title: Dual Targeting of Intracellular Pathogenic Bacteria with a Cleavable Conjugate of Kanamycin and an Antibacterial Cell-Penetrating Peptide.
abstract: Bacterial infection caused by intracellular pathogens, such as Mycobacterium, Salmonella, and Brucella, is a burgeoning global health epidemic that necessitates urgent action. However, the therapeutic value of a number of antibiotics, including aminoglycosides, against intracellular pathogenic bacteria is compromised due to their inability to traverse eukaryotic membranes. For this significant problem to be addressed, a cleavable conjugate of the antibiotic kanamycin and a nonmembrane lytic, broad-spectrum antimicrobial peptide with efficient mammalian cell penetration, P14LRR, was prepared. This approach allows kanamycin to enter mammalian cells as a conjugate linked via a tether that breaks down in the reducing environment within cells. Potent antimicrobial activity of the P14KanS conjugate was demonstrated in vitro, and this reducible conjugate effectively cleared intracellular pathogenic bacteria within macrophages more potently than that of a conjugate lacking the disulfide moiety. Notably, successful clearance of Mycobacterium tuberculosis within macrophages was observed with the dual antibiotic conjugate, and Salmonella levels were significantly reduced in an in vivo Caenorhabditis elegans model.
authors: Anna
authors: A
authors: Brezden
authors: Department of Comparative Pathobiology, Purdue University , 625 Harrison Street, West Lafayette, Indiana 47907-2027, United States.
authors: Mohamed F
authors: MF
authors: Mohamed
authors: Manish
authors: M
authors: Nepal
authors: John S
authors: JS
authors: Harwood
authors: Jerrin
authors: J
authors: Kuriakose
authors: Department of Comparative Pathobiology, Purdue University , 625 Harrison Street, West Lafayette, Indiana 47907-2027, United States.
authors: Mohamed N
authors: MN
authors: Seleem
authors: Jean
authors: J
authors: Chmielewski
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism; D001419:Bacteria / Q000187:drug effects*; D001692:Biological Transport; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology*; D007612:Kanamycin / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013438:Sulfhydryl Compounds / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D057846:Cell-Penetrating Peptides; D013438:Sulfhydryl Compounds; D007612:Kanamycin