title: Surprising alteration of antibacterial activity of 5"-modified neomycin against resistant bacteria.
abstract: A facile synthetic protocol for the production of neomycin B derivatives with various modifications at the 5'' position has been developed. The structural activity relationship (SAR) against aminoglycoside resistant bacteria equipped with various aminoglycoside-modifying enzymes (AMEs) was investigated. Enzymatic and molecular modeling studies reveal that the superb substrate promiscuity of AMEs allows the resistant bacteria to cope with diverse structural modifications despite the observation that several derivatives show enhanced antibacterial activity compared to the parent neomycin. Surprisingly, when testing synthetic neomycin derivatives against other human pathogens, two leads exhibit prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) that are known to exert a high level of resistance against clinically used aminoglycosides. These findings can be extremely useful in developing new aminoglycoside antibiotics against resistant bacteria. Our result also suggests that new biological and antimicrobial activities can be obtained by chemical modifications of old drugs.
authors.affiliation: Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, Utah 84322-0300, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhang
authors.forename: Fang-I
authors.initials: FI
authors.lastname: Chiang
authors.forename: Long
authors.initials: L
authors.lastname: Wu
authors.forename: Przemyslaw Greg
authors.initials: PG
authors.lastname: Czyryca
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.forename: Cheng-Wei Tom
authors.initials: CW
authors.lastname: Chang
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D016983:Enterococcus / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005601:Framycetin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D019868:Kanamycin Kinase / Q000037:antagonists & inhibitors; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D020713:Vancomycin Resistance / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D005601:Framycetin; D019868:Kanamycin Kinase