Antibacterial Drugs: Discovering Antibiotics Through Soil Metagenomics

RESEARCH HIGHLIGHTS

Nature Reviews Drug Discovery | Published online 16 Mar 2018; doi:10.1038/nrd.2018.36

Next, the authors cloned DNA from a desert soil in the malacidin branch of their phylogenetic tree and recovered a complete malacidin BGC, which they expressed in Streptomyces albus J1074. Extracts Getty Images/Alice Cahill from S. albus cultures were anti bacterial towards multidrug-resistant Staphylococcus aureus (MRSA) and they contained clone-specific metabolites. Analysis of two of these metabolites by mass spectrometry and NMR spectroscopy revealed that malacidins are ten‑membered cyclic lipopeptides that do not contain the Asp-X-Asp-Gly calcium-binding motif. Despite this, the antibacterial activity of malacidins towards MRSA was dependent on calcium. ANTIBACTERIAL DRUGS Indeed, the authors showed that malacidins kill MRSA by binding, in a calcium-dependent manner, to Discovering antibiotics through a downstream intermediate of a cell wall precursor, causing this cell wall precursor to accumulate. soil metagenomics Further characterization of malacidins revealed that the topical administration of one of these The identification of bacterial natural product sequence tags (NPSTs) that compounds, malacidin A, eliminated products with antimicrobial proper- mapped to an adenylation domain MRSA from infected wounds on the ties has been hampered by the fact malacidins are from a known calcium-dependent skin of rats after 24 h. Furthermore, that many bacteria cannot be cultured a promising antibiotic biosynthetic gene cluster no malicidin A-resistant S. aureus in the laboratory, and those that can (BGC). As only 13% of these NPSTs clones were identified after 20 days do not produce all of their natural new class had a high nucleotide identity to in culture with sublethal levels of products in this setting. Hover et al. of calcium- adenylation domains in characterized this antibiotic, suggesting that there have devised a culture-free method dependent calcium-dependent antibiotics, the is a high barrier to the emergence of for the discovery of bacterial natural antibiotics majority of adenylation domain- antibiotic resistance, and malacidins products and used it to identify containing lipopeptides encoded by were not toxic to mammalian cells in malacidins (metagenomic acidic lipo- the global soil metagenome might be culture. peptide antibiotic-cidins) as a distinct uncharacterized. In short, malacidins are a promis- class of antibiotics. By analysing their next-generation ing new class of calcium-dependent Calcium-dependent antibiotics sequencing reads using a web-based antibiotics. Their discovery validates contain a conserved Asp-X-Asp-Gly tool called eSNaPD (environmental the use of BGC mining for discovering calcium-binding motif and are Surveyor of Natural Product natural products. biosynthesized by non-ribosomal Diversity), the authors created a Katharine H. Wrighton peptide synthetases (NRPSs). To phylogenetic tree derived from NRPS search for additional antibiotics adenylation domain-associated NPSTs. containing calcium-binding motifs, One eDNA-specific clade that was ORIGINAL ARTICLE Hover, B. M. et al. Culture-independent discovery of the malacidins the authors screened environmental not associated with known BGCs was as calcium-dependent antibiotics with activity DNA (eDNA) from >2,000 soil sam- found in 19% of metagenomes, and the against multidrug-resistant Gram-positive pathogens. Nat. Microbiol. https://doi. ples by PCR with primers targeting authors proposed that the BGCs asso- org/10.1038/s41564‑018‑0110‑1 (2018) NRPS adenylation domains, followed ciated with these NPSTs represented FURTHER READING Cully, M. Roche taps by next-generation sequencing. an uncharacterized family of anti potential antibiotics mine with Warp Drive Bio. Nat. Rev. Drug Discov. 17, 8–9 (2018) 75% of sequenced soils had natural biotics, which they called malacidins.