title: Structure-activity relationships of hygromycin A and its analogs: protein synthesis inhibition activity in a cell free system.
abstract: Several analogs of hygromycin A were tested in an Escherichia coli cell free protein synthesis inhibition assay and in a Serpulina hyodysenteriae whole cell assay. The aminocyclitol moiety is essential for antibacterial activity in both cell free and whole cell assays. However a 4'-O-allyl ether of hygromycin A aglycone showed an equivalent MIC to hygromycin A, while having a less potent IC50 in the cell free assay. Hence 6-deoxy-5-keto-D-arabino-hexofuranose can be replaced by a hydrophobic allyl group and still retain antibacterial activity. However, this replacement reduces the intrinsic protein synthesis inhibition activity. The loss of intrinsic activity with replacement by the allyl group may be compensated for by better transport into the bacterial cell. In addition to the SAR analysis, we demonstrated that the ineffectiveness of hygromycin A against Gram-negative enteric bacteria such as Escherichia coli is mainly due to the efflux mechanism (Acr A/B pump) existing widely among the enteric bacteria rather than the impermeable barrier of the outer membrane.
authors.affiliation: Pfizer Inc., Central Research Division, Groton, CT 06340, U.S.A.
authors.forename: S F
authors.initials: SF
authors.lastname: Hayashi
authors.forename: L J
authors.initials: LJ
authors.lastname: Norcia
authors.forename: S B
authors.initials: SB
authors.lastname: Seibel
authors.forename: A M
authors.initials: AM
authors.lastname: Silvia
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis*; D017401:Brachyspira hyodysenteriae / Q000187:drug effects / Q000378:metabolism; D002474:Cell-Free System; D002701:Chloramphenicol / Q000493:pharmacokinetics / Q000494:pharmacology; D002934:Cinnamates; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006921:Hygromycin B / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D011500:Protein Synthesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002934:Cinnamates; D011500:Protein Synthesis Inhibitors; D006921:Hygromycin B; C026273:hygromycin A; D002701:Chloramphenicol