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Cryo-EM structure of fidaxomicin binding to M. tuberculosis RNAP (PDB ID: 6FBV)¹⁸ a Fidaxomicin (cyan), protein (surface representation/gray). Interaction of C3”-OH with H2O. Limited space around isobutyric ester moiety. b Detailed view on the binding pocket of fidaxomicin’s noviose moiety. C3”-OH points toward an “open space.” C4”-isobutyric ester fits into its pocket. c Detailed view on the interactions of the noviose part to the protein. C2”-OH is blocked by an interaction with Arg412 (blue).
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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 pharmac...
Citations
... This methodology may be particularly relevant in the development of new antibiotics, an especially tough endeavor [23]. Recent examples include a programmed and selective structural modification of complex compounds to improve their potency [24,25], and even to repurpose different drugs for antibiotic activity [26]. In a previous work, we promoted a more drastic transformation, based on the reactivity of functional groups present in the structure of the drug through Multicomponent Reactions (MCRs, Figure 1A). ...
... Bacterial growth was quantified by an automatic register of OD at 850 nm/minute for the first 25 min, and then at 15-minute intervals thereafter. These first 25 Analysis was conducted in R, and figures were produced using the packages ggformula [41] and ggplot2 [42]. Since the aerobic growth of G. jacobaea MV-1 and N. cyriacigeorgica in agitation promotes aggregates of varying sizes, thus disturbing the measurements, a non-parametric method (loess or lowess; locally weighted scatterplot smoothing) using the ggformula package [41] was applied to calculate and plot the curves. ...
New antibiotic agents were prepared using Povarov and Ugi multicomponent reactions upon the known drugs sulfadoxine and dapsone. The prepared derivatives, with increased lipophilicity, showed improved efficiency against Mycolata bacteria. Microbiological guidance for medicinal chemistry is a powerful tool to design new and effective antimicrobials. In this case, the readily synthesized compounds open new possibilities in the search for antimicrobials active on mycolic acid-containing bacteria.
... Despite its potent activity, the utilization of Fidaxomicin as a TB drug is limited by its poor solubility. Previous attempts to structurally modify fidaxomicin have been made to address this limitation by synthesizing fidaxomicin derivatives and further testing using fluorescencebased assay [128,129]. ...
Mycobacterium tuberculosis (MTB) is the main source of tuberculosis (TB), one of the oldest known diseases in the human population. Despite the drug discovery efforts of past decades, TB is still one of the leading causes of mortality and claimed more than 1.5 million lives worldwide in 2020. Due to the emergence of drug-resistant strains and patient non-compliance during treatments, there is a pressing need to find alternative therapeutic agents for TB. One of the important areas for developing new treatments is in the inhibition of the transcription step of gene expression; it is the first step to synthesize a copy of the genetic material in the form of mRNA. This further translates to functional protein synthesis, which is crucial for the bacteria living processes. MTB contains a bacterial DNA-dependent RNA polymerase (RNAP), which is the key enzyme for the transcription process. MTB RNAP has been targeted for designing and developing antitubercular agents because gene transcription is essential for the mycobacteria survival. Initiation, elongation, and termination are the three important sequential steps in the transcription process. Each step is complex and highly regulated, involving multiple transcription factors. This review is focused on the MTB transcription machinery, especially in the nature of MTB RNAP as the main enzyme that is regulated by transcription factors. The mechanism and conformational dynamics that occur during transcription are discussed and summarized. Finally, the current progress on MTB transcription inhibition and possible drug target in mycobacterial RNAP are also described to provide insight for future antitubercular drug design and development.
... D. Takahashi and K. Toshima found aromatic boronic acids could catalyze glycosylation of both protected 21 and unproctected 22 sugar acceptors with epoxide ring in a regioselective manner via SNi-type mechanism in the presence of water. Site-selective sulfonation unprotected monosaccharides catalyzed by chiral benzazaborole in MeCN 23 and site-selective acylation catalyzed by Shimada's boronic acid catalyst in dioxane 24 was also reported very recently. Encouraged by this progress and our previous knowledge 25 on arylboronic acid catalyzed amide formation from carboxylic acids and amines, we envisaged that arylboronic acids might be possible to act as a catalyst instead of a reagent in upgrade of glucosamines for deoxyfructosazine under a suitable condition. ...
Chitin is the most abundant N-containing polysaccharides in nature and D-glucosamine is one of most successful commercial monomer products in current market. Here we reported an arylboronic acids catalyzed upgrade of glucosamines in aqueous solution for deoxyfructosazine which is an important high-value compound in pharmaceutical and food industries, as well as a promising bio-based platform molecule for speciality chemicals and sustainable functional materials. Such direct integration of deoxyfructosazine into development of renewable chemicals/functional materials might be a practical way for utilization of chitin as a renewable nitrogen source. A mechanism focusing on catalytic cycle of arylboronic acid via a boron transfer was also proposed.
... D. Takahashi and K. Toshima found aromatic boronic acids could catalyze glycosylation of both protected 21 and unproctected 22 sugar acceptors with epoxide ring in a regioselective manner via SNi-type mechanism in the presence of water. Site-selective sulfonation unprotected monosaccharides catalyzed by chiral benzazaborole in MeCN 23 and site-selective acylation catalyzed by Shimada's boronic acid catalyst in dioxane 24 was also reported very recently. Encouraged by this progress and our previous knowledge 25 on arylboronic acid catalyzed amide formation from carboxylic acids and amines, we envisaged that arylboronic acids might be possible to act as a catalyst instead of a reagent in upgrade of glucosamines for deoxyfructosazine under a suitable condition. ...
Chitin is the most abundant N-containing polysaccharides in nature and D-glucosamine is one of most successful commercial monomer products in current market. Here we reported an arylboronic acids catalyzed upgrade of glucosamines in aqueous solution for deoxyfructosazine which is an important high-value compound in pharmaceutical and food industries, as well as a promising bio-based platform molecule for speciality chemicals and sustainable functional materials. Such direct integration of deoxyfructosazine into development of renewable chemicals/functional materials might be a practical way for utilization of chitin as a renewable nitrogen source. A mechanism focusing on catalytic cycle of arylboronic acid via a boron transfer was also proposed.
... D. Takahashi and K. Toshima found aromatic boronic acids could catalyze glycosylation of both protected 21 and unproctected 22 sugar acceptors with epoxide ring in a regioselective manner via SNi-type mechanism in the presence of water. Site-selective sulfonation unprotected monosaccharides catalyzed by chiral benzazaborole in MeCN 23 and site-selective acylation catalyzed by Shimada's boronic acid catalyst in dioxane 24 were also reported very recently. Encouraged by this progress and our previous knowledge 25 on arylboronic acid catalyzed amide formation from carboxylic acids and amines, we envisaged that arylboronic acids might be possible to act as a catalyst instead of a reagent in upgrade of glucosamines for deoxyfructosazine under a suitable condition. ...
Chitin is the most abundant N-containing polysaccharides in nature and D-glucosamine is one of most successful commercial monomer products in current market. Here we reported an arylboronic acids catalyzed upgrade of glucosamines in aqueous solution for deoxyfructosazine which is an important high-value compound in pharmaceutical and food industries, as well as a promising bio-based platform molecule for speciality chemicals and sustainable functional materials. Such direct integration of deoxyfructosazine into development of renewable chemicals/functional materials might be a practical way for utilization of chitin as a renewable nitrogen source. A mechanism focusing on catalytic cycle of arylboronic acid via a boron transfer was also proposed.
Fidaxomicin (Fdx) constitutes a glycosylated natural product with excellent antibacterial activity against various Gram-positive bacteria but is approved only for Clostridioides difficile infections. Poor water solubility and acid lability preclude its use for other infections. Herein, we describe our strategy to overcome the acid lability by introducing acid-stable S-linked glycosides. We describe the direct, diastereoselective modification of unprotected Fdx without the need to avoid air or moisture. Using our newly established approach, Fdx was converted to the single atom exchanged analogue S-Fdx, in which the acid labile O-glycosidic bond to the noviose sugar was replaced by the acid stable S-glycosidic bond. Studies of the antibacterial activity of a structurally diverse set of thioglycoside derivatives revealed high potency of acyl derivatives of S-Fdx against Clostridioides difficile (MIC range: 0.12–4 μg/mL) and excellent potency against Clostridium perfringens (MIC range: 0.06–0.5 μg/mL).
A protocol for the isolation of the antibiotic fidaxomicin (Fdx) from Actinoplanes deccanensis and the isolation of shunt metabolites from A. deccanensisfdxG2‐ is reported. We constructed the mutant strain A. deccanensisfdxG2‐ by genetic manipulation which enabled the isolation of shunt metabolites as useful starting points for semisynthetic analogues of Fdx. Furthermore, a synthetic protocol for the conversion of complex A. deccanensisfdxG2‐ extracts into the single compound FdxG2‐OH via methanolysis is presented. This synthetic procedure is complemented by images and practical notes. Full structure assignment is given in the SI and the characterization data files are published to aid experimentalists. The protocol is also suitable as an undergraduate laboratory project. We hope to facilitate research into new Fdx derivatives through the availability of this procedure.
A formal total synthesis of the natural macrolide antibiotic tiacumicin B is described featuring successive and selective glycosylations of tiacumicinone. The challenging β‐facial selectivity of these key glycosylation steps was achieved by using noviosyl or rhamnosyl donors equipped with a phenyl sulfoxide leaving group and a 3‐O‐picoloyl group ensuring an efficient remote stereodirecting effect. Compared with our former total synthesis, this strategy enables us to save steps and gain access to new analogs. This was demonstrated by the replacement of the rhamnosidic moiety by a d‐mannose derivative.
Fidaxomicin (Fdx) is a natural product antibiotic with potent activity against Clostridioides difficile and other Gram‐positive bacteria such as Mycobacterium tuberculosis. Only a few Fdx derivatives have been synthesized and examined for their biological activity in the 50 years since its discovery. Fdx has a well‐studied mechanism of action, namely inhibition of the bacterial RNA polymerase. Yet, the targeted organisms harbor different target protein sequences, which poses a challenge for the rational development of new semisynthetic Fdx derivatives. We introduced substituents on the two phenolic hydroxy groups of Fdx and evaluated the resulting trends in antibiotic activity against M. tuberculosis, C. difficile, and the Gram‐negative model organism Caulobacter crescentus. As suggested by the target protein structures, we identified the preferable derivatisation site for each organism. The derivative ortho‐methyl Fdx also exhibited activity against the Gram‐negative C. crescentus wild type, a first for fidaxomicin antibiotics. These insights will guide the synthesis of next‐generation fidaxomicin antibiotics.
