title: Design, synthesis and microbiological evaluation of ampicillin-tetramic acid hybrid antibiotics.
abstract: Exploiting iron-uptake pathways by conjugating β-lactam antibiotics with iron-chelators, such as catechol and hydroxamic acid is a proven strategy to overcome permeability-related resistance in Gram-negative bacteria. As naturally occurring iron-chelating tetramic acids have not been previously examined for this purpose, an exploratory series of novel ampicillin-tetramic acid hybrids that structurally resemble ureidopenicillins was designed and synthesized. The new analogs were evaluated for the ability to chelate iron and their MIC activities determined against a representative panel of clinically significant bacterial pathogens. The tetramic acid β-lactam hybrids demonstrated a high affinity to iron in the order of 10-30M3. The hybrids were less active against Gram-positive bacteria. However, against Gram-negative bacteria, their activity was species dependent with several hybrids displaying improved activity over ampicillin against wild-type Pseudomonas aeruginosa. The anti-Gram-negative activities of the hybrids improved in the presence of clavulanic acid revealing that the tetramic acid moiety did not provide added protection against β-lactamases. In addition, the hybrids were found to be efflux pump substrates as their activities markedly improved against pump-inactivated strains. Unlike the catechol and hydroxamic acid siderophore β-lactam conjugates, the activities of the hybrids did not improve under iron-deficient conditions. These results suggest that the tetramic acid hybrids gain permeability via different membrane receptors, or they are outcompeted by native bacterial siderophores with stronger affinities for iron. This study provides a foundation for the further exploitation of the tetramic acid moiety to achieve novel β-lactam anti-Gram-negative agents, providing that efflux and β-lactamase mediated resistance is addressed.
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Philip T
authors.initials: PT
authors.lastname: Cherian
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Deshpande
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Martin N
authors.initials: MN
authors.lastname: Cheramie
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Bruhn
authors.affiliation: Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.|Department of Microbial and Molecular Pathogenesis, Texas A&M Health Science Center, College of Medicine, Bryan, TX, USA.
authors.forename: Julian G
authors.initials: JG
authors.lastname: Hurdle
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D000667:Ampicillin / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D017262:Siderophores / Q000378:metabolism; D013045:Species Specificity; D001618:beta-Lactamases / Q000378:metabolism; D047090:beta-Lactams / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D011760:Pyrrolidinones; D017262:Siderophores; D047090:beta-Lactams; C009435:tetramic acid; D000667:Ampicillin; D001618:beta-Lactamases