Synthesis, characterization and biological activity evaluation of a dual-drug based on the antibacterial peptide lugdunin functionalized with the Carbonic Anhydrase sulfonamide inhibitor acetazolamide

Fo r travel g ra n t to M ich a el Q u a g lia ta Fo r M ich a el Q u a g lia ta 's P h D sch o la rsh ipLugdunin is an antibiotic thiazolidine-containing cyclopeptide.It was isolated in 2016 fromStaphylococcus lugdunensis.This cyclopeptide displays potent antimicrobial activity against a broad spectrum of Gram-positive bacteria, including challenging-to-treat methicillin-resistant Staphylococcus aureus (MRSA) (MIC = 3.9 M).In particular, it inhibits target bacteria by dissipating their membrane potential, forming supramolecular peptide channels [3,4].An Ala-scan performed by Schilling et al. showed that changing L-Val 5 with an L-Ala 5 residue does not influence the antimicrobial activity [5].CA is a zinc-containing enzyme that plays a crucial role in various physiological processes by catalyzing the reversible hydration of carbon dioxide (CO 2 ) into carbonic acid (H 2 CO 3 ).This family of metal enzymes is a promising target for the development of antibacterial compounds because it plays a key role for the survival of the microorganism.AAZ is a therapeutic used to treat glaucoma, epilepsy, acute mountain sickness, periodic paralysis, idiopathic intracranial hypertension, heart failure and to alkalinize urine.Moreover, acetazolamide is a first-generation carbonic anhydrase inhibitor Potent inhibitor Ca rbo n ic a n hydra se (CA) D u a l dr u g L u g du n in -Aceta zo la m ide O H N Fmoc O NBoc Fmoc-L-Trp(Boc) Wang resin 0.54 mmol/g