Combination therapy for anthrax using antibiotics and protease inhibitors
The invention provides compositions for treatment anthrax infection. The composition comprises a therapeutically effective amount of at least one B. anthracis metalloprotease inhibitor. The composition may further include an antimicrobial agent. The invention also provides methods for treating anthrax infection in a human or an animal subject. The method comprises administering to the subject a therapeutically effective amount of a composition of the present invention.
1 . A composition for treating an anthrax infection comprising a therapeutically effective amount of at least one B. anthracis metalloprotease (MP) inhibitor, wherein MP is other than lethal factor (LF).
2 . The composition of claim 1 , wherein the MP is a member of M4 or M9 family of MPs.
3 . The composition of claim 2 , wherein the MP is encoded by the gene BA3442, BA0555, BA3299, BA3584, BA5282, A0599, or BA2730.
4 . The composition of claim 1 , wherein the MP inhibitor is a chemical inhibitor.
5 . The composition of claim 4 , wherein the chemical inhibitor is selected from the group consisting of ethylenediamine-tetraacetic acid (EDTA), phosphoramidon, soybean trypsin inhibitor (SBTI), o-phenanthroline, aprotinin, galardin, disulfram, and ebelactone B.
6 . The composition of claim 1 , wherein the MP inhibitor is an antibody raised against a MP.
7 . The composition of claim 6 , wherein the antibody is raised against at least one peptide comprising a sequence SEQ ID NO:1, HEFTHYLQGRYEVPGL; SEQ ID NO:2, DVIGHELTHAVTE; SEQ ID NO:3, ADYTRGQGIETY, or a conservative modification of any of these sequences.
8 . The composition of claim 7 , wherein the antibody is a polyclonal or a monoclonal antibody.
9 . The composition of claim 1 , wherein the MP inhibitor is an antiserum containing at least one antibody raised against at least one peptide comprising a sequence SEQ ID NO:1, HEFTHYLQGRYEVPGL; SEQ ID NO:2, DVIGHELTHAVTE; SEQ ID NO:3, ADYTRGQGIETY, or a conservative modification of any of these sequences.
10 . The composition of claim 1 , 4 , or 6 further comprising a physiologically acceptable antimicrobial agent.
11 . A composition for treating an anthrax infection comprising a therapeutically effective ratio of at least one B. anthracis MP inhibitor and an antimicrobial agent.
12 . The composition of claim 11 , wherein the MP inhibitor is a chemical inhibitor.
13 . The composition of claim 12 , wherein the chemical inhibitor is selected from the group consisting of EDTA, phosphoramidon, SBTI, o-phenanthroline, aprotinin, galardin, disulfram, and ebelactone B.
14 . The composition of claim 11 , wherein the MP inhibitor is an antibody raised against a MP.
15 . The composition of claim 14 , wherein the antibody is raised against at least one peptide comprising a sequence SEQ ID NO:1, HEFTHYLQGRYEVPGL; SEQ ID NO:2, DVIGHELTHAVTE; SEQ ID NO:3, ADYTRGQGIETY, or a conservative modification of any of these sequences.
16 . The composition of claim 15 , wherein the antibody is a monoclonal or a polyclonal antibody.
17 . The composition of claim 11 , wherein the antimicrobial agent is an antibiotic.
18 . The composition of claim 17 , wherein the antibiotic is selected from a group of antibiotics effective against anthrax infection.
19 . The composition of claim 18 , wherein the antibiotic is selected from a group consisting of fluoroqinalones, tetracyclines, and β lactams.
20 . The composition of claim 19 , wherein the antibiotic is ciprofloxacin hydrochloride (ciprofloxacin) or doxcycline.
21 . The composition of claim 20 , wherein the antibiotic is ciprofloxacin and the chemical inhibitor selected from a group consisting of o-phenanthroline, aprotinin, and galardin.
22 . The composition of claim 20 , wherein the antibiotic is doxycycline and the chemical inhibitor is disulfuram or galardin.
23 . The composition of claim 11 further comprising at least one additional active ingredient effective against anthrax infection.
24 . The composition of claim 11 , wherein the antimicrobial agent and the B. anthracis MP inhibitor are administered at the same time.
25 . The composition of claim 11 , wherein the antimicrobial agent and the B. anthracis MP inhibitor are administered serially, with either the antibiotic or the MP inhibitor administered first.
26 . A method for treating anthrax infection in a human or an animal subject comprising administering to the subject a therapeutically effective amount of a composition comprising at least one B. anthracis MP inhibitor.
27 . The method of claim 26 , wherein the MP is a member of M4 or M9 family of MPs.
28 . The method of claim 26 , wherein the MP inhibitor is a chemical inhibitor selected from the group consisting of EDTA, phosphoramidon, SBTI, o-phenanthroline, aprotinin, galardin, disulfram, and ebelactone B.
29 . The method of claim 26 , wherein the MP inhibitor is an antibody raised against a MP.
30 . The method of claim 29 , wherein the antibody is raised against at least one peptide comprising a sequence SEQ ID NO:1, HEFTHYLQGRYEVPGL; SEQ ID NO:2, DVIGHELTHAVTE; SEQ ID NO:3, ADYTRGQGIETY, or a conservative modification of any of these sequences.
31 . A method for treating anthrax infection in a human or an animal subject, wherein the method comprises administering to the subject a composition comprising a therapeutically effective ratio of at least one B. anthracis MP inhibitor and an antimicrobial agent.
32 . The method of claim 31 , wherein the antimicrobial agent is an antibiotic selected from a group consisting of fluoroqinalones, tetracyclines, and B lactams.
33 . The method of claim 32 , wherein the antibiotic is ciprofloxacin or doxcycline.
34 . The method of claim 26 or claim 31 , wherein the administering step is delayed at least 24 hours from the time of exposure of the subject to B. anthracis.