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Thomas Wetzlar

Structure-activity relationships of antimycobacterial cyclopeptides

The cyclic hexapeptides wollamide A and B, originally isolated from a Streptomyces species in 2014, inhibit in vitro the growth of Mycobacterium tuberculosis. The basic scaffold is a fifteen-membered macrocyclecomposed of six amino acids. Ornithine, a non-proteinogenic amino acid, and leucine occur as D-isomers. The activity and pharmacokinetic effects of both wollamides are almost similar. They differ structurally by an exchange of Valin (wollamide B) with allo-isoleucine (wollamide A).

In the course of my project, I prepared wollamide analogues via solid-phase peptide synthesis. The analogues differ as to amino acid configuration and sequence as well as in size of the macrocycle. A few peptide- mimics were also prepared.

The antimycobacterial activity and other esp. pharmacokinetic parameters of the synthesized agents were determined through cooperation with GlaxoSmithKline, Spain.

The aim of the project is the enhancement of the low metabolic stability and membrane permeability of the wollamides, while maintaining the excellent activity, plasma stability and water-solubility of the substances to develop new antimycobacterial agents for the treatment of tuberculosis.

Publications:

Bioorganic & Medicinal Chemistry Letters: An efficient   synthetic route for preparation of antimycobacterial wollamides and   evaluation of their in vitro and in vivo efficacy (H. Asfaw, T. Wetzlar, M. S. Martinez-Martinez, P. Imming)

Talks:

3rd TRI-SUSTAIN Graduate School (Gaborone, Botswana): Cyclohexapeptides with antimycobacterial activity

Poster presentations:

Pharma Research Day (Martin-Luther-Universität, Halle): Antimycobacterial cyclopeptides: Activity and SAR of wollamide B and derivatives (T. Wetzlar, H. Asfaw, F. Cunningham, M. S. Martinez-Martinez, J. C. Cuevas-Zurita, L. Ballell-Pages, P. Imming)

Tuberculosis Drug Discovery and Development, Gordon Research Conference (Lucca, Italien): New antimycobacterial cyclopeptides: Activity and SAR of wollamides and lugdunins (T. Wetzlar, H. Asfaw, F. Cunningham, M. S. Martinez-Martinez, J. C. Cuevas-Zurita, L. Ballell-Pages, P. Imming)

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