Methods of inhibiting
Method of at least partially inhibiting the function of Klebsiella pneumoniae carbapenemase-2 (KPC-2) or a variant thereof, the method including contacting the KPC-2 with a benzoxaborole selected from the group consisting of 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, and mixtures thereof useful in the treatment of beta-lactam antibiotic resistant bacteria infections in a subject.
1 . A method of reversing a beta-lactam antibiotic resistance in bacteria, the method comprising inhibiting an enzyme activity of Klebsiella pneumoniae carbapenemase-2 (KPC-2) or a variant thereof in the bacteria by a benzoxaborole selected from the group consisting of 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, and mixtures thereof, thereby restoring a bactericidal effect of the beta-lactam antibiotic on the bacteria within the first 5 hours of contacting the bacteria with the benzoxaborole and the beta-lactam antibiotic concurrently or sequentially, wherein the beta-lactam antibiotic comprises cephalosporin, carbapenem, penam, or monobactam; said bacteria are at least carbapenem-resistant comprising carbapenem-resistant or hypervirulent Klebsiella pneumoniae , carbapenem-resistant or hypervirulent Escherichia coli , or carbapenem-resistant or hypervirulent Enterobacter cloacae.
2 . The method of claim 1 , wherein the benzoxaborole is 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole.
3 . The method of claim 1 , wherein the KPC-2 variant is KPC-93.
4 . The method of claim 1 , wherein the benzoxaborole is 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole and the KPC-2 variant is KPC-93.
5 . A method of treating a bacterial infection in a subject in need thereof, the method comprising co-administering a therapeutically effective amount of a beta-lactam antibiotic and a benzoxaborole selected from the group consisting of 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, and mixtures thereof, the benzoxaborole inhibiting an enzyme activity of Klebsiella pneumoniae carbapenemase-2 (KPC-2) or a variant thereof in bacteria causing the bacterial infection, reversing a beta-lactam antibiotic resistance in the bacteria, thereby restoring a bactericidal effect of the beta-lactam antibiotic on the bacteria within the first 5 hours of said co-administering the therapeutically effective amount of the beta-lactam antibiotic and the benzoxaborole concurrently or sequentially to said subject, wherein the beta-lactam antibiotic is selected from cephalosporin, carbapenem, penam, or monobactam; said bacteria are at least carbapenem-resistant comprising carbapenem-resistant or hypervirulent Klebsiella pneumoniae , carbapenem-resistant or hypervirulent Escherichia coli , or carbapenem-resistant or hypervirulent Enterobacter cloacae.
6 . The method of claim 5 , wherein the bacteria further comprise Aeromonas caviae, Aeromonas hydrophila, Aeromonas veroni, Citrobacter amalonaticus, Citrobacter freundii, Citrobacter koseri, Citrobacter portucalensis, Citrobacter youngae, Enterobacter asburiae, Enterobacter cloacae, Enterobacter hormaechei, Enterobacter kobei, Escherichia coli, Klebsiella aerogenes, Klebsiella michiganensis, Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella quasipneumoniae, Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Raoultella planticola, Salmonella enterica , or Serratia marcescens.
7 . The method of claim 5 , wherein the beta-lactam antibiotic is a carbapenem.
8 . The method of claim 5 , wherein the beta-lactam antibiotic is a carbapenem selected from the group consisting of Biapenem, Ertapenem, Doripenem, Imipenem, Meropenem, Tebipenem and Panipenem.
9 . The method of claim 5 , wherein the carbapenem is Meropenem.
10 . The method of claim 5 , wherein the benzoxaborole is 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole.
11 . The method of claim 5 , wherein the KPC-2 variant is KPC-93.
12 . The method of claim 5 , wherein the bacteria is carbapenem-resistant Klebsiella pneumoniae , hypervirulent Klebsiella pneumoniae, Escherichia coli , or Enterobacter cloacae , the benzoxaborole is 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, and the beta-lactam antibiotic is a carbapenem selected from the group consisting of Biapenem, Ertapenem, Doripenem, Imipenem, Meropenem, Tebipenem and Panipenem.
13 . The method of claim 5 , wherein the bacteria is carbapenem-resistant Klebsiella pneumoniae or hypervirulent Klebsiella pneumoniae , the benzoxaborole is 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, and the beta-lactam antibiotic is a carbapenem is Meropenem.
14 . The method of claim 13 , wherein the KPC-2 variant is KPC-93.