Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens
Bradley M. Hover, Seong-Hwan Kim, Micah Katz, Zachary Charlop-Powers, Jeremy G. Owen, Melinda A. Ternei, Jeffrey Maniko, Andreia B. Estrela, Henrik Molina, Steven Park, David S. Perlin & Sean F. Brady
Nature Microbiology (2018)
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Antibiotics Bacterial infection Drug discovery Metagenomics Natural products
Received: 15 July 2017 Accepted: 03 January 2018
Published online: 12 February 2018
Source/Fonte: Peggy Greb/USDA-ARS via flickr
Abstract
Despite the wide availability of antibiotics, infectious diseases remain a leading cause of death worldwide1. 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.
Acknowledgements
We thank F. Rubino and D. Kahne for discussion and an aliquot of lipid II. HEK293 cells and MRC5 cells were kindly provided by the High-throughput Screening Resource Center at the Rockefeller University. This work was supported in part by a grant from the Gates Foundation and NIH U19AI109713. B.M.H. was supported by NIH Grant F32 AI124479. Z.C.-P. was supported by NIH Grant F32 AI1100029.
Author information
Affiliations
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, NY, USA
Bradley M. Hover, Seong-Hwan Kim, Micah Katz, Zachary Charlop-Powers, Jeremy G. Owen, Melinda A. Ternei, Jeffrey Maniko, Andreia B. Estrela & Sean F. Brady
Proteomics Resource Center, The Rockefeller University, New York, NY, USA
Henrik Molina
Public Health Research Institute, Rutgers University—New Jersey Medical School, Newark, NJ, USA
Steven Park & David S. Perlin
Contributions
B.M.H. and S.F.B. designed research; B.M.H., S.-H.K., M.K., J.G.O., M.A.T., J.M., A.E. and H.M. performed research; B.M.H., S.-H.K. and Z.C.-P. analysed data; and B.M.H. and S.F.B. wrote the paper.
Competing interests
The following authors, S.F.B., B.M.H., M.K., Z.C.-P., declare competing financial interests as they are employees or consultants of Lodo Therapeutics.
Corresponding author
Correspondence to Sean F. Brady.
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