 30S subunit of membrane-associated ribosomes and inhibiting or interfering with bacterial protein synthesis. Thus, combinations of antibiotics, in particular aminoglycosides, with other antibiotic substances are known per se. The recurrent problem with antibiotics in the prior art is that pathogens may develop resistance to drugs used to treat the disease they cause. Accordingly, new active pharmaceutical ingredients are continually sought. The problem of developing resistance is even more serious when antibiotic substances that do not act synergistically but are directed only against different pathogens are used in combination. In those cases, pathogens that are not the primary target of the first antibiotic may develop complete resistance to such first antibiotic. Lysin was first isolated from the fermentation broth of Lysobacter (Lysobacter sp.) SC-14076 (ATCC 53042). Independently, scientists found katanosin A and B from soil bacteria associated with the genus mucor (Cytophaga) (production strain PBJ-5356). Katanosin B proved to be identical to lysin. Bacterial cell wall biosynthesis is the primary target for these antibiotics, however, the mechanism of action is different from that of vancomycin. Lysin is a cyclic depsipeptide containing several non-proteinogenic D-and L-amino acids (depsipetide). In US 4,754,018, the natural product lysin and some derivatives are described as having antibacterial activity. Isolation and antibacterial activity of lysin is also described in EP 196042 A1 and JP 01-132600. The antibacterial activity of lysin and katanosin A is further described in O' Sullivan, J. Et al, J. Antiboot (1988) 41:1740-1744, bonner, D.P. et al, J. Antiboot (1988) 41:1745-1751, shoji, J. Et al, J. Antiboot (1988) 41:713-718 and Tymiak, A. Et al, J. Org. Chem (1989) 54:1149-1157. Contrary to the mode of action of cefalexin and kanamycin, lysin has been shown to interact directly with bacterial cell wall precursor lipid II (Lee, W. Et al Am. chem. Soc. (2016) 138 (1): 100-113 and Breukink E. And de Kruijff B., nat. Rev. Drug disc. (2006) 5:321-323). Derivatives of lysin are the subject matter ：WO 2004/099239 A1、WO 2006/042653 A1、WO 2006/042654 A1、WO 2006/042655 A1、WO 2006/048139 A1、WO 2006/048140 A1、WO 2006/048156 A1、WO 2007/085456 A1、WO 2007/118691 A1 of the following patent applications and WO 2007/118693 A1. None of the listed prior art relates to the treatment of bovine mastitis with lysin. In p