Abstract
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.
Highlights
Tuberculosis (TB) remains one of the deadliest infectious diseases
These include the use of p-Trp by the first A-domain, and Leu by the third and sixth A-domains (Figure 1a).[11−13] A phylogenetic analysis of all cyclomarin/rufomycin A-domain sequences indicated that the domains responsible for incorporating p-Trp are most highly conserved among these two evolutionarily related biosynthetic gene clusters (BGC) (Figure 1b) and we focused on this domain to track cyclomarin/rufomycin-like BGCs in NPST data from soil metagenomes
BlastN analysis of this collection of library-derived A-domain amplicon sequences identified eight cyclomarin/ rufomycin-like p-Trp NPSTs from six different eDNA libraries. These NPSTs span all three subclades we identified in the original soil screen, suggesting that the BGCs captured in our archived metagenomic libraries are representative of the cyclomarin/rufomycin-like biosynthetic diversity that we identified in ∼2000 soil metagenomes (Figure 2a)
Summary
Tuberculosis (TB) remains one of the deadliest infectious diseases. 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). BlastN analysis of this collection of library-derived A-domain amplicon sequences identified eight cyclomarin/ rufomycin-like p-Trp NPSTs from six different eDNA libraries.
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