Structure-Activity Relationships of Wollamide Cyclic Hexapeptides with Activity against Drug-Resistant and Intracellular Mycobacterium tuberculosis

Antimicrob Agents Chemother. 2019 Feb 26;63(3):e01773-18. doi: 10.1128/AAC.01773-18. Print 2019 Mar.

Abstract

Wollamides are cyclic hexapeptides, recently isolated from an Australian soil Streptomyces isolate, that exhibit promising in vitro antimycobacterial activity against Mycobacterium bovis Bacille Calmette Guérin without displaying cytotoxicity against a panel of mammalian cells. Here, we report the synthesis and antimycobacterial activity of 36 new synthetic wollamides, collated with all known synthetic and natural wollamides, to reveal structure characteristics responsible for in vitro growth-inhibitory activity against Mycobacterium tuberculosis (H37Rv, H37Ra, CDC1551, HN878, and HN353). The most potent antimycobacterial wollamides were those where residue VI d-Orn (wollamide B) was replaced by d-Arg (wollamide B1) or d-Lys (wollamide B2), with all activity being lost when residue VI was replaced by Gly, l-Arg, or l-Lys (wollamide B3). Substitution of other amino acid residues mainly reduced or ablated antimycobacterial activity. Significantly, whereas wollamide B2 was the most potent in restricting M. tuberculosis in vitro, wollamide B1 restricted M. tuberculosis intracellular burden in infected macrophages. Wollamide B1 synergized with pretomanid (PA-824) in inhibiting M. tuberculosis in vitro growth but did not antagonize prominent first- and second-line tuberculosis antibiotics. Furthermore, wollamide B1 exerted bactericidal activity against nonreplicating M. tuberculosis and impaired growth of multidrug- and extensively drug-resistant clinical isolates. In vivo pharmacokinetic profiles for wollamide B1 in rats and mice encourage further optimization of the wollamide pharmacophore for in vivo bioavailability. Collectively, these observations highlight the potential of the wollamide antimycobacterial pharmacophore.

Keywords: Mycobacterium tuberculosis; cyclic hexapeptides; multidrug resistance; structure-activity relationships; wollamides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Drug Resistance, Multiple, Bacterial / genetics
  • Hep G2 Cells
  • Humans
  • Macrophages / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / growth & development
  • Mycobacterium tuberculosis / isolation & purification
  • Peptides, Cyclic / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Tuberculosis / drug therapy*

Substances

  • Peptides, Cyclic
  • wollamide A
  • wollamide B