An antimycobacterial pleuromutilin analogue effective against dormant bacilli

Bioorg Med Chem. 2018 Sep 15;26(17):4787-4796. doi: 10.1016/j.bmc.2018.07.034.

Maddie R Lemieux ¹, Shajila Siricilla ¹, Katsuhiko Mitachi ¹, Shakiba Eslamimehr ¹, Yuehong Wang ², Dong Yang ³, Jeffrey D Pressly ¹, Ying Kong ³, Frank Park ¹, Scott G Franzblau ², Michio Kurosu ⁴

Affiliations

1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN 38163-0001, United States.
2 Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612, United States.
3 Department of Microbiology, Immunology & Biochemistry, University of Tennessee Health Science Center, 858 Madison Avenue, Memphis, TN 38163-0001, United States.
4 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN 38163-0001, United States. Electronic address: mkurosu@uthsc.edu.

PMID: 30145051 DOI: 10.1016/j.bmc.2018.07.034

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.

Keywords

Antimycobacterial activity; Dormant tuberculosis; Intracellular Mycobacterium tuberculosis; Pharmacokinetics; Pleuromutilin.

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