Novel fidaxomicin antibiotics through site-selective catalysis

Abstract

Fidaxomicin (FDX) is a marketed antibiotic for the treatment of Clostridioides difficile infections (CDI). Fidaxomicin displays antibacterial properties against many Gram-positive bacteria, yet the application of this antibiotic is currently limited to treatment of CDI. Semisynthetic modifications present a promising strategy to improve its pharmacokinetic properties and also circumvent resistance development by broadening the structural diversity of the derivatives. Here, based on a rational design using cryo-EM structural analysis, we implement two strategic site-selective catalytic reactions with a special emphasis to study the role of the carbohydrate units. Site-selective introduction of various ester moieties on the noviose as well as a Tsuji–Trost type rhamnose cleavage allow the synthesis of novel fidaxomicin analogs with promising antibacterial activities against C. difficile and Mycobacterium tuberculosis.

Phenolic Substitution in Fidaxomicin: A Semisynthetic Approach to Antibiotic Activity Across Species**

“…The allylprotecting group has been used successfully for the total synthesis of fidaxomicin and some of its derivatives by our group. [19,20,22] Applying this knowledge, o-methyl fidaxomicin (3) was obtained in 13 % over three steps (Scheme 1, Conditions B). Since scalable access to p-allyl fidaxomicin is crucial for the synthesis of further derivatives, we optimized the alkylation by varying solvent and temperature.…”

“…Our group achieved the first total synthesis of fidaxomicin in 2015 [18,19] and developed protocols for the semisynthesis of new derivatives. [20][21][22][23] In addition, several other groups achieved the synthesis of Fdx fragments or intermediates, [24][25][26][27] and also achieved total synthesis. [28] A remaining challenge consists in the identification of the best approach to develop promising new derivatives for the different target organisms.…”

Synthesis and Antimicrobial Evaluation of New Cephalosporin Derivatives Containing Cyclic Disulfide Moieties

“…1 H NMR (500 MHz, CDCl 3 ) δ 8.55 (dd, J = 1.5, 4.5 Hz, 2H), 7.20 (dd, J = 1.5, 4. 5 Procedures for the Synthesis of Cephalosporin Derivatives with the Thiophene Side Chain. General Procedure.…”

“…Over the last few decades, the understanding of the relevant biological pathways and targets for antibiotic activity has been significantly expanded. Historically, activity on the bacterial target was most importantly optimized and has been constantly improved by molecular design, − synthetic chemistry, − and analytical techniques up to recently introduced cryo-EM structure determination . Less studied but equally important, several additional factors strongly contribute to overall antibiotic performance, including bacterial uptake of antibiotics, their biotransformation to inactive substances, the active efflux of those agents by bacteria, and others. , As a consequence, performance enhancement of antibiotics has recently grown to also include these aspects.…”

Synthesis and antimicrobial evaluation of new cephalosporin derivatives containing cyclic disulfide moieties

“…Over the last decades, the understanding of the relevant biological pathways and targets for antibiotic activity has been significantly expanded. Historically, activity on the bacterial target was most importantly optimized and has been constantly improved by molecular design, 1-3 synthetic chemistry, [3][4][5][6][7][8] and analytical techniques up to recently introduced cryo EM structure determination. 9 Less studied but equally important, several additional factors strongly contribute to overall antibiotic performance, including bacterial uptake of antibiotics, their biotransformation to inactive substances, the active efflux of those agents by bacteria, and others.…”