Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens
| Autor: | Steven Park, Seong-Hwan Kim, Zachary Charlop-Powers, Jeremy G. Owen, Micah Katz, David S. Perlin, Andreia B. Estrela, Sean F. Brady, Melinda A. Ternei, Bradley M. Hover, Henrik Molina, Jeffrey Maniko |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Methicillin-Resistant Staphylococcus aureus medicine.medical_specialty medicine.drug_class Immunology Antibiotics Drug resistance Microbial Sensitivity Tests Biology medicine.disease_cause Applied Microbiology and Biotechnology Microbiology Peptides Cyclic Bacterial genetics Cell Line 03 medical and health sciences Lipopeptides Medical microbiology Daptomycin Drug Resistance Multiple Bacterial Genetics medicine Animals Humans Microbiome Soil Microbiology Cell Biology Staphylococcal Infections biology.organism_classification 3. Good health Anti-Bacterial Agents Rats Multiple drug resistance 030104 developmental biology HEK293 Cells Staphylococcus aureus Calcium Bacteria |
| Zdroj: | Nature microbiology. 3(4) |
| ISSN: | 2058-5276 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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