PHAGE-DERIVED COMPOSITIONS FOR IMPROVED MYCOBACTERIAL THERAPY

1 . A method for treating a subject having a mycobacterial infection, comprising administering to the subject:

a) an outer membrane acting biologic; and

b) a mycobacterial chemotherapeutic,

wherein the outer membrane acting biologic and mycobacterial therapeutic act synergistically to reduce mycobacteria, thereby treating the subject.

2 . The method of claim 1 , wherein the outer membrane acting biologic is not LysA, or a fragment thereof having LysA activity.

3 . The method of claim 1 , wherein less than 90% of the standard dose of mycobacterial chemotherapeutic is administered or the mycobacterial chemotherapeutic is administered for less than 90% of the standard duration of treatment.

4 . The method of claim 1 , wherein the Fractional Inhibitory Concentration (FIC) index is less than 0.6.

5 . The method of any one of the foregoing claims, wherein the outer membrane acting biologic and mycobacterial chemotherapeutic are both administered within a period of 2 days.

6 . The method of claim 1 , wherein the outer membrane acting biologic is administered before the mycobacterial chemotherapeutic or both are administered simultaneously.

7 . The method of claim 1 , wherein the outer membrane acting biologic, mycobacterial chemotherapeutic, or both are administered topically or in a slow release formulation.

8 . The method of claim 1 , further comprising administering

a) a biologic or therapeutic compound which increases accessibility of the mycobacterial chemotherapeutic to a mycobacterial cell inside a macrophage or monocyte;

b) a biologic or therapeutic compound which increases accessibility of the mycobacterial chemotherapeutic to the interior of a granuloma; or

c) a biologic or therapeutic compound that increases permeability of a macrophage or monocyte.

9 . The method of claim 1 , wherein the subject:

a) is immunosuppressed;

b) is HIV positive;

c) has been diagnosed with cystic fibrosis, alpha-1 antitrypsin deficiency, Marfan's syndrome, or Primary Ciliary Dyskenesia; or

d) is a mammal, reptile, amphibian, or fish.

10 . The method of claim 1 , wherein the mycobacterial infection is:

a) a tuberculosis infection;

b) environmental mycobacteria;

c) atypical mycobacteria;

d) a mycobacteria other than tuberculosis (MOTT) or non-tuberculosis mycobacteria (NTMB);

e) latent;

f) active;

g) disseminated;

h) extrapulmonary or lymphatic;

i) multidrug resistant; or

j) a post-traumatic abscess, swimming pool granuloma, Buruli ulcer, or leprosy.

11 . The method of claim 1 , wherein the outer membrane acting biologic:

a) decreases the amount of mycobacterial chemotherapeutic or duration of mycobacterial chemotherapeutic treatment required to treat the mycobacterial infection in the subject;

b) increases permeability of a granuloma;

c) acts on a mycolic acid or lipoarabinomanin;

d) acts on a mycobacterial cell wall or outer membrane;

e) is an esterase;

f) is a lipase;

g) is a cutinase;

i) is an alpha/beta hydrolase;

j) is mycolylarabinogalactan esterase;

k) is phage LysB;

l) is D29 phage LysB; or

m) is in a sterile or buffered formulation.

12 . The method of claim 1 , further comprising administering a therapeutic compound that increases the permeability of a macrophage, monocyte, or granuloma.

13 . The method of claim 1 , wherein said mycobacterial chemotherapeutic is selected from the group consisting of:

a) a front line mycobacterial therapeutic such as isoniazid, pyrazinamide, ethambutol, or rifampin;

b) a second line mycobacterial therapeutic such as a fluoroquinolone (e.g., ciprofloxacin, levefloxacin, moxifloxacin), a cyclic peptide (e.g., capromycin, viomycin, enviomycin), a thioamide (e.g., ethionamide, prothionamide), cycloserine, terizidone, an aminoglycoside, PAS, kanamycin, capreomycin, amikacin, or streptomycin;

c) a third or subsequent line mycobacterial therapeutic;

d) one of a microlide, a β-lactam, a β-lactamase inhibitor, clavulenic acid, trimethoprim, or sulfamethoxazole;

e) one of clarithromycin, rifampicin, rifabutin, amikacin, azithromycin, or moxifloxacin; and

f) one of diarylquinoline, dedaquiline, TMC207, a nitroimdazole, PA-824, OPC-67683, an oxazolidinone, linezolid, sutezolid, AZD5847, BTZ043, and SQ109.

14 . The method of claim 1 , wherein the administering results in

a) reduced mycobacterial levels in the subject with a lower dose of mycobacterial chemotherapeutic than would be required in the absence of the outer membrane acting biologic;

b) reduced mycobacterial levels in the subject with a shorter duration of treatment with the mycobacterial chemotherapeutic than would be required in the absence of the outer membrane acting biologic;

c) reduced side effects;

d) reduced mycobacterial levels in the subject with a reduced number of mycobacterial chemotherapeutics than would be required in the absence of the outer membrane acting biologic.

15 . A kit, compartment, or therapeutic composition comprising:

a) an outer membrane acting biologic; and

b) a mycobacterial chemotherapeutic.

16 . The kit, compartment, or therapeutic composition of claim 15 , wherein the outer membrane acting biologic and mycobacterial therapeutic act synergistically to reduce mycobacteria.

17 . The kit, compartment, or therapeutic composition of claim 15 , wherein the kit comprises a compartment holding outer membrane acting biologic and a compartment holding the mycobacterial chemotherapeutic.

18 . The kit, compartment, or therapeutic composition of claim 15 , wherein the kit, compartment, or therapeutic composition is packaged in single dosage form.

19 . A method for treating a subject having a mycobacterial infection, comprising administering to the subject a LysB biologic, wherein the LysB biologic reduces mycobacteria, thereby treating the subject.

20 . The method of claim 19 , further comprising administering a mycobacterial chemotherapeutic.

21 . The method of claim 19 , wherein the mycobacterial infection is tuberculosis.