WO2011110716A2 - Compuestos peptídicos útiles como agentes antibacterianos - Google Patents
Compuestos peptídicos útiles como agentes antibacterianos Download PDFInfo
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- WO2011110716A2 WO2011110716A2 PCT/ES2011/070153 ES2011070153W WO2011110716A2 WO 2011110716 A2 WO2011110716 A2 WO 2011110716A2 ES 2011070153 W ES2011070153 W ES 2011070153W WO 2011110716 A2 WO2011110716 A2 WO 2011110716A2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000005313 fatty acid group Chemical group 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- PTCGDEVVHUXTMP-UHFFFAOYSA-N flutolanil Chemical compound CC(C)OC1=CC=CC(NC(=O)C=2C(=CC=CC=2)C(F)(F)F)=C1 PTCGDEVVHUXTMP-UHFFFAOYSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000006150 trypticase soy agar Substances 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/60—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation occurring through the 4-amino group of 2,4-diamino-butanoic acid
- C07K7/62—Polymyxins; Related peptides
Definitions
- the present invention relates to compounds that are active against Gram-positive and Gram-negative bacteria, their preparation process, pharmaceutical compositions containing them, and their use in the treatment of bacterial infections.
- Methylicin-resistant Staphylococcus aureus Vancomincin-resistant Enterococcus and certain Gram-negative bacteria such as Pseudomonas aeruqinosa, Acinetobacter baumannii and Klebsiella pneumoniae.
- Such infections are very difficult to control and a constant cause of disease and death.
- Conventional antibiotics act
- antimicrobial peptides AMP
- Antimicrobials offer a new class of therapeutic agents to which bacteria are not able to develop genetic resistance, since they act primarily on the lipid component of cell membranes.
- PxB polymyxin B
- PxB polymyxin B
- Polymyxins in particular polymyxin B, constitute a family of antibiotics discovered in 1947 with high activity against Gram-negative bacteria.
- Polymyxin B is an antibiotic lipopeptide isolated from
- Bacillus polvmvxa Its basic structure consists of a polycationic peptide cycle from which a tripeptide linked to a fatty acid chain hangs.
- Polymyxin B has resurfaced in medical practice in recent years and its use will continue to increase due to the limited development of new antibiotics by pharmaceutical companies and the increasing worldwide prevalence of nosocomial infections caused by multiresistant Gram-negative bacteria ("multidrug resistant ", MDR).
- MDR multiresistant Gram-negative bacteria
- Polymyxin B and other members of the polymyxin family are drugs that are used as a last resort to treat infections caused by multiresistant bacteria and are sometimes the only active antibiotic available.
- resistance to polymyxin is rare and generally adaptive and therefore reversible.
- Polymyxin B is also capable of inhibiting the biological activity of bacterial lipopolysaccharide (LPS) through high affinity binding to lipid A, thus being the agent of choice for the treatment of septic shock induced by LPS.
- LPS bacterial lipopolysaccharide
- polymyxin B has no activity against Gram-positive or anaerobic bacteria.
- polymyxins are of limited use because they have some
- peptide compounds with antibiotic activity that act on the lipid component of bacterial membranes and that are active against both Gram-positive and Gram-negative bacteria. These compounds are based on the structure of natural polymyxin. However, unlike polymyxins, these compounds are active not only against Gram-negative bacteria but also in Gram-positive in the micromolar range. This is advantageous since they can act in response to infections caused by both types of bacteria.
- one aspect of the present invention is related to providing compounds of formula (I),
- Rn is a peptide sequence selected from the group consisting of Ala-Leu-Arg, Ala-Leu-Arg-Ala-Leu-Arg, Gly-Arg-Val-Glu-Val-Leu-Tyr-Arg-Gly-Ser-Trp , Lys-Val-Leu, Lys-Val-Leu-Lys-Val-Leu, Leu-Met-Trp-Trp-Met-Leu,
- Orn-Orn_Orn Gln-Arg-GLy-Arg-Ala-Glu-Glu-Val-Tyr-Tyr-Ser-Gly-Thr, and Glu- (Y-Spermide) -Arg-GLy-Arg-Ala-Glu-Glu -Val-Tyr-Tyr-Ser-Gly-Thr;
- u is CH 2 or S;
- v is NH or S;
- w CH 2 or CO; with the proviso that when R 9 is CONH 2 , then one of the following conditions occurs: (a) R 5 or R 6 is -CH (CH 3 ) (OH), (b) R 5 and Re are H; (c) the configuration of C linked to R 9 is S (D-cysteine side chain) or (d) the configuration of C linked to R 5 is R; and with the proviso that when R 9 is -CH (CH 3 ) OH (threonine side chain), then R 8 is GF (CH 2 ) n where
- the compounds of formula (I) are those mentioned above where R 2 is -CH (CH 3 ) (OH).
- the compounds of formula (I) are those where u is CH 2 , v is NH, w is CO, R 9 is -CH (CH 3 ) (OH) and the configuration of C attached to R 9 is S. These compounds have the formula (la).
- the compound of formula (la) is the nonanoyl-Arq-Thr-Dab-cycle (4-10) rDab-Dab-DPhe-Leu-Arq-Dab-Thr1, (lai).
- cycle (4-10) means a macrocycle in which the terminal carboxyl of the threonine in position 10 forms an amide bond with the side chain of the Dab in position 4.
- D-amino acids The configuration of the D-amino acids has been indicated with a D. When the configuration is not indicated, it is understood that it is an L-amino acid.
- the compounds of formula (I) are those where u is S, v is S and w is CH 2 , which have the formula (Ib).
- the compounds of formula (Ib) are those compounds where R 9 is CONHRn and Rn is a peptide sequence selected from the group consisting of Ala-Leu-Arg, Ala-Leu-Arg-Ala-Leu- Arg , Gly-Arg-Val-Glu-Val-Leu-Tyr-Arg-Gly- Ser-Trp, Lys-Val-Leu, Lys-Val-Leu-Lys-Val-Leu, Leu-Met-Trp-Trp-Met -Leu, Orn-Orn-Orn, Gln-Arg-Gly-Arg- Ala-Glu-Glu-Val-Tyr-Tyr-Ser-Gly-Thr, Glu (y-sperm) -Arg-Gly-Arg-Ala- Glu-Glu-Val-Tyr-Tyr-Ser-Gly-Thr, and Glu (Arg-Gly-Arg-Ala-Glu-Glu-Val-Tyr-Tyr-Tyr-
- Trp-Trp-Met-Leu ( 6 lb);
- cycle (S-S) means a macrocycle formed by a disulfide bridge between the two tanks.
- the compounds of formula (Ib) are selected from the following list: nonanoil-Arq-Thr-Arq-cycle (SS) rCvs-Dab-Phe-Leu-Arq-Dab-Cysl, (lb 10 ) ; nonanoil-Arq-Thr-Arq-cycle (SS) rCvs-Dab-DPhe-Leu-Arq-Dab-DCys1, (Ibn); nonanoil-Arq-Thr-Dab-cycle (SS) rCvs-Dab-Phe-Leu-Arq-Dab-Cvs1, (lb 2 ); and nonanoil-Arq-Thr-Dab-cycle (SS) rCvs-Dab-DPhe-Leu-Arq-Dab-DCys1, (lb 3 ).
- the compounds of formula (Ib) are selected from nonanoyl-Arg-Thr-Arg- cycle (SS) rCvs-Dab-DPhe-Leu-Arg-Dab-DCys1, (Ibn); and nonanoil-Arg-Thr-Dab-cycle (SS) rCvs-Dab-DPhe-Leu-Arg-Dab-DCys1, (lbi 3 ).
- the compound of formula (Ib) is nonanoyl-Arg-Thr-Dab-cycle (SS) rCvs-Dab-DPhe-Leu-Arg-Dab-DCysl, (lb 13 ).
- the compounds of formula (Ib) are those in which R 6 is - (CH) (CH 3 ) (OH).
- the compounds of formula (Ib) are selected from the following list: nonanoil-Arg-Thr-Arg-cycle (SS) rCvs-Dab-DPhe-Thr-Arg-Dab-Cys1, (lb 4 ); nonanoil-Arg-Thr-Arg-cycle (SS) rCvs-Dab-Phe-Thr-Arg-Dab-Cys1, (lb 5 );
- nonanoil-Arg-Thr-Dab-cycle SS
- SS nonanoil-Arg-Thr-Dab-cycle
- SS nonanoil-Arg-Thr-Dab-cycle
- SS nonanoil-Arg-Thr-Dab-cycle
- SS nonanoil-Arg-Thr-Arg-cycle
- SS nonanoil-Arg-Thr-Arg-cycle
- SS rCvs-Dab-Trp-Thr-Arg-Dab-Cys1, (lb 8 );
- nonanoil-Arg-Thr-Arg-cycle [Cvs-Dab-DLeu-Thr-Arg-Dab-Cysl, (lb 20 ); nonanoil-Arg-Thr-Dab-cycle (SS) rCvs-Dab-DLeu-Thr-Arg-Dab-Cys1, (lb 2 i); decanoil-Arg-Thr-Arg-cycle (SS) rCvs-Dab-DTrp-Thr-Dab-Dab-Cys1, (lb 22 ); decanoil-Arg-Thr-Dab-cycle (SS) rCvs-Dab-DLeu-Thr-Arg-Dab-Cys1, (lb 23 ) decanoil-Arg-Thr-Dab-cycle (SS) rCvs-Dab-Trp-Thr- Arg-Dab-Cysl, (lb 24 ); and dodecanoyl-Arg-Thr
- the compounds of formula (Ib) are selected from the following list: nonanoil-Arg-Thr-Arg-cycle (SS) rCvs-Dab-Glv-Glv-Arg-Dab-Cys1, (lb 26 ) ;
- nonanoil-Ara-Thr-Arq-cycle SS
- SS nonanoil-Arq-Thr-Dab-cycle
- SS nonanoil-Arq-Thr-Dab-cycle
- SS nonanoil-Arg-Thr-Dab-cycle
- SS nonanoil-Arg-Thr-Dab-cycle
- SS rCvs-Dab-Glv-Leu-Arg-Dab-Cys1, (lb 30 ).
- the compounds of formula (Ib) are selected from the following list: octanoyl-Arq-Thr-Arq-cycle (SS) rCvs-Dab-DPhe-Leu-Arq-Dab-Cvs1, (lb 3 i) ; (S) -6-methyl heptanoyl-Arq-Thr-Arq-cycle (SS) rCvs-Dab-DPhe-Leu-Arg-Dab-Cys], (lb 32 );
- the most preferred compounds of formula (I) are those from the following list: nonanoyl-Arq-Thr-Dab-cycle (4-10) rDab-Dab-DPhe-Leu-Arq-Dab-Thr1, (lai); nonanoil-Arq-Thr-Dab-cycle (SS) rCvs-Dab-DPhe-Leu-Arq-Dab-Cvs1-Glv-Arq- Val-Glu-Val-Leu-Tyr-Arg-Gly-Ser-Trp], ( lb 3 );
- the compounds of the present invention can be prepared by solid phase synthesis Fmoc / tBu.
- the preparation process for each amino acid comprises the following steps: (i) various resin washes with
- DMF ⁇ , ⁇ -dimethylformamide
- the peptides obtained by the above procedures can be purified by preparative HPLC, whereby a purity greater than 90%, preferably greater than 95%, can be obtained.
- the compounds of the present invention are easily prepared by chemical synthesis according to the procedure mentioned above while commercial polymyxin is obtained by fermentation.
- Another aspect of the present invention are the compounds of formula (I), for use as antibacterial agents against Gram-positive bacteria.
- the medically relevant Gram-positive bacteria are several of the well-known genus such as Bacillus, Listeria, Staphylococcus, Micrococcus, Streptococcus, Enterococcus, Clostridium, Mvcoplasma and
- Gram-positive bacteria are selected from Micobacterium phlei, Staphylococcus aureus and Micrococcus luteus. In a particular embodiment, Gram-positive bacteria are selected from Micobacterium phlei ATCC41423, Staphylococcus aureus ATCC 6538 and Micrococcus luteus ATCC 9341.
- This aspect of the invention can also be formulated as the use of a compound as defined above, for the preparation of a medicament for the treatment of a bacterial infection caused by Gram-positive bacteria in a mammal, including a human.
- the invention is also related to a method for the treatment and / or prophylaxis of a mammal, including a human, that suffers or is susceptible to bacterial infections caused by Gram-positive bacteria, in particular to the aforementioned infections, said method comprising administration to said patient of a therapeutically effective amount of compounds of the present invention, together with pharmaceutically acceptable excipients or carriers.
- Gram-negative bacteria include Escherichia coli, Salmonella, Enterobacteriaceae, Pseudomonas, Moraxella, Helicobacter, Leqionella, Hemophilus influenzae, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Serratia marcescens and Acinetobacter baumannii.
- Gram-negative bacteria are selected from Salmonella tvphimurium, Pseudomonas aeruginosa, Escherichia coli and Acinetobacter sp.
- Gram-negative bacteria are selected from Salmonella tvphimurium 14028, Pseudomonas aeruginosa 9027, Escherichia coli 8739 and Acinetobacter sp ATCC 5798.
- This aspect of the invention can also be formulated as the use of a compound of formula (I) as defined above for the preparation of a medicament for the treatment of a bacterial infection caused by Gram-negative bacteria in a mammal, including a human.
- the invention is also related to a method for the treatment and / or prophylaxis of a mammal, including a human who suffers or is susceptible to bacterial infections caused by Gram-negative bacteria, in particular to any of the infections mentioned above, the method
- the compounds of the present invention can be used analogously to other known antibacterial agents. These can be used alone or in combination with other appropriate bioactive compounds.
- the compounds of formula (I) can be used in the treatment of bacteremias and / or septicemia resulting from infections by Gram-negative bacteria, administered alone or in combination with conventional antibiotics.
- the compounds of formula (I) of the present invention are used topically, or orally for decontamination of the digestive tract prior to surgery.
- a further aspect of the present invention is related to a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of the compounds of formula (I), together with appropriate amounts of pharmaceutically acceptable excipients or carriers.
- compositions may be prepared by combining the compounds of formula (I) of the present invention with pharmaceutically acceptable solid or liquid carriers or excipients, following standard pharmaceutical practices.
- compositions of the present invention can be administered in a manner suitable for the disease to be treated, for example by oral, parenteral, inhalation, rectal, transdermal or topical route.
- said pharmaceutical compounds or compositions are preferably administered at a dose to obtain or maintain a concentration, that is, a amount or level in blood of the active component in the patient following the treatment that is effective as an antibacterial.
- said amount or dose that is effective as an antibacterial will be in the approximate range of 0.1 to 100 mg / kg, plus
- the doses may vary depending on the requirements of the patient, the severity of the bacterial infection to be treated and the particular compound used.
- Boc tert-butoxycarbonyl
- Dab 2,4-diaminobutyric acid
- DIEA N.N-diisopropylethylamine
- Dde N - [1 - (4,4-dimethyl-2,6-dioxcyclohex-1-ylidene) ethyl]
- DIPCDI ⁇ , ⁇ '-diisopropylcarbodiimide
- DMF N.N-dimethylformannide
- ES electrospray
- Fmoc 9-fluorenylmethoxycarbonyl
- HATU 2- (7-Aza-1 H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium hexafluorophosphate
- HBTU 2- (1 H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium hexafluorophosphate
- HOBt 1-
- the general solid phase synthesis protocol Fmoc / tBu has been used to prepare the compounds of the examples.
- the Fmoc / tBu synthesis protocol for each synthetic cycle consists of the following steps: (i) washing the resin with DMF (5 x 30 s); (ii) treatment with 20% piperidine / DMF (1 x 1 min + 2 x 10 min, Fmoc deprotection); (iii) washing with DMF (5 x 30 s); (iv) acylation with the amino acid Fmoc protected (3 times excess) and HBTU / DIEA (3: 6 times excess, respectively) in the minimum amount of DMF; (v) wash with DMF (5 x 30 s) and CH 2 CI 2 (5 x
- the general method of de-anchoring and deprotection of the peptides consisted of a treatment with TFA / thioanisole / 1,2-ethanodithiol / triisopropylsilane / water
- Each peptide crude was then dissolved in a DMSO solution in 10% water at a concentration of approximately 1 mM or slightly lower for the formation of the disulfide bond.
- the solution was stirred in an open system for 12-36 h. Cyclization took place by oxidation in the air that was followed by HPLC and MS.
- the peptides were characterized by MALDI-TOF mass spectrometry in a VOYAGER-DE (PerSeptive Biosystems) mass spectrometer.
- the amino acids of the Sequence were introduced according to a standard Fmoc / 'Bu solid phase synthesis protocol as described above.
- nonanoic acid (134 ⁇ , 0.85 mmol, 3 times excess) was coupled with HBTU / DIEA (3 and 6 times excess, respectively) in the minimum amount of DMF.
- the resin was washed with DMF (5 x 30 s) and CH 2 CI 2 (5 x 30 s).
- the weight of the peptide crude after de-anchoring and deprotection according to the method indicated above was 300mg (yield 90%). Purification by preparative HPLC yielded 30mg of pure peptide (10% yield).
- Amino acids of the sequence were introduced according to a standard Fmoc / 'Bu solid phase synthesis protocol as described above.
- the amino acid bridge Dab 4 was introduced as Fmoc-Dab (Dde) -OH.
- nonanoic acid (228 ⁇ , 1.44 mmol, 3 times excess) was introduced by activating it with HBTU / DIEA (3 and 6 times excess,
- the protected peptide was treated with hydrazine (1% in DMF) to deprotect the Dde group.
- the peptide was removed from the resin with a gentle treatment with TFA (1% in CH2CI2) keeping the rest of the protecting groups intact (of type tBu and Pbf). Cyclization between Dab 4 and Thr 10 in C-terminal was carried out in DMF: CHCI 3 (1: 1, 0.3M peptide concentration) with
- the cyclic and protected peptide crude was purified on a silica column and then treated with the TFA / thioanisole / 1, 2-ethanodithiol / triisopropylsilane / water acidolytic solution (70: 10: 10: 1: 3.5; 3h) to remove the rest of protective groups.
- the weight of the peptide crude obtained was 130mg (yield 21%). Purification by preparative HPLC yielded 1.1 mg of pure peptide (8.5% yield).
- the antibacterial activity of synthetic lipopeptides was determined in sterile 96-well plates (Corning Costar 3598 microtiter plates) with a final volume of 200 ⁇ _ as follows: aliquots (100 ⁇ _) of a bacterial suspension at a concentration of 10 5 colony forming units / mL in culture medium (MH, Muller Hinton Broth, Difco, USA) at pH 7.4, were added to 100 ⁇ _ of lipopeptide solution prepared from a stock solution in water of 1 mg / mL, in dilutions double dilution series in MH at pH 7.4 (Jorgensen & Turnide, 2003).
- Microorganisms were stored in cryoballs (EAS Victoria, France) at -20 ° C.
- the strains of the bacteria used to carry out the antibacterial activity test were obtained from: the American Type Culture Collection (ATCC, Rockville, MD, USA):
- the molecular weight of the compounds of the invention is greater than that of PxB, which means that the MIC antibacterial activity expressed in micromolar units instead of ⁇ g ml is greater.
- Table 4 Antibacterial activity (MIC) in Gram negative expressed in a micromolar units Salmonella compound Pseudomonas Escherichia Acinetobacter (microM) tvphimurium aeruqinosa coli 8739 so ATCC
- Acinetobacter sp ATCC 5798 is a model of Acinetobacter baumannii that is one of the most problematic bacteria in nosocomial infections
- Staphylococcus aureus is one of the important bacteria because of the resistance it generates to antibiotics
- Micobacterium phlei is a model non-pathogen of the causative agent of tuberculosis, Mycobacterium tuberculosis.
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Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/583,091 US20130053305A1 (en) | 2010-03-10 | 2011-03-09 | Peptide compounds that can be used as antibacterial agents |
RU2012143143/04A RU2012143143A (ru) | 2010-03-10 | 2011-03-09 | Пептидные соединения, пригодные для использования в качестве антибактериальных средств |
EP11752896A EP2548883A2 (en) | 2010-03-10 | 2011-03-09 | Peptide compounds that can be used as antibacterial agents |
BR112012022589A BR112012022589A2 (pt) | 2010-03-10 | 2011-03-09 | compostos de peptídeo úteis como agentes antibacterianos |
CA2792674A CA2792674A1 (en) | 2010-03-10 | 2011-03-09 | Peptide compounds that can be used as antibacterial agents |
CN2011800220133A CN102939301A (zh) | 2010-03-10 | 2011-03-09 | 作为抗菌剂使用的肽化合物 |
JP2012556552A JP2013521330A (ja) | 2010-03-10 | 2011-03-09 | 抗菌剤として有用なペプチド化合物 |
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ES201000349A ES2374779B1 (es) | 2010-03-10 | 2010-03-10 | Compuestos péptidicos útiles como agentes antibacterianos. |
ESP201000349 | 2010-03-10 |
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EP (1) | EP2548883A2 (es) |
JP (1) | JP2013521330A (es) |
CN (1) | CN102939301A (es) |
BR (1) | BR112012022589A2 (es) |
CA (1) | CA2792674A1 (es) |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2506715A1 (es) * | 2013-04-12 | 2014-10-13 | Universitat De Barcelona | Compuestos peptídicos útiles como agentes antibióticos |
EP3173421A1 (en) | 2015-11-30 | 2017-05-31 | Universitat de Barcelona | Peptidic compounds useful as antibacterial agents |
EP3636659A1 (en) | 2018-10-08 | 2020-04-15 | Universitat de Barcelona | Polymyxin-based compounds useful as antibacterial agents |
Families Citing this family (3)
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CA3023438A1 (en) * | 2016-05-13 | 2017-11-16 | Spero Potentiator, Inc. | Spr741 human pharmacokinetics and efficacious dose |
AU2018359018B2 (en) | 2017-11-02 | 2022-11-24 | The University Of Queensland | Peptide antibiotics |
PL441789A1 (pl) * | 2022-07-19 | 2024-01-22 | Uniwersytet Warszawski | Lipooligomoczniki, kompozycja farmaceutyczna, oraz lipooligomoczniki do zastosowania jako lek |
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US6951652B2 (en) * | 1998-07-29 | 2005-10-04 | Biosynth S.R.L. | Vaccine for prevention of gram-negative bacterial infections and endotoxin related diseases |
WO2001044272A2 (en) * | 1999-12-15 | 2001-06-21 | Cubist Pharmaceuticals, Inc. | Daptomycin analogs as antibacterial agents |
NZ544750A (en) * | 2003-07-17 | 2009-06-26 | Migenix Inc | Compositions of amphomycin or aspartocin based lipopeptide antibiotic derivatives and methods of use thereof |
US20060004185A1 (en) * | 2004-07-01 | 2006-01-05 | Leese Richard A | Peptide antibiotics and peptide intermediates for their prepartion |
CN1616484A (zh) * | 2004-09-27 | 2005-05-18 | 沈阳药科大学 | 一种新的环肽类抗肿瘤抗病毒抗菌活性化合物 |
CN101189253A (zh) * | 2004-11-12 | 2008-05-28 | 丘比斯特药物股份有限公司 | 抗感染脂肽类 |
CN101602792B (zh) * | 2009-04-14 | 2012-02-01 | 华东师范大学 | 一种新型抗菌脂肽及其制备和应用 |
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2011
- 2011-03-09 BR BR112012022589A patent/BR112012022589A2/pt not_active IP Right Cessation
- 2011-03-09 WO PCT/ES2011/070153 patent/WO2011110716A2/es active Application Filing
- 2011-03-09 US US13/583,091 patent/US20130053305A1/en not_active Abandoned
- 2011-03-09 JP JP2012556552A patent/JP2013521330A/ja not_active Withdrawn
- 2011-03-09 RU RU2012143143/04A patent/RU2012143143A/ru not_active Application Discontinuation
- 2011-03-09 CA CA2792674A patent/CA2792674A1/en not_active Abandoned
- 2011-03-09 EP EP11752896A patent/EP2548883A2/en not_active Withdrawn
- 2011-03-09 CN CN2011800220133A patent/CN102939301A/zh active Pending
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2506715A1 (es) * | 2013-04-12 | 2014-10-13 | Universitat De Barcelona | Compuestos peptídicos útiles como agentes antibióticos |
WO2014167160A1 (es) * | 2013-04-12 | 2014-10-16 | Universitat De Barcelona | Compuestos peptídicos útiles como agentes antibióticos |
EP3173421A1 (en) | 2015-11-30 | 2017-05-31 | Universitat de Barcelona | Peptidic compounds useful as antibacterial agents |
WO2017093210A1 (en) | 2015-11-30 | 2017-06-08 | Universitat De Barcelona | Peptidic compounds useful as antibacterial agents |
EP3636659A1 (en) | 2018-10-08 | 2020-04-15 | Universitat de Barcelona | Polymyxin-based compounds useful as antibacterial agents |
WO2020074405A1 (en) | 2018-10-08 | 2020-04-16 | Universitat De Barcelona | Polymyxin-based compounds useful as antibacterial agents |
Also Published As
Publication number | Publication date |
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ES2374779A1 (es) | 2012-02-22 |
CA2792674A1 (en) | 2011-09-15 |
WO2011110716A3 (es) | 2012-12-20 |
JP2013521330A (ja) | 2013-06-10 |
ES2374779B1 (es) | 2012-12-27 |
US20130053305A1 (en) | 2013-02-28 |
EP2548883A2 (en) | 2013-01-23 |
CN102939301A (zh) | 2013-02-20 |
BR112012022589A2 (pt) | 2016-08-30 |
RU2012143143A (ru) | 2014-04-20 |
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