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Peptide antibiotics Number:6,784,283 from the United States Patent and Trademark Office (PTO) owispatent

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Title: Peptide antibiotics

Abstract: N- and C-modified linear cationic peptides having antibiotic activity are disclosed, which peptides are particularly active against gram positive bacteria.

Patent Number: 6,784,283 Issued on 08/31/2004 to Andersen,   et al.


Inventors: Andersen; Raymond J. (Vancouver, CA), Kelly; Michael T. (Surrey, CA), Barsby; Todd A. (Vancouver, CA)
Assignee: The University of British Columbia (Vancouver, GB)
Ocean Pharmaceuticals, Inc. (Vancouver, GB)
Appl. No.: 09/794,229
Filed: February 26, 2001


Current U.S. Class: 530/327 ; 530/324; 530/325; 530/326
Field of Search: 530/324-330 514/12-17


Foreign Patent Documents
WO 98/04584 Feb., 1998 WO

Other References

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Edmond MB. et al. (1995) Clinical Infectious Diseases 20(5):1126-1133.* .
Fournier A. et al. (1988) Int. J. Peptide Protein Res. 31:86-97.* .
Fuji N. et al. (1987) J. Chem. Soc. Chem. Comm. 274-275.* .
Gerard J. et al. (1996) Tetrahedron Letters 37:7201-7204.* .
Kaiser ET. et al. (1970) Anal. Biochem. 34(2):595-598.* .
Katz E. & Demain AL. (1977) Bacteriol. Rev. 41(2):449-474.* .
Kosui N. et al. (1981) Int. J. Peptide Protein Res. 18(2):127-134. .
Merrifield RB. (1963) J. Am. Chem. Soc. 85(14):2149-2154. .
Ohno M. & Izumiya N. (1966) J. Am. Chem. Soc. 88(2):376-378. .
Okamato K. et al. (1977) Bull. Chem. Soc. Jpn. 50:231-236. .
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Primary Examiner: Low; Christopher S. F.
Assistant Examiner: Lukton; David
Attorney, Agent or Firm: Field; Bret E. Bozicevic, Field & Francis

Parent Case Text



this application claims the benefit of provisional Application No. 60/185,097 filed Feb. 25, 2000.
Claims



What is claimed is:

1. An isolated antibiotic peptide or salt of an antibiotic peptide of formula: ##STR16##

wherein: a, b, and c are independently selected integers, wherein a=1-5, b=2-6, and c=2-5; Y is selected from the group consisting of: H; OH; and, a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms; LPAA is an amino acid residue having the structure --NX--C.sup..alpha. R.sup.1 --CO--, wherein for each LPAA in the peptide, R.sup.1 is selected from the group consisting of: hydrogen; a linear, branched or cyclic, saturated or unsaturated alkyl containing one to ten carbons atoms optionally substituted with --OH, --OR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --O.sub.2 CR, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --SOR, or --SO.sub.2 R; benzyl, in which a phenyl ring of the benzyl is optionally substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, or --SO.sub.2 R; and, arylalkyl in which an alkyl group of the arylalkyl has two to ten carbon atoms and is linear, branched or cyclic, saturated or unsaturated, optionally substituted with --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, or --SO.sub.2 R, and in which an aryl ring of the arylalkyl is phenyl, or indole, optionally substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR--NO.sub.2, --SOR, or --SO.sub.2 R; wherein for R.sup.1, R in a substituent is a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms, and providing that when R.sup.1 is joined to C.sup..alpha. by a single bond, H is also present joined to C.sup..alpha. ; and, for each LPAA in the peptide, X is selected from the group consisting of: H; OH; and, a linear, branched or cyclic, saturated or unsaturated alkyl group containing one to ten carbons; BAA is an amino acid residue having the structure --NX--CHR.sup.2 --CO--, wherein for each BAA in the peptide, R.sup.2 is selected from the group consisting of: a linear, branched or cyclic, saturated or unsaturated alkyl group of one to ten carbons, substituted with one of NH.sub.2, NRH, N(R).sub.2, N(R).sub.3.sup.+, --NH--CNH--NH.sub.2, or imidazole, and optionally additionally substituted with --OH, --OR, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --O.sub.2 CR, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --SOR, or SO.sub.2 R; benzyl in which a phenyl ring of the benzyl is substituted with one of NH.sub.2, NRH, N(R).sub.2, or N(R).sub.3.sup.+ ; and optionally additionally substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, or --SO.sub.2 R; arylalkyl in which an alkyl of the arylalkyl is linear, branched or cyclic, saturated or unsaturated of two to ten carbons, optionally additionally substituted with --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, or --SO.sub.2 R, and in which an aryl ring of the arylalkyl is phenyl substituted with one of NH.sub.2, NRH, N(R).sub.2, N(R).sub.3.sup.+, indole substituted with one of NH.sub.2, NRH, N(R).sub.2, N(R).sub.3.sup.+, pyridine, or imidazole; and wherein the aryl ring is optionally additionally substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, or --SO.sub.2 R; wherein for R.sup.2, R in a substituent is a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms and for each BAA in the peptide, X is selected from the group consisting of: H; OH; and a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbons; and, R.sup.3 and R.sup.4.dbd.R.sup.1, and R.sup.3 and R.sup.4 are the same or different.

2. The peptide or salt of claim 1, wherein R.sup.1 is a linear, branched or cyclic, saturated or unsaturated alkyl of 1-10 carbon atoms wherein the alkyl is unsubstituted or is substituted with one or more substituents selected from the group consisting of: --OH, --OR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --O.sub.2 CR, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --SOR, and --SO.sub.2 R.

3. The peptide or salt of claim 1, wherein R.sup.1 is benzyl in which a phenyl ring of the benzyl is unsubstituted or is substituted with one or more substituents selected from the group consisting of: R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, and --SO.sub.2 R.

4. The peptide or salt of claim 1, wherein R.sup.1 is arylalkyl in which an alkyl group of the arylalkyl is unsubstituted or is substituted with one or more substituents selected from the group consisting of: --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, and --SO.sub.2 R.

5. The peptide or salt of claim 1, wherein R.sup.1 is arylalkyl in which an aryl ring of the arylalkyl is unsubstituted or is substituted with one or more substituents selected from the group of: R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl--, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, and --SO.sub.2 R.

6. The peptide or salt of claim 1, wherein R.sup.2 is a linear, branched or cyclic, saturated or unsaturated alkyl of 1-10 carbon atoms wherein the alkyl substituents are optionally additionally substituted with one or more substituents selected from the group consisting of: --OH, --OR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --O.sub.2 CR, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --SOR, or --SO.sub.2 R.

7. The peptide or salt of claim 1, wherein R.sup.2 is benzyl in which a phenyl ring of the benzyl substituents are optionally additionally substituted with one or more substituents selected from the group consisting of: R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, or --SO.sub.2 R.

8. The peptide or salt of claim 1, wherein R.sup.2 is arylalkyl in which an alkyl group of the arylalkyl substituents are optionally additionally substituted with one or more substituents selected from the group consisting of: --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, or --SO.sub.2 R.

9. The peptide or salt of claim 1, wherein R.sup.2 is arylalkyl in which an aryl ring of the arylalkyl substituents are optionally additionally substituted with one or more substituents selected from the group consisting of: R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, and --SO.sub.2 R.

10. The peptide or salt of claim 1, wherein: LPAA is an amino acid selected from the group consisting of: glycine; alanine; valine; butyrine; leucine; isoleucine; asparagine; glutamine; tryptophan; tyrosine; phenylalanine; methionine; methionine sulfoxide; threonine; serine; cysteine; and .alpha.,.beta.-unsaturated analogs of each of said amino acids except glycine; BAA is selected from the group consisting of: ornithine; lysine; histidine; and arginine; and, R.sup.3 and R.sup.4 are independently selected from the group consisting of: hydrogen; methyl; ethyl; n-propyl; isopropyl; n-butyl; isobutyl; sec-butyl; benzyl; and, p-hydroxybenzyl.

11. The peptide or salt of claim 1, wherein: LPAA is selected from the group consisting of: valine; leucine; isoleucine; tyrosine; phenylalanine; methionine; methionine sulfoxide; threonine; and dehydrobutyrine; BAA is selected from the group consisting of: ornithine; lysine; and arginine; and R.sup.3 and R.sup.4 are independently selected from the group consisting of: hydrogen; methyl; ethyl; n-propyl; isopropyl; n-butyl; isobutyl; sec-butyl; benzyl and p-hydroxybenzyl.

12. The peptide or salt of claim 1, wherein: LPAA is selected from the group consisting of: valine; leucine; isoleucine; tyrosine; phenylalanine; methionine; methionine sulfoxide; threonine; and dehydrobutyrine; BAA is selected from the group consisting of: ornithine; lysine; and arginine; and, R.sup.3 and R.sup.4 are independently selected from the group consisting of: isopropyl; isobutyl; and sec-butyl.

13. The peptide or salt of claim 1, wherein: a is 1-5; c is 2-5; and, b is 2-6.

14. The peptide or salt of claim 1, wherein: a is 2; c is 3; and, b is 2-3.

15. The peptide or salt of claim 1, wherein: R.sup.3.dbd.--CH(CH).sub.3 CH.sub.2 CH.sub.3.

16. The peptide or salt of claim 1, wherein: Y.dbd.H.

17. The peptide or salt of claim 1, wherein: R.sup.4.dbd.--CH(CH.sub.3).sub.2.

18. The peptide or salt of claim 1, wherein the peptide is selected from the group consisting of structures A, B, C, and D: ##STR17## ##STR18##

19. The peptide or salt of claim 1, wherein the peptide has the structure: ##STR19##

20. A composition comprising a pharmaceutically acceptable carrier and an antibiotic peptide or salt of an antibiotic peptide of formula: ##STR20##

wherein: a, b, and c are independently selected integers, wherein a=1-5, b=2-6, and c=2-5; Y is selected from the group consisting of: H; OH; and, a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms; LPAA is an amino acid residue having the structure --NX--C.sup..alpha. R.sup.1 --CO--, wherein for each LPAA in the peptide, R.sup.1 is selected from the group consisting of: hydrogen; a linear, branched or cyclic, saturated or unsaturated alkyl containing one to ten carbons atoms optionally substituted with --OH, --OR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --O.sub.2 CR, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --SOR, or --SO.sub.2 R; benzyl, in which a phenyl ring of the benzyl is optionally substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, or --SO.sub.2 R; and, arylalkyl in which an alkyl group of the arylalkyl has two to ten carbon atoms and is linear, branched or cyclic, saturated or unsaturated, optionally substituted with --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR or --SO.sub.2 R, and in which an aryl ring of the arylalkyl is phenyl, or indole, optionally substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR--NO.sub.2, --SOR, or --SO.sub.2 R; wherein for R.sup.1, R in a substituent is a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms, and providing that when R.sup.1 is joined to C.sup..alpha. by a single bond, H is also present joined to C.sup..alpha. ; and, for each LPAA in the peptide, X is selected from the group consisting of: H; OH; and, a linear, branched or cyclic, saturated or unsaturated alkyl group containing one to ten carbons; BAA is an amino acid residue having the structure --NX--CHR.sub.2 --CO--, wherein for each BAA in the peptide, R.sup.2 is selected from the group consisting of: a linear, branched or cyclic, saturated or unsaturated alkyl group of one to ten carbons, substituted with one of NH.sub.2, NRH, N(R).sub.2, N(R).sub.3.sup.+, --NH--CNH--NH.sub.2, or imidazole, and optionally additionally substituted with --OH, --OR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --O.sub.2 CR, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --SOR, or SO.sub.2 R; benzyl in which a phenyl ring of the benzyl is substituted with one of NH.sub.2, NRH, N(R).sub.2, or N(R).sub.3.sup.+ ; and optionally additionally substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, or --SO.sub.2 R; arylalkyl in which an alkyl of the arylalkyl is linear, branched or cyclic, saturated or unsaturated of two to ten carbons, optionally additionally substituted with --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, or --SO.sub.2, and in which an aryl ring of the arylalkyl is phenyl substituted with one of NH.sub.2, NRH, N(R).sub.2, N(R).sub.3.sup.+, indole substituted with one of NH.sub.2, NRH, N(R).sub.2, N(R).sub.3.sup.+, pyridine, or imidazole; and wherein the aryl ring is optionally additionally substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CON(R).sub.2, --COSR, --NO.sub.2, --SOR, or --SO.sub.2 R; wherein for R.sup.2, R in a substituent is a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms and for each BAA in the peptide, X is selected from the group consisting of: H; OH; and a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbons; and, R.sup.3 and R.sup.4.dbd.R.sup.1, and R.sup.3 and R.sup.4 are the same or different.

21. The composition of claim 20, wherein: LPAA is selected from the group consisting of: valine; leucine; isoleucine; tyrosine; phenylalanine; methionine; methionine sulfoxide; threonine; and dehydrobutyrine; BAA is selected from the group consisting of: ornithine; lysine; and arginine; and, R.sup.3 and R.sup.4 are independently selected from the group consisting of: hydrogen; methyl; ethyl; n-propyl; isopropyl; n-butyl; isobutyl; sec-butyl; benzyl; and p-hydroxybenzyl.

22. The composition of claim 21, wherein: a is 1-5; c is 2-5; and, b is 2-6.

23. The composition of claim 21, wherein: a is 2; c is 3; and, b is 2-3.

24. The composition of claim 20, wherein the peptide is selected from the group consisting of structures A, B, C, and D: ##STR21## ##STR22##

25. The composition of claim 20, wherein the peptide has the structure: ##STR23##
Description



TECHNICAL FIELD

The present invention relates to cationic peptides having antibiotic activity.

BACKGROUND OF THE INVENTION

Methicillin-resistant strains of Staphylococcus aureus (MRSA) cause infections that are refractory to standard anti-staphylococci antibiotics, and in many cases vancomycin is the antibiotic of last resort. Consequently, it is of great concern that vancomycin-resistant strains of MRSA may develop.

Infections due to enterococci have been difficult to treat for many years because these organisms are intrinsically resistant to many antibiotics. Ampicillin has been the mainstay for treatment of uncomplicated enterococcal infections, but many strains have now become resistant to ampicillin. vancomycin is again the only effective treatment for these ampicillin-resistant enterococcal infections. In the past few years, vancomycin-resistant enterococcal strains(VRE) have begun to appear and they are rapidly spreading across North America. There are no effective antibiotics currently available for such organisms and the recent report of an outbreak of VRE with a 73% mortality rate has highlighted the seriousness of the situation, See Edmond, M. B. et al., Clinical Infections Diseases 20: 1126-33, 1995.

New compounds are needed for the treatment of antibiotic-resistant pathogens, particularly gram positive strains of human pathogens. The present invention is directed to fulfilling this need, and provides related advantages as described herein.

SUMMARY OF THE INVENTION

This invention provides an antibiotic peptide of formula (1): ##STR1##

wherein:

a, b, and c are independently selected integers, wherein a=1-10, b=1-10, and c=2-5;

Y is selected from the group consisting of: H; OH; and, a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms;

LPAA is an amino acid residue having the structure --NX--C.sup..alpha. R.sup.1 --CO--, wherein for each LPAA in the peptide, R.sup.1 is independently selected from the group consisting of: hydrogen; a linear, branched or cyclic, saturated or unsaturated alkyl containing one to ten carbons atoms optionally substituted with --OH, --OR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F --CN, --O.sub.2 CR, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CONR.sub.2, --COSR, --SOR, or --SO.sub.2 R; benzyl, in which a phenyl ring of the benzyl is optionally substituted with R, --OH, --OR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CONR.sub.2, --COSR --NO.sub.2, --SOR, or --SO.sub.2 R; and, arylalkyl in which an alkyl group of the arylalkyl has two to ten carbon atoms and is linear, branched or cyclic, saturated or unsaturated, optionally substituted with --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CONR.sub.2, --COSR --NO.sub.2, --SOR, or --SO.sub.2 R, and in which an aryl ring of the arylalkyl is phenyl, or indole, optionally substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CONR.sub.2, --COSR --NO.sub.2, --SOR, or --SO.sub.2 R; wherein for R.sup.1. R is a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms, and providing that when R.sup.1 is joined to C.sup..alpha. by a single bond, H is also present joined to C.sup..alpha. ; and, for each LPAA in the peptide, X is independently selected from the group consisting of: H; OH; and, a linear, branched or cyclic, saturated or unsaturated alkyl group containing one to ten carbons;

BAA is an amino acid residue having the structure --NX--CHR.sup.2 --CO--, wherein for each BAA in the peptide, R.sup.2 is independently selected from the group consisting of: a linear, branched or cyclic, saturated or unsaturated alkyl group of one to ten carbons, substituted with one of NH.sub.2, NRH, NR.sup.2, NR.sub.3.sup.+, guanidinyl (--NH--CNH--NH.sub.2), and imidazole, and optionally substituted with --OH, --OR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --O.sub.2 CR, --COR, --CONH.sub.2, --CONHR, --CONR.sub.2, --COSR, --SOR, or --SO.sub.2 R; benzyl in which a phenyl ring of the benzyl is substituted with one of NH.sub.2, NRH, NR.sub.2, NR.sub.3.sup.+, and optionally substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CONR.sub.2, --COSR --NO.sub.2, --SOR, or --SO.sub.2 R; arylalkyl in which an alkyl of the arylalkyl is linear, branched or cyclic, saturated or unsaturated of two to ten carbons, optionally substituted with --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2 --CONHR, --CON.sub.2, --COSR, --NO.sub.2, --SOR, or --SO.sub.2 R, and in which an aryl ring of the arylalkyl is phenyl substituted with one of NH.sub.2, NRH, NR.sub.2, NR.sup.+, indole substituted with one of NH.sub.2, NRH, NR.sub.2, NR.sub.3.sup.+, pyridine, or imidazole; and wherein the aryl ring is optionally substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CONR.sub.2, --COSR --NO.sub.2, --SOR, or --SO.sub.2 R; wherein for R.sup.2, R is a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbon atoms; and, for each BAA in the peptide X is independently selected from the group consisting of: H; OH; and a linear, branched or cyclic, saturated or unsaturated alkyl of one to ten carbons; and,

R.sup.3 and R.sup.4 =R.sup.1, and R.sup.3 and R.sup.4 are the same or different.

The term LPAA denotes an amino acid residue having a lipophilic character as compared to BAA. For example, LPAA includes the amino acids glycine, alanine, valine, butyrine, leucine, isoleucine, asparagine, glutamine, tryptophan, tyrosine, phenylalanine, methionine, methionine sulfoxide, threonine, serine, cysteine, and the .alpha.,.beta.-unsaturated analogs of these amino acids except glycine. The term BAA denotes an amino acid residue having a basic character as compared to LPAA. For example, BAA includes the amino acids ornithine, lysine, histidine, and arginine.

The peptide of formula (1) has an N-terminus modified by the presence of an alpha hydroxy acyl group, and a C-terminus reduced to a primary alcohol. R.sup.3 at the N-terminus may be an alkyl group such as --CH(CH.sub.3)CH.sub.2 CH.sub.3 as is the case for Bogorol A-D as disclosed herein. At the C-terminus, Y in formula (1) may be hydrogen and R.sup.4 may be --CH(CH.sub.3).sub.2, as is the case for Bogorol A-D described herein.

The values of each a, b, and c integer in formula (1) are independently selected The structure of each BAA or LPAA in the peptide may be the same or different as compared to any other BAA or LPAA in the peptide. The number of LPAA components may differ as between different regions along the linear structure of the peptide. Thus, each-[-BAA-(-LPAA).sub.b -]-unit of the peptide may have a different BAA residue, different value for b, and different LPAA residues, as compared to any other such unit.

A peptide of formula (1) preferably will have from 10-25 LPAA and BAA residues combined, more preferably from 10-20 and even more preferably from 12-18, which numbers do not include the C-terminal modified amino acid residue Preferably, the number of BAA residues (denoted by the integer c), will be 2-3. Bogorol A-D have a total of 12 LPAA and BAA residues combined, which when added to the modified C-terminal residue, results in a total of 13 amino acid and modified amino acid residues, including 3 BAA residues. Preferably the integer b will be 2-6, more preferably 2-4, and most preferably 2-3. Each BAA residue is preferably separated by from 2-4 and more preferably 2-3 LPAA residues, which means that the integer b is 2-4 or 2-3, but not necessarily at the C-terminus of the peptide. Preferably, the number of LPAA residues at each of the N and C termini of the peptide will be 1-5, more preferably 1-3 and most preferably, 2.

Peptides of this invention may be ordered such that a basic side group of each BAA is aligned along an axis parallel to a central axis of the peptide when the peptide is in an .alpha.-helix configuration. This ordering may be achieved by spacing each BAA residue according to the number of residues in each turn of such a helix and providing a particular stereochemical configuration for each BAA residue. For example, the stereochemical configuration of the ornithine and lysine residues of Bogorol A-D (from the N to the C terminus) may be D, D, L or D, L, D, with each of these basic amino acid residues being separated by 2-3 (preferably 3) LPAA residues.

Preferred peptides of this invention have one or more of the following limitations: 1) LPAA is an amino acid selected from the group consisting of: glycine; alanine; valine; butyrine; leucine; isoleucine; asparagine; glutamine; tryptophan, tyrosine; phenylalanine; methionine; methionine sulfoxide; threonine; serine; cysteine; and .alpha.,.beta.-unsaturated analogs of each of said amino acids except glycine; BAA is selected from the group consisting of: ornithine; lysine; histidine; and arginine; and, R.sup.3 and R.sup.4 are independently selected from the group consisting of: hydrogen; methyl; ethyl; n-propyl; isopropyl; n-butyl; isobutyl; sec-butyl; benzyl; and, p-hydroxybenzyl; 2) LPAA is selected from the group consisting of: valine; leucine; isoleucine; tyrosine; phenylalanine; methionine; methionine sulfoxide; threonine; and dehydrobutyrine (DBH); BAA is selected from the group consisting of: ornithine; lysine; and arginine; and, R.sup.3 and R.sup.4 are independently selected from the group consisting of: hydrogen; methyl; ethyl; n-propyl; isopropyl; n-butyl; isobutyl; sec-butyl; benzyl; and p-hydroxybenzyl; 3) LPAA is selected from the group consisting of: valine; leucine; isoleucine; tyrosine; phenylalanine; methionine; methionine sulfoxide; threonine; and dehydrobutyrine (DBH); BAA is selected from the group consisting of: ornithine; lysine; and arginine; and, R.sup.3 and R.sup.4 are independently selected from the group consisting of: isopropyl; isobutyl; and sec-butyl; 4) a is 1-5; c is 2-5; b is 2-6; and 5) a is 2; c is 3; b is 2-3.

Preferred peptides of this invention may comprise (in a N to C terminal direction) a tyrosine-isoleucine dipeptide as the two LPAA residues immediately preceding the modified C-terminal amino acid residue. Preferred peptides may also comprise (in a N to C terminal direction) the following sequence of amino acid residues: (leucine, methionine, or valine)-ornithine-isoleucine-valine-valine-lysine-valine-leucine-lysine. Preferred peptides may also comprise DHB or threonine (preferably DHB) as the LPAA at the N-terminus of the peptide. When an LPAA comprises R.sup.1 joined to the .alpha.-carbon of the residue (C.sup..alpha.) by a single bond, hydrogen is also joined to C.sup..alpha., as would be the case for a common amino acid such as valine or leucine. When an LPAA comprises R.sup.1 joined to C.sup..alpha. by a double bond (such as is the case for DHB), there is no hydrogen joined to C.sup..alpha..

Naturally occurring peptides of this invention are provided as isolated peptides, i.e. in a substantially purified form. A substantially purified form is one wherein one or more peptides of this invention constitute at least about 1 weight percent of a composition, preferably at least about 10 weight percent, more preferably at least about 30 weight percent, still more preferably at least about 50 weight percent, yet still more preferably at least about 70 weight percent, and yet still more preferably at least about 95 weight percent, and most preferably at least about 99 weight percent.

Peptides of this invention may be provided as salts, which salts include acid or base addition salts, depending on whether the moiety on the peptide (e.g. an amino acid side group) being connected to a salt is a basic or acidic moiety. Preferably, the salt will be acceptable for pharmaceutical purposes.

This invention also provides peptides of this invention and pharmaceutically acceptable salts thereof, in a pharmaceutical composition. A pharmaceutical composition of the invention may not necessarily contain a peptide of this invention in a substantially purified form because the composition may contain carriers, diluents, or other materials suitable for use in pharmaceutical compositions, in admixture with the peptide.

This invention also provides a method of treating bacterial infection, comprising administering to a patient having a bacterial infection, an effective amount of a peptide, peptide salt, or pharmaceutical composition of this invention. Preferably, the effective amount will be sufficient to relieve one or more symptoms associated with or due to the bacterial infection.

This invention also provides the use of a peptide, peptide salt, or a pharmaceutical composition of this invention as an antibiotic. Such antibiotic use includes use for the treatment of bacterial infections, including infections by gram-positive bacteria.

This invention also provides the use of a peptide, peptide salt, or pharmaceutical composition of this invention for the preparation of an antibiotic medicament. Such a medicament may be suitable for use against bacteria, including gram-positive bacteria.

DETAILED DESCRIPTION OF THE INVENTION

Peptides of the invention include the solvates, salts (acid-or base-addition salts, depending on whether the amino acid sidechain being converted to a salt is basic or acidic, respectively), and derivatives or analogs such as esters (derivatives of alcohol functionalities on the C and N terminal residues and/or a tyrosine phenol), amines (derivatives of amino acid sidechains containing an amino group), ethers (derivatives of amino acid and N- and C-terminal modified amino acid sidechains containing an hydroxyl group) and amides (derivatives of amino acid sidechains containing either an amine or carboxylic acid group).

Salts may contain at least one negatively charged ion selected from chloride, bromide, sulfate, phosphate, C.sub.1-15 carboxylate, methanesulfonate and p-toluenesulfonate, which are exemplary only. Exemplary C.sub.1-15 carboxylates include acetate, glycolate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, malate, tartarate, citrate, ascorbate, maleate, hydroxymaleate, benzoate, hydroxybensoate, phenylacetate, cinnamate, salicylate and 2-phenoxybenzoate.

Salts may contain at least one positively charged ion selected from lithium, sodium, potassium, beryllium, magnesium, calcium and quaternary ammonium ions, which are exemplary positively charged ions. Exemplary quaternary ammonium ions include tetraalkylammonium, and trialkylaralkylammonium ions.

Derivatives or analogs may have an amine group of an ornithine or lysine sidechain being a secondary, tertiary or quaternary amine group. Other amino acid sidechains may be in a derivative form as well. Exemplary ornithine or lysine sidechains have the formula --CH.sub.2 --CH.sub.2 --CH.sub.2 --NHR, --CH.sub.2 --CH.sub.2 --CH.sub.2 --N(R).sub.2 or --CH.sub.2 --CH.sub.2 --CH.sub.2 --N(R).sub.3 wherein R is an alkyl group that may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities; or an acyl group that may be of straight chain, or where possible of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities.

In other derivatives, a hydroxyl group of a tyrosine sidechain, a hydroxyl group of the .alpha.-hydroxy acyl N-terminal residue, or the primary alcohol of the C-terminal residue may be converted to an ether or ester group, and other amino acid sidechains are optionally in a derivative form as well. For example, a tyrosine sidechain may have the formula --CH.sub.2 --C.sub.6 H.sub.4 --O--R, wherein C.sub.6 H.sub.4 is an aromatic ring and --O--R is in the para position, and R is a C.sub.1-15 alkyl group so as to form an ether where the alkyl group may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities; or a C.sub.1-15 acyl group so as to form an ester, where the acyl group may be of straight chain, or where possible, of cyclic or branched structure and contain one or more alkene, alkyne, or aromatic functionalities.

Peptides of this invention include peptides having a "non-natural" stereochemistry at one or more of the carbons of the component amino acids as well as either epimer of the modified C- and N-terminal residues. The term "non-natural" refers to stereochemistry that differs from that of naturally occurring peptides of this invention, such as Bogorol A. In structural formula of naturally occurring peptides such as Bogorol A as set out herein, "natural" stereochemistry may be indicated by wedged and dashed lines according to the standard stereochemical convention. Use of `wavy` lines attached to a chiral center indicates that no particular configuration is represented by the formula.

This invention is directed to various analogs of naturally occurring compounds. In the below-listed structure, no stereochemistry is designated because the analogs of the invention may have any possible stereochemistry at each atom capable of having more than one stereochemical arrangement of substituents.

Peptides of this invention may be described in terms of formula (2): ##STR2##

wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 may independently be hydrogen; or a linear, branched or cyclic, saturated or unsaturated alkyl group containing one to ten carbons optionally substituted with --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NH.sub.2, --NHR, --NHR.sub.2, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 H, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR.sub.2 --CONR.sup.2, --COSH, --COSR --NO.sub.2, --SO.sub.3 --, --SOR, --SO.sub.2 R, --NH--CN--NH.sub.2 (guanidinyl); or benzyl where the phenyl ring may be substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NH.sub.2, --NHR, --NHR.sub.2, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 H, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CONR.sub.2, --COSH, --COSR --NO.sub.2, --SO.sub.3 --, --SOR, --SO.sub.2 R; or arylalkyl where the alkyl group may be linear, branched or cyclic, saturated or unsaturated containing two to ten carbons that may be substituted with --OH, --OR, --O.sub.2 CR --SH, --SR, --SOCR, --NH.sub.2, --NHR, --NHR.sub.2, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 H, --CO.sub.2 R, --CHO, --COR, CONH.sub.2, --CONHR, --CONR.sub.2, --COSH, --COSR --NO.sub.2, --SO.sub.3 --, --SOR, --SO.sub.2 R and where the aryl ring may be phenyl, indole, or imidazole substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NH.sub.2, --NHR, --NHR.sub.2, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 H, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CONR.sub.2, --COSH, --COSR --NO.sub.2, --SO.sub.3 --, --SOR, --SO.sub.2 R; and R is a linear, branched or cyclic, saturated or unsaturated alkyl group containing one to ten carbons. Preferred analogs may have one to four amino acid residue as present in Bogorol A replaced with a different amino acid residue.

In another aspect, peptides of this invention are linear compounds which may be described in terms of the shorthand structure shown below. ##STR3##

In Formula A, AA2 through AA13 are generic symbols, each representing an amino acid residue, or a salt or derivative thereof as defined herein. RA14 represents a modified carboxyl terminal amino acid where the carboxyl group has been reduced to a primary alcohol (e.g. valinol). .alpha.OHAA1 represents an alpha hydroxy acid modified residue. Each line between neighbouring (attached) residues represents an amide (also known as a peptide) bond formed between neighbouring residues, as well as the isosteres thereof. "Isostere" means a modified form of the normal peptide bond (--C(O)NH--) between attached amino acid residues, such as --CH.sub.2 NH-- (reduced), C(O)N(SH.sub.3) (N-methylamide), --COCH.sub.2 -- (keto), --CH(OH)CH.sub.2 -- (hydroxy), --CH(NH.sub.2)CH.sub.2 -- (amino), --CH.sub.2 CH.sub.2 -- (hydrocarbon), or --NHC(O)-- (inverted normal peptide bond). Preferably the compounds of the present invention are not in isosteric forms.

Except where otherwise stated, throughout this specification the recitation of a compound denotes all possible isomers within the structural formula given for those compounds, in particular optical isomers. Unless otherwise stated definitions are to be regarded as covering mixtures of isomers, and individual isomers, including racemic mixtures, where they can be resolved.

The compounds of the present invention contain multiple asymmetric carbon atoms and thus exist as enantiomers and diastereomers. Unless otherwise noted, the present invention includes all enantiomeric and diastereomeric forms of the compounds. Pure stereoisomers, mixtures of enantiomers and/or diastereomers, and mixtures of different compounds of the invention are included within the scope of the present invention. Also included are epimers of the C and N terminal modified amino acids.

Except if otherwise stated, definitions of compounds in this specification may be regarded as covering all possible esters of the compounds. In particular, except if otherwise stated, the recitation of amino acid residue having a carboxylic acid group is to be regarded as a recitation of all possible esters of that carboxylic acid.

Except if otherwise stated, definitions of compounds in this specification having phenolic groups may be regarded as covering all possible ethers or esters of the phenolic hydroxyl group.

Peptides of this invention may be described in terms of formula (3) shown below: ##STR4##

wherein: R.sup.1, R.sup.2, and R.sup.3 may independently represent a hydrogen atom: or an alkyl group that may be of straight chain or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities; or an acyl group that may be of straight chain, or where possible, of cyclic or branched structure and way contain one or more alkene, alkyne, or aromatic functionalities.

Peptides of this invention may also be described in terms of Formula B. ##STR5##

wherein: R.sup.1 R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 may independently be hydrogen; or a linear, branched or cyclic, saturated or unsaturated alkyl group containing one to ten carbons optionally substituted with --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NH.sub.2, --NHR, --NHR.sub.2, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 H, --CO.sub.2 R, --CHO --COR, --CONH.sub.2, --CONHR, --CONR.sub.2, --COSH, --COSR, --NO.sub.2, --SO.sub.3 --, --SOR, --SO.sub.2 R, --NH--CN--NH.sub.2 (guanidinyl); or benzyl where the phenyl ring may be substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NH.sub.2, --NHR, --NHR.sub.2, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 H, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CONR.sub.2, --COSH, --COSR, --NO.sub.2, --SO.sub.3 --, --SOR, --SO.sub.2 R; or arylalkyl where the alkyl group may be linear, branched or cyclic, saturated or unsaturated containing two to ten carbons that may be substituted with --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NH.sub.2, --NHR, --NHR.sub.2, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 H, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CONR.sub.2, --COSH, --COSR, --NO.sub.2, --SO.sub.3 --, --SOR, --SO.sub.2 R and where the aryl ring may be phenyl, indole, or imidazole substituted with R, --OH, --OR, --O.sub.2 CR, --SH, --SR, --SOCR, --NH.sub.2, --NHR, --NHR.sub.2, --NHCOR, --I, --Br, --Cl, --F, --CN, --CO.sub.2 H, --CO.sub.2 R, --CHO, --COR, --CONH.sub.2, --CONHR, --CONR.sub.2, --COSH, --COSR, --NO.sub.2, --SO.sub.3 --, --SOR, --SO.sub.2 R; and R is a linear, branched or cyclic, saturated or unsaturated alkyl group containing one to ten carbons.

Peptides of this invention include the following peptides termed Bogoral A-D: ##STR6## ##STR7##

The compounds of the present invention may be prepared in vitro, using solid phase or solution peptide synthesis techniques, or may be prepared in vivo, from micro-organism ATCC 55797. Solution phase techniques as set forth in K. Okamato, K. et al. Bull. Chem. Soc. Jpn. 50:231-236 (1977), Ohno, M. et al. J. Am. Chem. Soc. 88(2):376-377 and Kosui, N. et al. Int. J. Peptide Protein Res. 18:127-134 (1981) may be modified to prepare the linear peptides of the present invention, merely by appropriate substitution of the suitably protected amino acids, reduced amino acids, or .alpha.-hydroxy acids. The compounds of the invention may also be isolated from micro-organism ATCC 55797 under appropriate conditions.

Ion exchange techniques can be used to prepare the various salts of the invention, where such techniques are well known in the art. For example, hydrochloric acid may be added to a neutral compound of the invention to prepare the hydrochloride salt thereof. Dialysis techniques may also be employed effect ion exchange and so obtain a desired salt of the invention from another salt of the invention.

The isolation and synthesis procedures described herein, especially when taken with the general knowledge in the art, provide sufficient guidance to those of ordinary skill in the art to perform the synthesis, isolation, and purification of the compounds described herein and other analogous compounds. Individual enantiomers may be obtained, if desired, from mixtures of the different forms by known methods of resolution, such as the formation of diastereomers, followed by recrystallisation. Alternatively, isomerically pure starting materials may be employed in the synthesis of a compound of the invention or various diastereomers may be separated by chromatography.

Peptides of this invention have utility as antibiotics, and may be used and administered in a manner analogous to antibiotics (particularly antibiotic peptides) known in the art, to provide the beneficial effects desired of antibiotics. The modified linear peptides of the invention may be used against gram negative and gram positive bacteria, but are particularly effective against gram-positive bacterial including Staphylococcus aureus and Enterococcus faecalis.

In using a peptide of this invention, the peptide is preferably administered to a patient in a pharmaceutical (including veterinary) composition comprising a pharmaceutically acceptable carrier, and optionally, one or more other biologically active ingredients. Such compositions may be in any form used for oral, topical, vaginal, parenteral, rectal and inhalatory application. The compositions may be provided in discrete dose units. The carriers may be particulate, with compositions being, for example, tablets or powders, or liquid, with the compositions being for example, oral syrups or injectable liquids, or gaseous, for inhalatory application.

For oral administration, an excipient and/or binder may be present. Examples are sucrose, kaolin, glycerin, starch destrins, sodium alginate, carboxymethylcellulose and ethyl cellulose. Coloring and/or flavoring agents may be present. A coating shell may be employed. For rectal administration oleaginous bases may be employed, for example, lanolin or cocoa butter. For an injectable formulation, buffers, stabilizers and isotonic agens may be included.

It will be evident to those of ordinary skill in the art that the optimal dosage of a peptide or pharmaceutical composition of this invention may depend on the weight and physical condition of the patient, on the severity and longevity of We illness; and on the particular form of the active ingredient, the manner of administration and the composition employed.

A peptide of this invention may be used in therapy with the peptide being bound to an agent, for example, a monoclonal or polyclonal antibody, a protein or a liposome, which assist the delivery of the peptide to the site of infection.

In a further embodiment, the present invention provides a method for the treatment of a patient afflicted with a bacterial infection comprising the administration thereto of a therapeutically effective amount of a compound or composition of this invention.

The term "therapeutically effective amount" refers to an amount which is effective, upon single or multiple dose administration to the patient, in providing relief of symptoms associated with bacterial infections. As used herein, "relief of symptoms" of a bacterial infection refers to a decrease in severity over that expected in the absence of treatment and does not necessarily indicate a total elimination or cure of the infection or condition caused thereby. In determining the therapeutically effective amount or dose, a number of factors are considered by the attending diagnostician, including, but limited to; the species of mammal; its size, age, and general health; the specific infection involved; the degree of or involvement or the severity of the infection or condition arising therefrom; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

As used herein, the term "patient" refers to a warm-blooded animal such as a mammal which is afflicted with a particular inflammatory disease state. It is understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of animals within the scope of the meaning of the term.

A therapeutically effective amount of a compound of Bogorol A is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts are expected to vary from about 0.5 to about 10 mg/kg/day.

In effecting treatment of a patient afflicted with a condition described above, a compound or composition of this invention can be administered in any form or mode which makes the compound bioavailable in effective amounts, including oral, aerosol, and parenteral routes. For example, compounds can be administered orally. by aerosolization, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, topically, and the like. Oral or aerosol administration is generally preferred. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition, and other relevant circumstances. See, eg., Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990).

Peptides or salts of peptides of this invention can be administered alone or in the form of pharmaceutical composition in combination with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the solubility and chemical properties of the compound selected, the chosen route of administration, and standard pharmaceutical practice.

In another embodiment, the present invention provides peptides or salts of peptides in admixture or otherwise in association with one or more inert carriers. These compositions are useful, for example, as assay standards, as convenient means of making bulk shipments, or as pharmaceutical compositions. An assayable amount of a compound of this invention is an amount which is readily measurable by standard assay procedures and techniques as are well known and appreciated by those skilled in the art. Assayable amounts will generally vary from about 0.001T to 75% of the composition by weight. Inert carriers can be any material which does not degrade or otherwise covalently react with the compound. Examples of suitable inert carriers are water; aqueous buffers, such as those which are generally useful in High Performance Liquid Chromatography (HPLC) analysis; organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable carriers or excipients.

The pharmaceutical compositions of this invention may be prepared in manners well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition may be adapted for oral, parenteral, or topical use and may be administered to the patient in the form of tablets, capsules, suppositories, solution, suspensions, or the like.

The compounds or compositions of the present invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 4% of the compound of the invention, the active ingredient, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of the compound present in compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 5.0-300 milligrams of a compound of the invention. The tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavours. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the compounds of the present invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of a compound of the invention, but may be varied to be between 0.1 and about 50% of the weight thereof. The amount of the inventive compound present in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 5.0 to 100 milligrams of the compound of the invention.

Compounds or compositions of the present invention may also be administered by aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system which dispenses the active ingredients. Aerosols may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient. Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like. Preferred aerosols are able to be determined by one skilled in the art.

The compounds or compositions of this invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base. The base, for example, may comprise one or more of the following: petrolaum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Topical formulations may contain a concentration of the compound of this invnention of from about 0.1 to about 10% w/v (weight per unit volume).

Solutions or suspensions according to this invention may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of toxicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Peptides or peptide salts of the invention may be combined with one or more known antibiotics to provide a composition having a particularly desired efficacy.

The following examples are offered by way of illustration and not by way of limitation.

EXAMPLES

Symbols and abbreviations used herein are in accordance with the recommendation of IUPAC-IUB Commissioner on Biochemical Nomenclature, J. Biol. Chem. 1971, 247, 977. Abbreviations: "bp" refers to boiling point; BOP=benzotriazol-1-yl-oxy-tris-(dimethylamino) phosphonium hexafluorophosphate; "BrZ" refers to bromobenzyloxycarbonyl; "Bzl" refers to benzyl; ".degree.C." refers to degrees Celsius; "DCC" referes to N,N-dicyclohexylcarbodiimide; DCM dichloromethane; DIEA=N,N-diisopropylethylamine; DMF=N,N-dimethylformamide; "DPPA" refers to diphenylphosphorylazide; FAR-MS=fast atom bombardment mass spectrometry; "HOBt" refers to 1-hydroxybenzotriazole; "g" refers to grams; "Leu" refers to leucine; "mL" refers to milliliters; "mm Hg" refers to millimeters of mercury; "mmol" refers to millimoles; "NMP" refers to N-methylpyrrolidone; "Orn" refers to ornithine; "TEA" refers to triethylamine; TMSOTf=trimethylsilyl trifluoromethanesulfonate; "Tos" refers to p-toluenesulfonyl; "Trp" refers to tryptophan; "Tyr" refers to tyrosine; "Val" refers to valine, Z=benzyloxycarbonyl; "mg" refers to micrograms; "mL" refers to microliters; and "mM" refers to micromolar.

A. PREPARATIVE EXAMPLES

Example A1

Bogorol A may be isolated after fermentation of ATCC 55797 as described below. The marine bacterial isolate MK-PNG-276A, tentatively identified as a Bacillus laterosporus by MIDI analysis of cellular fatty acids, was obtained from the tissues of an unidentified tube worm collected at -15 m off of Lolata Island, Papua New Guinea. MK-PNG-276A has been deposited with the American Type Culture Collection as ATCC 55797.

MK-PNG-276A was cultured on trays of solid tryptic soy agar supplemented with NaCl to concentrations of 1%. Twenty-one 400 mL agar trays (9".times.15") were cultured for five days after which the combined cells and agar were lyophilized. The dry cells were scrapped off the agar (21.5 g) and extracted with MeOH (500 mL) three times over a period of one week. The methanolic extract was combined, filtered, and reduced in vacuo to give a brown/gray tar. The tar was taken up in 250 mL H20/MeOH (4:1) and partitioned with 100% EtOAc (3.times.250 mL), the combined EtOAc extracts were reduced in vacuo to give a taupe/brown crystalline solid (6.5 g). In two portions, this extract was subjected to size-exclusion chromatography on a Sephadex LH-20 (100% MeOR) column to give 500 mg of a fast eluting ninhydrin positive fraction (Rf=0 on reversed-phase TLC (100% MeOH)) which showed broad spectrum antibiotic activity. This fraction was loaded onto a reversed-phase 10 g Sep-Pak, previously equilibrated with 100% water, by dissolving the sample in a minimum of quantity of MeOH. Upon addition to the top of the column an equivalent volume of water was added, precipitating the active component. The column was flushed first with 50 mL 100% H.sub.2 O which was subsequently discarded, followed by 100 mL of 60% H.sub.2 O (0.2% TFA) 40% MeCN which gave 90 mg of a mixture of large molecular weight peptides (1556-1618 Da.) as indicated by LRFABMS, which were responsible for the broad spectrum antibiotic activity. This process was repeated until approximately 2.0 g of crude peptide was obtained. 1.5 g of the crude was further separated into nine fractions (A-I) by reversed-phase HPLC on a dual pump Waters 486 TAD chromatograph using a Rainin Dynamax-60 C18 column, eluting with 60% H.sub.2 O (0.2% TFA) 40% MeCN. The nine fractions collected were shown to be of the same peptide family by LRFABMS and 1H NMR. Fraction E, which contained Bogorol A, was prioritized due to its potent antimicrobial profile.

Bogorol A gave a [M+H]+ ion in the HRFABMS at m/z 1584.08500 appropriate for a molecular formula of C.sub.8 OH.sub.142 O.sub.16 N.sub.16. Detailed analysis of the 500 MHz 1H, 13C, COSY, HOHAHA, HMQC, HMBC and ROESY data for Bogorol A led to the following partial structures. ##STR8##

Hydrolysis of Bogorol A (1) at 100.degree. C. with 6N HCl and examination of the pentafluropropionamide isopropyl ester derivatives of the liberated amino acids via chiral GC analysis confirmed the presence of L-valine, L-leucine, D-leucine, L-isoleucine, D-tyrosine, L-lysine, D-lysine, and D-ornithine. Bogorol A was converted into its hexaacetate derivative (5), and NMR data was acquired at 800 MHz. ##STR9##

Crude Bogorol A. (50 mg) was acetylated in a 3:1 mixture of anhydrous pyridine and acetic anhydride at room temperature for 16 hours. Solvent was removed in vacuo and the resulting solids were chromatographed on a reversed-phase silica Sep-Pak.TM.(2 g) eluting with a gradient of 100% H2O-100% MeOH. The fractions (30/70 through 10/90) were reduced in vacuo and further purified by reversed-phase HPLC (50/50 H2O/MeCN) yielding 16 mg hexaacetylbogorol (5).

TABLE 1 1H NMR Data (800 MHz) for Hexaacetylbogorol (5) (DMSO-D6) Res. .delta..sup.1 H Res. .delta..sup.1 H VOL- CH.sub.3 Acetate 2.07 LYS- .delta.CH.sub.2 1.34 OAc.sup.A,B CO Acetate -- NAc2 .epsilon.CH.sub.2 2.94 NH 7.76 NH 7.73 .alpha.CH 3.7 CO -- .beta.CH.sub.2 4.10, 3.85 VAL2 NH 7.76 .beta.CH 1.76 .alpha.CH 4.18 .gamma.CH.sub.3 x2.sup.E 0.86 .beta.CH 1.97 LEU1 NH 8.14 .gamma.CH.sub.3 x2.sup.E 0.84 .alpha.CH 4.28 CO -- .beta.CH.sub.2 1.41, 1.36 VAL3 NH 7.90 .gamma.CH 1.36 .alpha.CH 4.17 .delta.CH.sub.3 x2.sup.E 0.81, 0.77 .beta.CH 1.94 CO -- .gamma.CH.sub.3 x2.sup.E 0.81 TYR-OAc CH.sub.3 Acetate 2.22 CO -- CO Acetate -- ILE NH 7.67 NH 8.20 .alpha.CH 4.24 .alpha.CH 4.57 .beta.CH 1.74 .beta.CH.sub.2 2.96, 2.75 .gamma.CH.sub.3.sup.E 0.88 iC -- .gamma.CH.sub.2 1.36, 1.0 oCH 7.24 .delta.CH.sub.3 0.75 mCH 6.96 CO -- pCH -- ORN-NAc CH.sub.2 Acetate 1.76 CO -- CO Acetate -- LYS- CH.sub.2 Acetate 1.76 NH 7.98 NAc1 CO Acetate -- .alpha.CH 4.30 NH 7.91 .beta.CH.sub.2 1.62, 1.56 .alpha.CH 4.20 .gamma.CH.sub.2 1.39, 1.33 .beta.CH.sub.2 1.28, 1.38 .delta.CH.sub.2 2.96 .gamma.CH.sub.2 0.99 NH 7.75 .delta.CH.sub.2 1.24 CO -- .epsilon.CH.sub.2 2.92 LEU3 NH 7.89 NH 7.67 .alpha.CH 4.31 CO -- .beta.CH.sub.2 1.50 LEU2 NH 8.04 .gamma.CH 1.62 .alpha.CH 4.29 .delta.CH.sub.3 x2.sup.E 0.86, 0.84 .beta.CH.sub.2 1.43 CO -- .gamma.CH 1.53 DHB.sup.C NH 9.57 .delta.CH.sub.2 x2.sup.E 0.86, 0.84 .alpha.C -- CO -- .beta.CH 5.63 VAL1 NH 7.75 .gamma.CH.sub.3 1.76 .alpha.CH 4.17 CO -- .beta.CH 1.97 FA-OAc.sup.D CH.sub.2 Acetate 1.94 .gamma.CH.sub.2 x2.sup.E 0.79 CO Acetate -- CO -- .alpha.CH 4.73 LYS- CH.sub.2 Acetate 1.76 .beta.CH 1.84 NAc2 CO Acetate -- .gamma.CH.sub.3.sup.E 0.


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