Synthesis of Vitamin B₁₂-Antibiotic Conjugates with Greatly Improved Activity against Gram-Negative Bacteria

Abstract

There is an urgent need to discover new antibiotics and improve the efficacy of known antibiotics against Gram-negative bacteria. “Trojan horse” conjugates are novel and promising antibiotics. Herein we report the design and synthesis of vitamin-B12–ampicillin conjugates, which exhibited more than 500 times improved activity against Escherichia coli compared with ampicillin itself. Our studies demonstrate that the vitamin-B12 uptake pathway could be employed for effective antibiotic delivery and efficacy enhancement.

Funktionalisierte Cofaktor‐Analoga für die Erforschung von Interaktomen und darüber hinaus

“…[126] So wurde kürzlich über ein Vitamin-B 12 -Ampicillin-Konjugat berichtet, das im Vergleich zu Ampicillin selbst eine mehr als 500-mal höhere Aktivität gegen E. coli aufwies. [127] Darüber hinaus ermöglichte die Konjugation mit Vitamin B 12 die bisher nie erreichte Einschleusung von Antisense-RNA-Oligonukleotiden in E.-coli-und S.-Typhimurium-Zellen, was die potenzielle Leistungsfähigkeit dieses Ansatzes unterstreicht. [128] Durch Konjugation mit zu untersuchenden Biomolekülen können die vielfältigen biochemischen Funktionen von Cofaktoren genutzt werden, um neuartige Werkzeuge zu schaffen, deren Fähigkeiten größer sind als die der einzelnen Teile selbst.…”

Macrocycle-Antibiotic Hybrids: A Path to Clinical Candidates

“…Various other hybrid chemical entities have also been reported, including polymyxin B3-tobramycin hybrids with Pseudomonas eruginosa-selective antibacterial activity and strong potentiation of rifampicin, minocycline, and vancomycin (Domalaon et al, 2017), azithromycin-benzoxaborole hybrid derivatives (Tevyashova et al, 2019), as well as antitubercular rifampicin and clofazimine hybrid (Saravanan et al, 2021). Very recently, design and synthesis of vitamin B12-antibiotic conjugates led to advanced candidates with >500-fold improved activity against Gram-negative bacteria including E. coli, relative to ampicillin, demonstrating that the vitamin B12 conjugate strategy is effective for enabling cellular uptake and antibiotic delivery, thus improving antibacterial efficacy (Zhao et al, 2020). Furthermore, among numerous elegant examples by the Schweizer group (Gorityala et al, 2016a;Gorityala et al, 2016b;Yang et al, 2017;Domalaon et al, 2019), the use of antibiotic hybrids as adjuvants such as nebramine-based hybrids (Yang et al, 2019) and lysine-tobramycin conjugates (Lyu et al, 2019) has potentiated the activities of current existing antibiotics including rifampicin and erythromycin, respectively.…”

Glutathione-responsive multifunctional nanoparticles based on mannose-modified pillar[5]arene for targeted antibiotic delivery against intracellular methicillin-resistant S. aureus

“…7 So an ADS with functions of cellular imaging, real-time monitoring of drug release and targeted antibiotic delivery for killing intracellular bacteria is highly desired. Continuing our research studies in discovering novel targeted therapies for bacterial infections, especially intracellular bacterial infections, 7,34,[36][37][38] we designed a multifunctional supramolecular host-guest system (WP5 * G) based on WP5 and G (Scheme 1). The mannosylated WP5 could target the macrophages which express high levels of mannose receptors, 39,40 and G could serve as a fluorescence off-on probe for real-time monitoring of drug release and optical imaging.…”