STAPLED INTRACELLULAR-TARGETING ANTIMICROBIAL PEPTIDES TO TREAT INFECTION

1 . A compound having the formula:

or a pharmaceutically acceptable salt thereof,

wherein;

each R 1 and R 2 is independently H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl, any of which is substituted or unsubstituted;

each R 3 is independently alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted;

each x is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

each w and y is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;

z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each Xaa is independently an amino acid,

wherein the compound exhibits an intracellular antimicrobial effect against at least one microbe.

2 . The compound of claim 1 , wherein x is 2, 3, or 6.

3 . The compound of claim 2 , wherein x is 2; R 3 is C 8 alkylene, C 8 alkenylene, or C 8 alkynylene; and the sum of x, w, and y is at least 10.

4 . The compound of claim 1 , wherein x is 3; R 3 is C 8 alkylene, C 8 alkenylene, or C 8 alkynylene; and the sum of x, w, and y is at least 10.

5 . The compound of claim 1 , wherein R 3 is substituted with 1, 2, 3, 4, 5, or 6 R 4 , and each R 4 is independently —NH 3 or —OH, wherein each —NH 3 is optionally coupled with another chemical entity.

6 . The compound of claim 5 , wherein R 3 is substituted with 2 R 4 , and both R 4 are —OH.

7 . The compound of claim 5 , wherein R 3 is substituted with 2 R 4 , and one R 4 is an optionally substituted —NH 3 and the other R 4 is —OH.

8 . The compound of claim 1 , wherein at least one Xaa is an amino acid that is a non-natural amino acid.

9 . The compound of claim 1 , wherein the compound comprises a helix.

10 . The compound of claim 9 , wherein the helix is an α-helix.

11 . The compound of claim 1 , wherein R 3 spans from one to two turns on an α-helix.

12 . The compound of claim 1 , wherein the compound comprises an amino acid sequence that is at least 60% identical to an amino acid sequence selected from the group consisting of: SEQ ID NOs: 1-60.

13 . The compound of claim 1 , wherein the compound comprises an amino acid sequence that is at least 70% identical to an amino acid sequence selected from the group consisting of: SEQ ID NOs: 1-60.

14 . The compound of claim 1 , wherein the compound comprises an amino acid sequence that is at least 80% identical to an amino acid sequence selected from the group consisting of: SEQ ID NOs: 1-60.

15 . The compound of claim 1 , wherein the compound comprises an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of: SEQ ID NOs: 1-60.

16 . The compound of claim 1 , wherein the compound comprises an amino acid sequence that is any one of: SEQ ID NOs: 1-60.

17 . The compound of claim 1 , wherein the compound comprises BFStap(i+4)2, BFStap(i+4)3, BFStap(i+4)4, BFStap(i+4)6, BFStap(i+4)7, BFStap(i+4)8, BFStap(i+4)11, BFStap(i+7)1, BFStap(i+7)2, BFStap(i+7)3, BFStap(i+7)4, BFStap(i+7)5, BFStap(i+7)6, BFStap(i+7)7, BFStap(i+7)8, or BFStap(i+7)9.

18 . The compound of claim 1 , wherein the compound comprises the sequence of BFStap(i+4)7, BFStap(i+4)11, or BFStap(i+7) 6.

19 . The compound of claim 1 , wherein the antimicrobial effect is a minimum inhibitory concentration between about 0.1 μM and about 50 μM.

20 . The compound of claim 1 , wherein the antimicrobial effect is a minimum inhibitory concentration between about 0.5 μM and about 20 μM.

21 . The compound of claim 1 , wherein the microbe is a bacterial organism.

22 . The compound of claim 21 , wherein the bacterial organism is Gram-positive.

23 . The compound of claim 21 , wherein the bacterial organism is Gram-negative.

24 . The compound of claim 21 , wherein the bacterial organism is Mycobacterium tuberculosis.

25 . A method of treating an infection caused by a microbe, the method comprising administering a therapeutically-effective amount of a compound having the formula:

or a pharmaceutically acceptable salt thereof,

wherein;

each R 1 and R 2 is independently H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl, any of which is substituted or unsubstituted;

each R 3 is independently alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted;

each x is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

each w and y is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;

z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each Xaa is independently an amino acid,

to a subject having, or at risk of having, the infection caused by the microbe, wherein the compound exhibits an intracellular antimicrobial effect against at least one microbe.

26 . The method of claim 25 , wherein the subject is an animal.

27 . The method of claim 26 , wherein the animal is a mammal.

28 . The method of claim 26 , wherein the animal is a human.

29 . The method of claim 25 , wherein the subject is a plant.

30 . The method of claim 25 , wherein the microbe is a bacterial organism.

31 . The method of claim 30 , wherein the bacterial organism is Gram-positive.

32 . The method of claim 30 , wherein the bacterial organism is Gram-negative.

33 . The method of claim 25 , further comprising administering to the subject a therapeutically-effective amount of an antibiotic.

34 . The method of claim 33 , wherein the compound and the antibiotic act synergistically to treat the infection.

35 . The method of claim 33 , wherein the compound and the antibiotic act synergistically to overcome a resistance of the infection to the antibiotic.

36 . A pharmaceutical composition comprising a compound having the formula:

or a pharmaceutically acceptable salt thereof,

wherein;

each R 1 and R 2 is independently H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl, any of which is substituted or unsubstituted;

each R 3 is independently alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted;

each x is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

each w and y is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;

z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each Xaa is independently an amino acid,

wherein the compound exhibits an intracellular antimicrobial effect against at least one microbe.