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Fidaxomicin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Fidaxomicin (Dificlir) is a naturally occurring 18-membered macrocycle (tiacumicin B) that is derived from the fermentation of Dactylosporangium aurantiacum (Drugs in R&D, 2010). Fidaxomicin is bactericidal and acts via inhibition of RNA synthesis by bacterial RNA polymerase at a distinct site from that of rifamycins (Scott, 2013; Zhanel et al., 2015). The drug product is poorly absorbed and exerts its activity in the gastrointestinal (GI) tract. It is an unsaturated, 18-membered macrocyclic lactone ring with a 7-carbon sugar constituent at carbon 12 and a 6-deoxy sugar at carbon 21 (Figure 88.1). It is structurally related to lipiarmycin, which is thought to act at the early stages of transcription (Sonenshein and Alexander, 1979). It belongs to the class of glycosides with C52H74Cl2O18 as chemical structure and a molecular weight of 1056 g/mol. In vivo, fidaxomicin is primarily hydrolyzed at the fourth position isobutyryl ester by an unknown esterase to produce its main active metabolite, OP-1118. OP-1118 is a major metabolite of fidaxomicin that also exhibits a narrow spectrum of activity. Par Pharmaceuticals entered into a joint development agreement with Optimer for fidaxomicin (as PAR 101) in May 2005. However, in February 2007, Par returned all marketing rights for the product to Optimer. Optimer was acquired by Cubist Pharmaceuticals in 2013, which was itself acquired by Merck in December 2014. Fidaxomicin was formerly known under various names, including OPT-80 and PAR 101 (Drugs in R&D, 2010).
New therapeutic strategies for Mycobacterium abscessus pulmonary diseases – untapping the mycolic acid pathway
Published in Expert Review of Anti-infective Therapy, 2023
Matthéo Alcaraz, Thomas E. Edwards, Laurent Kremer
Pyridomycin is a natural product from Streptomyces pyridomycetes and Dactylosporangium fulvum, exhibiting bactericidal activity against Mtb [128] by acting as a direct competitive inhibitor in the NADH-binding site of InhAMTB [129], leading to the reduction of α-, methoxy- and keto-MA synthesis. Pyridomycin is efficient at low concentrations against Mtb (MIC = 0.72 µM). The absence of toxicity on human cells and its efficacy on other mycobacterial species, including Mabs, makes it a promising lead compound for future drug developments against NTM. However, a series of recent pyridomycin derivatives failed to show a better activity than the parental molecule [130], prompting for additional chemical optimization.