The glycoslated macrocyclic antibiotic fidaxomicin ( 1 , tiacumicin B, lipiarmycin A3) displays good to excellent activity against Gram-positive bacteria and was approved for the treatment of Clostridium difficile infections (CDI). Among the main limitations for this compound, its low water solubility impacts further clinical uses. We report on the synthesis of new fidaxomicin derivatives based on structural design and utilizing an operationally simple one-step protecting group-free preparative approach from the natural product. An increase in solubility of up to 25-fold with largely retained activity was observed. Furthermore, hybrid antibiotics were prepared that show improved antibiotic activities.

Mycobacterium abscessus exhibits arr (ADP-ribosyltransferase)-dependent rifampicin (RIF) resistance. In apparent contrast, rifabutin (RBT) has demonstrated promising activity in M. abscessus infection models implying that RBT might not be inactivated by Arr. RBT susceptibility testing of M. abscessus Δarr revealed a strongly decreased minimal inhibitory concentration (MIC). Our findings therefore suggest that the efficacy of RBT might be enhanced by rendering RBT resilient to Arr-dependent modification or by blocking M. abscessus Arr activity.

Genome mining and bioactivity studies suggested the sponge‐derived bacterium Aquimarina sp. Aq135 as a producer of new antibiotics. Activity‐guided isolation identified antibacterial peptides, named aquimarins, featuring a new scaffold with an unusual C‐terminal amino group and chlorine moieties. Responsible for the halogenation is the FeII/α‐ketoglutarate‐dependent chlorinase AqmA that halogenates up to two isoleucine residues in a carrier protein‐dependent fashion. Total syntheses of two natural aquimarins and eight non‐natural variants were developed. Structure–activity relationship (SAR) studies with these compounds showed that the synthetically more laborious chlorinations are not required for antibacterial activity but enhance cytotoxicity. In contrast, variants lacking the C‐terminal amine were virtually inactive, suggesting diamines similar to the terminal aquimarin residue as candidate building blocks for new peptidomimetic antibiotics.

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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.