Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 20, Pages 13988-14014Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01214
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Funding
- European Research Council (ERC Starting Grant, Sweetbullets) [716311]
- DZIF [TTU 09.718]
- German Center for Infection Research (DZIF) [TTU 09.719]
- European Research Council (ERC) [716311] Funding Source: European Research Council (ERC)
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In this study, lectin-targeted antibiotic prodrugs against Pseudomonas aeruginosa were synthesized by conjugating several fluoroquinolones to lectin probes. These prodrugs remained non-toxic in systemic distribution and were activated to exert bactericidal effects only at the infection site. Additionally, the prodrugs exhibited good ADME properties and reduced toxicity.
Chronic Pseudomonas aeruginosa infections are characterized by biofilm formation, a major virulence factor of P. aeruginosa and cause of extensive drug resistance. Fluoroquinolones are effective antibiotics but are linked to severe side effects. The two extracellular P. aeruginosa-specific lectins LecA and LecB are key structural biofilm components and can be exploited for targeted drug delivery. In this work, several fluoroquinolones were conjugated to lectin probes by cleavable peptide linkers to yield lectin-targeted prodrugs. Mechanistically, these conjugates therefore remain non-toxic in the systemic distribution and will be activated to kill only once they have accumulated at the infection site. The synthesized prodrugs proved stable in the presence of host blood plasma and liver metabolism but rapidly released the antibiotic cargo in the presence of P. aeruginosa in a self-destructive manner in vitro. Furthermore, the prodrugs showed good absorption, distribution, metabolism, and elimination (ADME) properties and reduced toxicity in vitro, thus establishing the first lectin-targeted antibiotic prodrugs against P. aeruginosa.
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