Methods and compositions for enhanced immunological therapy and targeting of gram-positive bacteria

Patent metadata

Field	Value
Publication number	US-10588971-B2
Application number	US-201715675240-A
Country	US
Kind code	B2
Filing date	Aug 11, 2017
Priority date	Jan 5, 2010
Publication date	Mar 17, 2020
Grant date	Mar 17, 2020

Abstract

The present invention relates to methods and compositions for use in modulating, including inhibiting the growth and/or reducing the virulence of, gram-positive bacteria. The present invention provides methods and compositions for disrupting the cell wall and/or cell membrane in gram-positive bacteria such that cell wall or cell membrane target(s) are rendered exposed or accessible and sensitive to a modulation thereof. Methods for modulation of one or more gram-positive bacterial cell wall or cell membrane targets in a gram-positive bacteria are provided comprising disrupting the cell wall such that the cell wall or cell membrane target, which is particularly a sortase, is rendered exposed or accessible and sensitive to a modifying, modulating or binding agent, which is particularly an antibody or fragment thereof, wherein the cell wall or cell membrane target is inaccessible or relatively insensitive to the modifying, modulating or binding agent in the absence of cell wall disruption.

First claim

What is claimed is:

1. A method of reducing virulence of a gram positive bacteria in a mammal comprising administering to said mammal one or more cell wall disrupting agent(s) and one or more cell wall or cell membrane target inhibiting agent(s), wherein the inhibiting agent reduces virulence of the bacteria to a significantly greater extent in the presence of the cell wall disrupting agent than in its absence, wherein the one or more cell wall disrupting agent(s) is selected from the group of antibiotics, anti-microbial peptides, polycationic peptides, cell wall degrading enzymes, and catalytic antibodies having inherent antibacterial activity, and wherein the one or more cell wall disrupting agent(s) is effective in the method at a concentration which is less than the minimally inhibitory concentration (MIC) of said one or more cell wall disrupting agent(s).

2. The method of claim 1 wherein the gram-positive bacteria is selected from Listeria, Staphylococcus, Streptococcus , and Enterococcus.

3. The method of claim 1 wherein the bacteria is antibiotic resistant.

4. The method of claim 3 wherein the bacteria is resistant to methicillin, vancomycin, or penicillin antibiotic.

5. The method of claim 1 wherein at least one of the one or more cell wall disrupting agent(s) is a cell wall degrading enzyme.

6. The method of claim 5 wherein the cell wall degrading enzyme is a phage lysin.

7. The method of claim 1 wherein at least one of the one or more cell wall disrupting agent(s) is an antibiotic that inhibits cell wall synthesis or cell membrane function.

8. The method of claim 1 wherein one of the one or more cell wall disrupting agents is a cell wall degrading enzyme, and one of the one or more cell wall disrupting agents is an antibiotic.

9. The method of claim 1 wherein one of the one or more cell wall or cell membrane target inhibiting agent(s) is selected from an antibody or antigen binding fragment thereof, a chemical compound, and a small molecule directed to a cell wall or cell membrane target.

10. The method of claim 1 wherein the cell wall or cell membrane target is selected from a sortase, penicillin binding protein, a pore protein or pore component, β-lactamase, an ABC transporter, or a channel protein.

11. The method of claim 1 wherein the bacteria is antibiotic resistant Staphylococcus or antibiotic resistant Streptococcus , and wherein the one or more cell wall disrupting agents are selected from a cell wall degrading enzyme, and an antibiotic.

12. A method of treatment or amelioration of a gram-positive bacterial infection in a mammal wherein the bacteria are Staphylococcus or Streptococcus bacteria comprising administering to said mammal one or more cell wall disrupting agent(s) and one or more cell wall or cell membrane target inhibiting agent(s), wherein the inhibiting agent inhibits or ameliorates the bacterial infection to a significantly greater extent in the presence of the cell wall disrupting agent than in its absence, wherein the one or more cell wall disrupting agent(s) is selected from the group of antibiotics, anti-microbial peptides, polycationic peptides, and cell wall degrading enzymes having inherent antibacterial activity, and wherein the one or more cell wall disrupting agent(s) is effective in the method at a concentration which is less than the minimally inhibitory concentration (MIC) of said one or more cell wall disrupting agent(s).

13. The method of claim 12 wherein the Staphylococcus or Streptococcus bacteria is antibiotic resistant.

14. The method of claim 13 wherein the antibiotic resistant Staphylococcus or the antibiotic resistant Streptococcus bacteria is resistant to methicillin, vancomycin, or penicillin antibiotic.

15. The method of claim 12 wherein one of the one or more cell wall or cell membrane target inhibiting agent(s) is selected from an antibody or antigen binding fragment thereof, a chemical compound, and a small molecule directed to a cell wall or cell membrane target.

16. The method of claim 12 wherein the cell wall or cell membrane target is selected from a sortase, penicillin binding protein, a pore protein or pore component, β-lactamase, an ABC transporter, or a channel protein.

17. The method of claim 12 wherein at least one of the one or more cell disrupting agent(s) is a cell wall degrading enzyme.

18. The method of claim 17 wherein the cell wall degrading enzyme is a phage lysin.

19. The method of claim 12 wherein at least one of the one or more cell wall disrupting agent(s) is an antibiotic that inhibits cell wall synthesis or cell membrane function.

20. The method of claim 12 wherein one of the one or more cell wall disrupting agents is a cell wall degrading enzyme, and one of the one or more cell wall disrupting agents is an antibiotic.

21. A method of inhibiting or preventing growth of Staphylococcus or Streptococcus bacteria by contacting said bacteria with one or more cell wall and/or cell membrane disrupter and one or more cell wall and/or cell membrane target inhibiting agent, wherein the one or more cell wall and/or cell membrane disrupter is selected from the group of antibiotics, anti-microbial peptides, polycationic peptides, and cell wall degrading enzymes having inherent antibacterial activity, and wherein the one or more cell wall disrupting agent(s) is effective in the method at a concentration which is less than the minimally inhibitory concentration (MIC) of said one or more cell wall disrupting agent(s).

22. The method of claim 21 wherein the bacteria is contacted with one or more antibiotic and/or cell wall degrading enzyme and with one or more target inhibiting agent selected from an antibody or antigen binding fragment thereof, a chemical compound, and a small molecule directed to a cell wall and/or cell membrane target.

23. The method of claim 21 wherein at least one of the one or more cell wall disrupting agent(s) is a cell wall degrading enzyme and is a phage lysin.

24. The method of claim 21 wherein one of the one or more cell wall disrupting agents is a cell wall degrading enzyme, and one of the one or more cell wall disrupting agents is an antibiotic.

25. The method of claim 21 wherein the antibiotic is selected from a glycopeptide, beta-lactam, and a polypeptide/lipopeptide antibiotic.

26. The method of claim 21 wherein the Staphylococcus or Streptococcus bacteria is antibiotic resistant.

Assignees

• Univ Rockefeller
• Contrafect Corp

Inventors

• Nowinski Robert C
• Fischetti Vincent A
• Raz Assaf

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61K31/18

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title

• G01N2500/02

  Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor) · CPC title

• C12N9/52

  derived from bacteria {or Archaea} · CPC title

• A61K31/407

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title