Antimicrobial analogues of gramicidin S
Disclosed herein are N-aminated variants of Gramicidin S and methods of using the same for treating infections in a subject.
1. A method of treating an infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein
R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen or —NH 2 ;
wherein at least one of R 1 , R 2 , R 3 , and R 4 is —NH 2 ; and
wherein the infection is
a fungal infection caused by Aspergillus, Candida, Coccidioides, Cryptococcus gatti, Pneumocystis jirovecii, Blastomyces, Cryptoccocus neoformans, Histoplasma , or Talaromyce , or a combination thereof;
a gram-positive bacterial infection caused by Actinomyces spp.; Aerococcus spp.; Bacillus spp.; Bacterionema spp.; Bifidobacterium spp.; Clostridium spp.; Corynebacterium spp.; Corprococcus spp.; Deinobacter spp.; Deinococcus spp.; Enterococcus spp.; Erysipelothrix spp.; Eubacterium spp.; Gemella spp.; Lactobacillus spp.; Lactococcus spp.; Leuconostoc spp.; Listeria spp.; Marinococcus spp.; Melissococcus spp.; Methanobacterium spp.; Micrococcus spp.; Mycobacterium spp.; Micropolyspora spp.; Nocardia spp.; Pediococcus spp.; Peptococcus spp.; Peptostreptococcus spp.; Planococcus spp.; Propionibacterium spp.; Rothia spp.; Ruminococcus spp.; Saccharococcus spp.; Salinococcus spp.; Carcina spp.; Staphylococcus spp.; Stomatococcus spp.; Streptococcus spp.; Streptomyces spp.; Trichococcus spp.; Vagococcus spp; or a combination thereof; or
a gram-negative bacterial infection caused by Acinetobacter spp.; Bacterioides spp.; Bordetella spp.; Borrelia spp.; Brucella spp.; Burkholderia spp.; Calymmatobacterium spp.; Campylobacter spp.; Chlamydia spp.; Chlamydophila spp.; Citrobacter spp.; Coxiella spp.; Edwardsiella spp.; Enterobacter spp.; Ehrlichia spp.; Escherichia spp.; Francisella spp.; Gardnerella spp.; Haemophilus spp.; Helicobacter spp.; Klebsiella spp.; Legionella spp.; Leptospira spp.; Moraxella spp.; Mycoplasma spp.; Neisseria spp.; Pasteurella spp.; Proteus spp.; Providencia spp.; Pseudomonas spp.; Rickettsia spp.; Salmonella spp.; Serratia spp.; Shigella spp.; Spirillaceae spp.; Streptobacillus spp.; Treponema spp.; Vibrio spp.; Yersinia spp., or a combination thereof.
2. The method of claim 1 , wherein R 3 is —NH 2 .
3. The method of claim 1 , wherein R 4 is —NH 2 .
4. The method of claim 1 , wherein two of R 1 , R 2 , R 3 , and R 4 are —NH 2 .
5. The method of claim 4 , wherein Wand R 3 are —NH 2 .
6. The method of claim 4 , wherein R 3 and R 4 are —NH 2 .
7. The method of claim 4 , wherein R 2 and R 3 are —NH 2 .
8. The method of claim 4 , wherein R 2 and R 4 are —NH 2 .
9. The method of claim 1 , wherein three of R 1 , R 2 , R 3 , and R 4 are —NH 2 .
10. The method of claim 9 , wherein R 1 , R 3 and R 4 are —NH 2 .
11. The method of claim 9 , wherein R 2 , R 3 and R 4 are —NH 2 .
12. The method of claim 1 , wherein each of R 1 , R 2 , R 3 , and R 4 are —NH 2 .
13. The method of claim 1 , wherein the infection is a multi-drug resistant infection.
14. The method of claim 1 , wherein the subject is a human.
15. The method of claim 1 , wherein the infection is a fungal infection caused by Aspergillus, Candida, Coccidioides, Cryptococcus gatti, Pneumocystis jirovecii, Blastomyces, Cryptoccocus neoformans, Histoplasma , or Talaromyce , or a combination thereof.
16. The method of claim 1 , wherein the infection is a gram-positive bacterial infection caused by a gram-positive bacterial infection caused by Actinomyces spp.; Aerococcus spp.; Bacillus spp.; Bacterionema spp.; Bifidobacterium spp.; Clostridium spp.; Corynebacterium spp.; Corprococcus spp.; Deinobacter spp.; Deinococcus spp.; Enterococcus spp.; Erysipelothrix spp.; Eubacterium spp.; Gemella spp.; Lactobacillus spp.; Lactococcus spp.; Leuconostoc spp.; Listeria spp.; Marinococcus spp.; Melissococcus spp.; Methanobacterium spp.; Micrococcus spp.; Mycobacterium spp.; Micropolyspora spp.; Nocardia spp.; Pediococcus spp.; Peptococcus spp.; Peptostreptococcus spp.; Planococcus spp.; Propionibacterium spp.; Rothia spp.; Ruminococcus spp.; Saccharococcus spp.; Salinococcus spp.; Carcina spp.; Staphylococcus spp.; Stomatococcus spp.; Streptococcus spp.; Streptomyces spp.; Trichococcus spp.; Vagococcus spp; or a combination thereof.
17. The method of claim 16 , wherein the gram-positive bacterial infection is caused by Enterococcus spp., Staphylococcus spp., or a combination thereof.
18. The method of claim 1 , wherein the infection is a gram-negative bacterial infection caused by Acinetobacter spp.; Bacterioides spp.; Bordetella spp.; Borrelia spp.; Brucella spp.; Burkholderia spp.; Calymmatobacterium spp.; Campylobacter spp.; Chlamydia spp.; Chlamydophila spp.; Citrobacter spp.; Coxiella spp.; Edwardsiella spp.; Enterobacter spp.; Ehrlichia spp.; Escherichia spp.; Francisella spp.; Gardnerella spp.; Haemophilus spp.; Helicobacter spp.; Klebsiella spp.; Legionella spp.; Leptospira spp.; Moraxella spp.; Mycoplasma spp.; Neisseria spp.; Pasteurella spp.; Proteus spp.; Providencia spp.; Pseudomonas spp.; Rickettsia spp.; Salmonella spp.; Serratia spp.; Shigella spp.; Spirillaceae spp.; Streptobacillus spp.; Treponema spp.; Vibrio spp.; Yersinia spp., or a combination thereof.
19. The method of claim 18 , wherein the gram-negative bacterial infection is caused by Acinetobacter spp., Enterobacter spp., Klebsiella spp., Pseudomonas spp., or a combination thereof.
20. The method of claim 1 , wherein the infection is
a gram-positive bacterial infection caused by Actinomyces israelii; Bacillus anthracis; Clostridium botulinum; Clostridium difficile; Clostridium perfringens; Clostridium tetani; Corynebacterium diphtherias; Enterococcus faecalis; Enterococcus faecium; Listeria monocytogenes; Mycobacterium avium; Mycobacterium leprae; Mycobacterium lepromatosis; Mycobacterium tuberculosis; Mycobacterium ulcerans; Nocardia asteroides; Staphylococcus aureus; Staphylococcus epidermidis; Staphylococcus saprophyticus; Streptococcus agalactiae; Streptococcus pneumoniae; Streptococcus pyogenes; Streptococcus viridans ; or a combination thereof; or
a gram-negative bacterial infection caused by Acinetobacter A. baumannii; Bacterioides fragilis; Bordetella pertussis; Borrelia burgdorferi; Borrelia garinii; Borrelia afzelii; Brucella abortus; Brucella canis; Brucella melitensis; Brucella suis; Burkholderia mallei; Burkholderia pseudomallei; Campylobacter fetus; Campylobacter jejuni; Chlamydia trachomatis; Chlamydia pneumoniae; Chlamydia psittaci; Chlamydophila pneumoniae; Coxiella burnetti; Ehrlichia canis; Ehrlichia chaffeensis; Escherichia coli; Francisella tularensis; Haemophilus influenzae; Helicobacter pylori; Klebsiella pneumoniae; Legionella pneumophila; Leptospira interrogans; Moraxella catarrhalis; Mycoplasma pneumoniae; Neisseria gonorrhoeae; Neisseria meningitidis; Pseudomonas aeruginosa; Pseudomonas mallei; Rickettsia akari; Rickettsia prowazekii; Rickettsia rickettsia; Salmonella enterica; Salmonella enterica enteritidis; Salmonella enterica hadar; Salmonella enterica Heidelberg; Salmonella enterica infantis; Salmonella enterica paratyphi; Salmonella enterica typhi; Salmonella enterica typhimurium; Shigella dysenteriae; Shigella sonnei; Spirillaceae minus; Streptobacillus moniliformis; Treponema pallidum; Vibrio cholerae; Yersinia enterocolitica; Yersinia pestis; Yersinia pseudotuberculosis ; or a combination thereof.