title: Inhibition of the tetracycline efflux antiport protein by 13-thio-substituted 5-hydroxy-6-deoxytetracyclines.
abstract: A series of 13-(alkylthio) and 13-(arylthio) derivatives of 5-hydroxy-6-deoxytetracycline (tetracycline, Tc) were synthesized and compared to the clinically used antibiotics tetracycline, methacycline, and minocycline for their ability to inhibit tetracycline efflux in an everted membrane vesicle assay of bacterial resistance to tetracyclines. The assay screened for the ability of tetracycline analogues to inhibit [3H]tetracycline uptake into everted membrane vesicles, thereby evaluating the molecular prerequisites for inhibition of an efflux-dependent resistant bacterial system. Thiol adducts attached at the exocyclic C13 carbon of methacycline led to an increase in inhibitor potency as compared to the reference antibiotics. The most potent inhibitors of [3H]tetracycline uptake into everted vesicles among these analogues, particularly members of the alkyl series, revealed important structure-activity relationships between inhibitor potency, steric parameters, and lipophilicity at the C13 sulfur position.
authors.affiliation: Department of Chemistry, Tufts University, Medford, Massachusetts 02144.
authors.forename: M L
authors.initials: ML
authors.lastname: Nelson
authors.forename: B H
authors.initials: BH
authors.lastname: Park
authors.forename: J S
authors.initials: JS
authors.lastname: Andrews
authors.forename: V A
authors.initials: VA
authors.lastname: Georgian
authors.forename: R C
authors.initials: RC
authors.lastname: Thomas
authors.forename: S B
authors.initials: SB
authors.lastname: Levy
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001693:Biological Transport, Active / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D013753:Tetracycline Resistance / Q000502:physiology*; D013754:Tetracyclines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D013754:Tetracyclines