Methods of treatment for bacterial infections

Abstract

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 an effective amount of a pharmaceutical composition comprising an aminocoumarin compound or salt thereof in combination with a pharmaceutical composition comprising a polymyxin compound or 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 is novobiocin or salt thereof. 
     
     
         3 . The method of  claim 1 , wherein the aminocoumarin compound is descarbamyl novobiocin or a salt thereof, novobiocin-adamantyl or a salt thereof, or novobiocin-aglycone or a salt thereof. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the aminocoumarin compound is clorobiocin, a clorobiocin analog, or a salt thereof. 
     
     
         7 . (canceled). 
     
     
         8 . The method of  claim 1 , wherein the aminocoumarin compound is coumermycin A1, a coumermycin A1 analog, or a salt thereof. 
     
     
         9 - 12  (canceled) 
     
     
         13 . The method of  claim 1 , wherein the pharmaceutical composition comprising the aminocoumarin compound or salt thereof is administered parenterally, intranasally, orally, or topically. 
     
     
         14 . The method of  claim 1 , wherein the aminocoumarin compound or salt thereof, is administered at a dose of 1 to 250 mg/kg/day. 
     
     
         15 - 16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein the polymyxin compound or salt thereof, is administered at a dose of 0.01 mg/kg/day to about 6 mg/kg/day. 
     
     
         18 - 21 . (canceled) 
     
     
         22 . The method of  claim 1 , wherein the pharmaceutical composition comprising the polymyxin compound or salt thereof is administered parenterally, orally, intranasally, or topically. 
     
     
         23 - 28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein the bacterial infection is a urinary tract infection, meningeal infection, eye infection, lung infection, or bacteremia. 
     
     
         30 - 61 . (canceled) 
     
     
         62 . A method of treating an individual having a bacterial infection caused by a Gram-negative bacterium, the method comprising administering to the individual an effective amount of a pharmaceutical composition comprising an aminocoumarin compound or salt thereof in combination with a pharmaceutical composition comprising a polymyxin compound or salt thereof;
 wherein the Gram-negative bacterium is an aminocoumarin-resistant bacterium and/or a polymyxin-resistant bacterium.   
     
     
         63 . The method of  claim 62 , wherein the Gram-negative bacterium is an aminocoumarin-resistant bacterium. 
     
     
         64 . The method of  claim 62 , wherein the Gram-negative bacterium is a polymyxin-resistant bacterium. 
     
     
         65 . The method of  claim 62 , wherein the Gram-negative bacterium is an aminocoumarin- and polymyxin-resistant bacterium. 
     
     
         66 . The method of  claim 62 , wherein the polymyxin compound is polymyxin B or a salt thereof. 
     
     
         67 . The method of  claim 62 , wherein the aminocoumarin compound is a novobiocin analog, or a salt thereof. 
     
     
         68 . The method of  claim 67 , wherein the novobiocin analog is descarbamyl novobiocin or a salt thereof, novobiocin-adamantyl or a salt thereof, or novobiocin-aglycone or a salt thereof. 
     
     
         69 . The method of  claim 62 , wherein the aminocoumarin compound is clorobiocin, a clorobiocin analog, or a salt thereof. 
     
     
         70 . The method of  claim 62 , wherein the aminocoumarin compound is coumermycin A1, a coumermycin A1 analog, or a salt thereof. 
     
     
         71 . The method of  claim 62 , wherein the aminocoumarin compound is novobiocin, or a salt thereof. 
     
     
         72 . The method of  claim 62 , wherein the bacterial infection is a urinary tract infection, meningeal infection, eye infection, lung infection, or bacteremia.