OBJECTIVES: To extend capuramycin spectrum of activity beyond mycobacteria and improve intracellular drug activity. METHODS: Three capuramycin analogues (SQ997, SQ922 and SQ641) were conjugated with different natural and unnatural amino acids or decanoic acid (DEC) through an ester bond at one or more available hydroxyl groups. In vitro activity of the modified compounds was determined against Mycobacterium spp. and representative Gram-positive and Gram-negative bacteria. Intracellular activity was evaluated in J774A.1 mouse macrophages infected with Mycobacterium tuberculosis (H37Rv). RESULTS: Acylation of SQ997 and SQ641 with amino undecanoic acid (AUA) improved in vitro activity against most of the bacteria tested. Conjugation of SQ922 with DEC, but not AUA, improved its activity against Gram-positive bacteria. In the presence of efflux pump inhibitor phenylalanine arginine β-naphthyl amide, MICs of SQ997-AUA, SQ641-AUA and SQ922-DEC compounds improved even further against drug-susceptible and drug-resistant Staphylococcus aureus. In Gram-negative bacteria, EDTA-mediated permeabilization caused 4- to 16-fold enhancement of the activity of AUA-conjugated SQ997, SQ922 and SQ641. Conjugation of all three capuramycin analogues with AUA improved intracellular killing of H37Rv in murine macrophages. CONCLUSIONS: Conjugation of capuramycin analogues with AUA or DEC enhanced in vitro activity, extended the spectrum of activity in Gram-positive bacteria and increased intracellular activity against H37Rv.
OBJECTIVES: To extend capuramycin spectrum of activity beyond mycobacteria and improve intracellular drug activity. METHODS: Three capuramycin analogues (SQ997, SQ922 and SQ641) were conjugated with different natural and unnatural amino acids or decanoic acid (DEC) through an ester bond at one or more available hydroxyl groups. In vitro activity of the modified compounds was determined against Mycobacterium spp. and representative Gram-positive and Gram-negative bacteria. Intracellular activity was evaluated in J774A.1 mouse macrophages infected with Mycobacterium tuberculosis (H37Rv). RESULTS: Acylation of SQ997 and SQ641 with amino undecanoic acid (AUA) improved in vitro activity against most of the bacteria tested. Conjugation of SQ922 with DEC, but not AUA, improved its activity against Gram-positive bacteria. In the presence of efflux pump inhibitor phenylalanine arginine β-naphthyl amide, MICs of SQ997-AUA, SQ641-AUA and SQ922-DEC compounds improved even further against drug-susceptible and drug-resistant Staphylococcus aureus. In Gram-negative bacteria, EDTA-mediated permeabilization caused 4- to 16-fold enhancement of the activity of AUA-conjugated SQ997, SQ922 and SQ641. Conjugation of all three capuramycin analogues with AUA improved intracellular killing of H37Rv in murine macrophages. CONCLUSIONS: Conjugation of capuramycin analogues with AUA or DEC enhanced in vitro activity, extended the spectrum of activity in Gram-positive bacteria and increased intracellular activity against H37Rv.
Authors: Boris V Nikonenko; Venkata M Reddy; Marina Protopopova; Elena Bogatcheva; Leo Einck; Carol A Nacy Journal: Antimicrob Agents Chemother Date: 2009-05-04 Impact factor: 5.191
Authors: Katsuhiko Mitachi; Rita G Kansal; Kirk E Hevener; Cody D Gillman; Syed M Hussain; Hyun Gi Yun; Gustavo A Miranda-Carboni; Evan S Glazer; William M Clemons; Michio Kurosu Journal: J Med Chem Date: 2020-09-18 Impact factor: 7.446
Authors: Elena Bogatcheva; Colleen Hanrahan; Boris Nikonenko; Gladys de los Santos; Venkata Reddy; Ping Chen; Francis Barbosa; Leo Einck; Carol Nacy; Marina Protopopova Journal: Bioorg Med Chem Lett Date: 2011-07-14 Impact factor: 2.823
Authors: Boris Nikonenko; Venkata M Reddy; Elena Bogatcheva; Marina Protopopova; Leo Einck; Carol A Nacy Journal: Antimicrob Agents Chemother Date: 2013-10-21 Impact factor: 5.191
Authors: John H Moore; Edward van Opstal; Glynis L Kolling; Jae Hyun Shin; Elena Bogatcheva; Boris Nikonenko; Leo Einck; Andrew J Phipps; Richard L Guerrant; Marina Protopopova; Cirle Alcantara Warren Journal: J Antimicrob Chemother Date: 2016-01-31 Impact factor: 5.790