Design, Synthesis, and Antibacterial Evaluation of Rifampicin-Siderophore Conjugates

The growing concern over antibiotic resistance has sparked increased attention toward developing alternative antibiotic strategies. One promising approach, known as the "Trojan horse" strategy, involves the use of siderophores to hijack bacteria's iron transport systems as a way of delivering antibiotics inside the bacterial cell. This method is particularly promising in tackling Gram-negative bacteria, which have an outer membrane that many antibiotics cannot penetrate. One such antibiotic is rifampicin, a drug used to treat tuberculosis and infections caused by Gram-positive bacteria. Although rifampicin binds to a highly conserved bacterial RNA subunit, its activity is generally poor against Gram-negative bacteria due to their outer membrane. Aiming to expand rifampicin's efficacy, we here report the design and synthesis of several rifampicin-siderophore conjugates that exhibit enhanced activity against Gram-negative pathogens. Our findings indicate that the structural features of both the linker and catechol are crucial for the activity of conjugates with compound 33, wherein rifampicin is connected to chlorocatechol via a short ester linker, showing an up to 32-fold improvement in activity.