An antimycobacterial pleuromutilin analogue effective against dormant bacilli

Maddie R. Lemieux, Shajila Siricilla, Katsuhiko Mitachi, Shakiba Eslamimehr, Yuehong Wang, Dong Yang, Jeffrey D. Pressly, Ying Kong, Frank Park, Scott G. Franzblau, Michio Kurosu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4787-4796
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number17
DOIs
StatePublished - Sep 15 2018

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Bacilli
Bacillus
Mycobacterium tuberculosis
Pharmacokinetics
Gram-Positive Bacteria
Rifampin
Biological Availability
Libraries
Bacteria
Screening
Anti-Bacterial Agents
Derivatives
pleuromutilin
Growth
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

An antimycobacterial pleuromutilin analogue effective against dormant bacilli. / 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.

In: Bioorganic and Medicinal Chemistry, Vol. 26, No. 17, 15.09.2018, p. 4787-4796.

Research output: Contribution to journalArticle

Lemieux, MR, Siricilla, S, Mitachi, K, Eslamimehr, S, Wang, Y, Yang, D, Pressly, JD, Kong, Y, Park, F, Franzblau, SG & Kurosu, M 2018, 'An antimycobacterial pleuromutilin analogue effective against dormant bacilli', Bioorganic and Medicinal Chemistry, vol. 26, no. 17, pp. 4787-4796. https://doi.org/10.1016/j.bmc.2018.07.034
Lemieux MR, Siricilla S, Mitachi K, Eslamimehr S, Wang Y, Yang D et al. An antimycobacterial pleuromutilin analogue effective against dormant bacilli. Bioorganic and Medicinal Chemistry. 2018 Sep 15;26(17):4787-4796. https://doi.org/10.1016/j.bmc.2018.07.034
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. / An antimycobacterial pleuromutilin analogue effective against dormant bacilli. In: Bioorganic and Medicinal Chemistry. 2018 ; Vol. 26, No. 17. pp. 4787-4796.
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