posted on 2021-02-23, 20:42authored byLei Li, Logan W. MacIntyre, Thahmina Ali, Riccardo Russo, Bimal Koirala, Yozen Hernandez, Sean F. Brady
Tuberculosis (TB) remains one of the deadliest infectious diseases.
Unfortunately, the development of antibiotic resistance threatens
our current therapeutic arsenal, which has necessitated the discovery
and development of novel antibiotics against drug-resistant Mycobacterium tuberculosis (Mtb). Cyclomarin
A and rufomycin I are structurally related cyclic heptapeptides assembled
by nonribosomal peptide synthetases (NRPSs), which show potent anti-Mtb activity with a new cellular target, the caseinolytic
protein ClpC1. An NRPS adenylation domain survey using DNA extracted
from ∼2000 ecologically diverse soils found low cyclomarin/rufomycin
biosynthetic diversity. In this survey, a family of cyclomarin/rufomycin-like
biosynthetic gene clusters (BGC) that encode metamarin, an uncommon
cyclomarin congener with potent activity against both Mtb H37Rv and multidrug-resistant Mtb clinical isolates
was identified. Metamarin effectively inhibits Mtb growth in murine macrophages and increases the activities of ClpC1
ATPase and the associated ClpC1/P1/P2 protease complex, thus causing
cell death by uncontrolled protein degradation.