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CN-122005829-A - Tobramycin-polymyxin conjugated compound and preparation method and application thereof

CN122005829ACN 122005829 ACN122005829 ACN 122005829ACN-122005829-A

Abstract

The invention discloses a tobramycin ‒ polymyxin conjugated compound, a preparation method and application thereof. The tobramycin ‒ polymyxin conjugated compound comprises tobramycin and polymyxin which are connected through chemical bonds, and specifically, the tobramycin and the polymyxin are connected through amide bonds or triazole. The tobramycin ‒ polymyxin conjugated compound disclosed by the invention can kill persistent bacteria with high efficiency under the condition of single administration, and especially, the tobramycin modified by the invention is connected with polymyxin B through an amide bond to obtain a compound AKPB1, so that the mutant strain with high persistent level of escherichia coli can be killed with high efficiency under the condition of single administration, and the dosage is low, so that the tobramycin polymyxin conjugated compound has potential important application value in the aspect of clinical antibacterial infection treatment, is expected to be used for treating bacterial infection diseases including but not limited to pneumonia, blood flow infection, urinary tract infection, respiratory tract infection, intestinal tract infection and the like, and is expected to be used for bacterial infection treatment of animals.

Inventors

  • QIAO CHUNHUA
  • ZHANG HONGYUAN

Assignees

  • 诺海医康(苏州)生物技术有限公司

Dates

Publication Date
20260512
Application Date
20260127
Priority Date
20260116

Claims (10)

  1. 1. A tobramycin-polymyxin conjugate compound comprising tobramycin and polymyxin linked by a chemical bond.
  2. 2. The tobramycin-polymyxin conjugate compound of claim 1, wherein tobramycin is linked to polymyxin by an amide bond or triazole.
  3. 3. The tobramycin-polymyxin conjugate compound of claim 1, wherein the polymyxin antibiotic comprises polymyxin or a salt, hydrate, solvate thereof.
  4. 4. A tobramycin-polymyxin conjugate according to claim 3, wherein tobramycin ‒ polymyxin conjugate is 6-methylheptanoic acid-Lys { Ac-Glu (Tobramycin-1D) } -Thr-Dab-Cyclo (Dab-dPhe-Leu-Dab-Thr) or 6-methylheptanoic acid-Lys (valeric acid-N3-Tobramycin-1 c) -Thr ‒ Dab ‒ Cyclo (Dab ‒ Dab ‒ D-Phe ‒ Leu ‒ Dab ‒ Dab ‒ Thr).
  5. 5. The process for preparing tobramycin-polymyxin conjugated compound according to claim 1, comprising the step of connecting tobramycin with polymyxin by chemical bond to obtain tobramycin-polymyxin conjugated compound.
  6. 6. A medicament for use in antibacterium comprising the tobramycin-polymyxin conjugate compound of claim 1.
  7. 7. A pharmaceutical formulation for use in antibacterial comprising the tobramycin-polymyxin conjugate of claim 1 and a clinically acceptable adjuvant.
  8. 8. Use of a tobramycin-polymyxin conjugate of claim 1, a medicament for use in antibacterium of claim 6 or a pharmaceutical formulation for use in antibacterium of claim 7 in the manufacture of a medicament for the treatment of a bacterial infection disorder, or use of a tobramycin-polymyxin conjugate of claim 1, a medicament for use in antibacterium of claim 6 or a pharmaceutical formulation for use in antibacterium of claim 7 in the manufacture of an antibiotic sensitization medicament.
  9. 9. A sterilization method characterized by using the tobramycin-polymyxin conjugate compound according to claim 1, the drug for antibacterial use according to claim 6 or the pharmaceutical preparation for antibacterial use according to claim 7.
  10. 10. The use according to claim 8 or the method of sterilization according to claim 9, wherein the bacteria comprise gram-negative bacteria, gram-positive bacteria.

Description

Tobramycin-polymyxin conjugated compound and preparation method and application thereof Technical Field The invention belongs to the biomedical technology, relates to an antibacterial drug, and in particular relates to a tobramycin-polymyxin conjugated compound, a preparation method and application thereof. Background Antibiotics have been developed slowly for nearly half a century, but the discovery and spread of clinically multi-drug resistant bacteria has a growing trend, and the development of new antibiotics has urgent and important clinical requirements. With the increasing severity of antibacterial drug resistance and drug resistance problems, the related studies are continuously in progress. Most pathogenic bacteria show retention phenomena, i.e. bacteria temporarily escape from antibiotic killing by phenotypic changes under antibiotic pressure, are reversible, and after pressure relief can resume growth and re-sensitize to drugs. And is believed to be a significant cause of chronic infections and disease persistence. A portion of the cells that remain viable after sufficient antibiotic killing (persisters) do not alter the drug minimum inhibitory concentration (Minimum inhibitory concentration, MIC) and recover to the original culture characteristics after antibiotic removal and normal growth. Thus, persisting bacteria are a significant cause of infection recurrence and chronic infections. In contrast, drug-resistant bacteria are bacteria that are resistant to one or more drugs, and that otherwise effectively inhibit or kill their loss of activity, and require an increase in drug concentration to be effective, in which case the MIC value of the drug is significantly increased. Therefore, it is difficult to improve bacterial retention by a treatment method for drug resistance. Existing antibiotic monotherapy or combination therapy often has difficulty killing pathogenic bacteria in a persistent state. Single medicine capable of efficiently killing and retaining germs in a clinically applicable concentration range has not been reported yet. The reported compound medicine is a combination of polymyxin antibiotics and aminoglycoside antibiotics, and the compound destroys cell membranes of remaining bacteria, so that most bacteria die. However, the prescription medicine needs to be used for simultaneously multiplexing two medicines according to the optimal proportion, and the toxicity problem of each of the two medicines still exists, and the metabolism problem and medicine-medicine interaction problem caused by the simultaneous administration of the two medicines are solved. In view of this, there is a need to develop new single drugs that solve the above-mentioned problems with the combination drugs and that can effectively kill pathogenic bacteria in a sustained state. Disclosure of Invention The invention discloses a tobramycin-polymyxin conjugated compound, a preparation method and application thereof, which can kill persistent bacteria with high efficiency under the condition of single administration, and particularly, the tobramycin modified by the invention is connected with polymyxin B through an amide bond to obtain a compound AKPB1, so that a mutant strain with high persistent level hipA of escherichia coli (ESCHERICHIA COLI, E.coli) and a wild E.coli with low persistent level can be killed with high efficiency under the condition of single administration. The invention adopts the following technical scheme. A tobramycin-polymyxin conjugate compound comprising tobramycin and polymyxin linked by a chemical bond. In the present invention, tobramycin and polymyxin are connected through an amide bond or triazole. In the present invention, the polymyxin antibiotic comprises polymyxin or a salt, hydrate, solvate thereof, and as an example, the polymyxin comprises polymyxin B. As an example, the tobramycin-polymyxin conjugate compound of the invention is 6-methylheptanoic acid-Lys { Ac-Glu (Tobramycin-1 d) } -Thr-Dab-Cyclo (Dab-dPhe-Leu-Dab-Thr). The invention discloses a preparation method of the tobramycin-polymyxin conjugated compound, which comprises the steps of connecting tobramycin with polymyxin through chemical bonds to obtain the tobramycin-polymyxin conjugated compound, and specifically comprises the following steps: The synthesis of the compounds AKPB1 and AKPB1 are all 20 synthesis steps, wherein the synthesis of the first 9 steps is identical to the synthesis of the last 11 steps, and the synthesis steps of the last 11 steps are different. The first 9 steps are solid phase synthesis, which comprises bonding Fmoc-Thr (tBu) -OH with 2-Cl resin, and condensing with amino acids in sequence to obtain 9 peptide ：Fmoc-Dab(Boc)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(DDE)-OH, Fmoc-Dab-Dab(Boc)-OH, Fmoc-Thr(t-Bu)-OH. The synthesis of AKPB1, the next 11 steps are that the 9 peptide obtained above is subjected to condensation reaction with Fmoc-Thr (t-Bu) -OH,