An antimycobacterial pleuromutilin analogue effective against dormant bacilli. Issue 17 (15th September 2018)

• Record Type: Journal Article
• Authors: Lemieux, Maddie R.; Siricilla, Shajila; Mitachi, Katsuhiko; Eslamimehr, Shakiba; Wang, Yuehong; Yang, Dong; Pressly, Jeffrey D.; Kong, Ying; Park, Frank; Franzblau, Scott G.; Kurosu, Michio
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 17(2018)
• Page Start: 4787
• Page End: 4796
• Publication Date: 2018-09-15
• Subjects: Pleuromutilin -- Antimycobacterial activity -- Dormant tuberculosis -- Intracellular Mycobacterium tuberculosis -- Pharmacokinetics; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.07.034
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Pleuromutilin is a promising pharmacophore to design new antibacterial agents for Gram-positive bacteria. However, there are limited studies on the development of pleuromutilin analogues that inhibit growth of Mycobacterium tuberculosis (Mtb). In screening of our library of pleuromutilin derivatives, UT-800 (1 ) was identified to kill replicating- and non-replicating Mtb with the MIC values of 0.83 and 1.20 μg/mL, respectively. UT-800 also kills intracellular Mtb faster than rifampicin at 2× MIC concentrations. Pharmacokinetic studies indicate that 1 has an oral bioavailability with an average F -value of 27.6%. Pleuromutilin may have the potential to be developed into an orally administered anti-TB drug.