Structure–Activity Relationship of Peptide-Conjugated Chloramphenicol for Inhibiting <i>Escherichia coli</i>

Abstract

Intravenous administration of a prodrug, chloramphenicol succinate (CLsu), is ineffective. Recently, we have shown that conjugation of diglycine of CLsu (CLsuGG) not only increases the antibiotic efficacy against <i>Escherichia coli</i> but also reduces adverse drug effects against bone marrow stromal cells. Here, we report the synthesis of structural analogues of CLsuGG and their activities against <i>E. coli</i>. These analogues reveal several trends: (i) except the water-insoluble analogues, the attachment of peptides to CLsu enhances the efficacy of the prodrugs; (ii) negative charges, high steric hindrance in the side chains, or a rigid diester decreases the activities of prodrugs in comparison to CLsuGG; (iii) dipeptides apparently increase the efficacy of the prodrugs most effectively; and so forth. This work suggests that conjugating peptides to CLsu effectively modulates the properties of prodrugs. The structure-activity relationship of these new conjugates may provide useful insights for expanding the pool of antibiotics.