Methods of treatment for bacterial infections
This invention features new compositions and methods that are useful in treating a host with a Gram-negative bacterial infection. Combination therapies comprising an aminocoumarin compound and a polymyxin compound are disclosed, including certain combinations that exhibit synergistic effects. Furthermore, aminocoumarin compounds are described having altered inhibition of DNA gyrase in Gram-negative bacteria and/or the ability to target the transport proteins responsible for assembling lipopolysaccharide in the outer membrane of Gram-negative bacteria.
1. A method of treating an individual having a bacterial infection caused by a Gram-negative bacterium, the method comprising administering to the individual a single pharmaceutical composition comprising both an aminocoumarin compound or a salt thereof and a polymyxin compound or a salt thereof;
wherein the polymyxin compound is polymyxin B or a salt thereof; and
wherein the Gram-negative bacterium is Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli , or an Enterobacter spp.
2. The method of claim 1 , wherein the aminocoumarin compound or salt thereof binds a Lpt protein in the Gram-negative bacterium.
3. The method of claim 2 , wherein the Lpt protein is LptB.
4. The method of claim 1 , wherein the aminocoumarin compound is a novobiocin analog, or a salt thereof.
5. The method of claim 4 , wherein the novobiocin analog is descarbamyl novobiocin or a salt thereof, novobiocin-adamantyl or a salt thereof, or novobiocin-aglycone or a salt thereof.
6. The method of claim 1 , wherein the aminocoumarin compound is clorobiocin, a clorobiocin analog, or a salt thereof.
7. The monotherapy method of claim 1 , wherein the aminocoumarin compound is coumermycin A1, a coumermycin A1 analog, or a salt thereof.
8. The method of claim 1 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
9. The method of claim 1 , wherein the pharmaceutical composition is in unit-dose form.
10. The method of claim 1 , wherein the pharmaceutical composition is formulated for parenteral administration, intranasal administration, topical administration, or oral administration.
11. The method of claim 1 , wherein the pharmaceutical composition is formulated for intramuscular administration, intravenous administration, intrathecal administration, or ophthalmic administration.
12. The method of claim 1 , wherein the bacterial infection is a urinary tract infection, meningeal infection, eye infection, lung infection, or bacteremia.
13. The method of claim 1 , wherein the Gram-negative bacterium is a non-opportunistic pathogen.
14. The method of claim 1 , wherein the method is effective at substantially reducing or eliminating the bacterial infection.
15. The method of claim 1 , wherein the aminocoumarin compound is novobiocin, or a salt thereof.
16. The method of claim 1 , wherein the Gram-negative bacterium is a polymyxin-resistant bacterium.
17. The method of claim 1 , wherein the Gram-negative bacterium is a novobiocin-resistant bacterium.
18. The method of claim 1 , wherein the Gram-negative bacterium is a novobiocin- and polymyxin-resistant bacterium.