title: Chemical modification of capuramycins to enhance antibacterial activity.
abstract: OBJECTIVE
  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.affiliation: Sequella, Inc., 9610 Medical Center Drive, Suite 200, Rockville, MD 20850, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Bogatcheva
authors.forename: Tia
authors.initials: T
authors.lastname: Dubuisson
authors.forename: Marina
authors.initials: M
authors.lastname: Protopopova
authors.forename: Leo
authors.initials: L
authors.lastname: Einck
authors.forename: Carol A
authors.initials: CA
authors.lastname: Nacy
authors.forename: Venkata M
authors.initials: VM
authors.lastname: Reddy
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D009161:Mycobacterium / Q000187:drug effects
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; C049983:capuramycin