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Nat Microbiol. 2018 Apr;3(4):415-422. doi: 10.1038/s41564-018-0110-1. Epub 2018 Feb 12.

Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens.

Author information

1
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, NY, USA.
2
Proteomics Resource Center, The Rockefeller University, New York, NY, USA.
3
Public Health Research Institute, Rutgers University-New Jersey Medical School, Newark, NJ, USA.
4
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, NY, USA. sbrady@rockefeller.edu.

Abstract

Despite the wide availability of antibiotics, infectious diseases remain a leading cause of death worldwide 1 . In the absence of new therapies, mortality rates due to untreatable infections are predicted to rise more than tenfold by 2050. Natural products (NPs) made by cultured bacteria have been a major source of clinically useful antibiotics. In spite of decades of productivity, the use of bacteria in the search for new antibiotics was largely abandoned due to high rediscovery rates2,3. As only a fraction of bacterial diversity is regularly cultivated in the laboratory and just a fraction of the chemistries encoded by cultured bacteria are detected in fermentation experiments, most bacterial NPs remain hidden in the global microbiome. In an effort to access these hidden NPs, we have developed a culture-independent NP discovery platform that involves sequencing, bioinformatic analysis and heterologous expression of biosynthetic gene clusters captured on DNA extracted from environmental samples. Here, we describe the application of this platform to the discovery of the malacidins, a distinctive class of antibiotics that are commonly encoded in soil microbiomes but have never been reported in culture-based NP discovery efforts. The malacidins are active against multidrug-resistant pathogens, sterilize methicillin-resistant Staphylococcus aureus skin infections in an animal wound model and did not select for resistance under our laboratory conditions.

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