Nature Microbiology, volume 3, issue 4, pages 415-422
Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens
Hover Bradley M
1
,
Kim Seong Hwan
1
,
Katz Micah
1
,
Charlop Powers Zach
1
,
Owen Jeremy G.
1
,
Ternei Melinda A
1
,
Maniko Jeffrey
1
,
Estrela Andreia B
1
,
Molina Henrik
2
,
Park Steven
3
,
Perlin David S.
3
,
Brady Sean F.
1
1
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, USA
|
2
Proteomics Resource Center, the Rockefeller University, New York, USA
|
3
Public Health Research Institute, Rutgers University—New Jersey Medical School, Newark, USA
|
Publication type: Journal Article
Publication date: 2018-02-12
PubMed ID:
29434326
Cell Biology
Genetics
Microbiology (medical)
Microbiology
Applied Microbiology and Biotechnology
Immunology
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. Analysis of secondary metabolite biosynthesis clusters from diverse soil samples identifies a distinct class of calcium-dependent antibiotics—the malacidins—that bind lipid II and are active against multidrug-resistant Gram-positive pathogens.
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- We do not take into account publications that without a DOI.
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Hover B. M. et al. Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens // Nature Microbiology. 2018. Vol. 3. No. 4. pp. 415-422.
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Hover B. M., Kim S. H., Katz M., Charlop Powers Z., Owen J., Ternei M. A., Maniko J., Estrela A. B., Molina H., Park S., Perlin D. S., Brady S. F. Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens // Nature Microbiology. 2018. Vol. 3. No. 4. pp. 415-422.
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TY - JOUR
DO - 10.1038/s41564-018-0110-1
UR - https://doi.org/10.1038%2Fs41564-018-0110-1
TI - Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens
T2 - Nature Microbiology
AU - Hover, Bradley M
AU - Kim, Seong Hwan
AU - Katz, Micah
AU - Charlop Powers, Zach
AU - Owen, Jeremy G.
AU - Ternei, Melinda A
AU - Maniko, Jeffrey
AU - Estrela, Andreia B
AU - Molina, Henrik
AU - Park, Steven
AU - Perlin, David S.
AU - Brady, Sean F.
PY - 2018
DA - 2018/02/12 00:00:00
PB - Springer Nature
SP - 415-422
IS - 4
VL - 3
PMID - 29434326
SN - 2058-5276
ER -
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@article{2018_Hover,
author = {Bradley M Hover and Seong Hwan Kim and Micah Katz and Zach Charlop Powers and Jeremy G. Owen and Melinda A Ternei and Jeffrey Maniko and Andreia B Estrela and Henrik Molina and Steven Park and David S. Perlin and Sean F. Brady},
title = {Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens},
journal = {Nature Microbiology},
year = {2018},
volume = {3},
publisher = {Springer Nature},
month = {feb},
url = {https://doi.org/10.1038%2Fs41564-018-0110-1},
number = {4},
pages = {415--422},
doi = {10.1038/s41564-018-0110-1}
}
Cite this
MLA
Copy
Hover, Bradley M., et al. “Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens.” Nature Microbiology, vol. 3, no. 4, Feb. 2018, pp. 415-422. https://doi.org/10.1038%2Fs41564-018-0110-1.