Human Microbiome Inspired Antibiotics with Improved β-Lactam Synergy against MDR Staphylococcus aureus
| Autor: | Ricardo Gallardo-Macias, John Chu, Sean F. Brady, Mark Jaskowski, Xavier Vila-Farrés, Daigo Inoyama, Joel S. Freundlich, Shruthi Satish |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Methicillin-Resistant Staphylococcus aureus Models Molecular Staphylococcus aureus medicine.drug_class Antibiotics Microbial Sensitivity Tests medicine.disease_cause beta-Lactams Article Microbiology 03 medical and health sciences Structure-Activity Relationship Bacterial Proteins Drug Resistance Multiple Bacterial Drug Discovery medicine Humans Phospholipid Transfer Proteins biology Lipid II Microbiota Human microbiome Drug Synergism Flippase Potentiator biochemical phenomena metabolism and nutrition biology.organism_classification Methicillin-resistant Staphylococcus aureus Anti-Bacterial Agents 030104 developmental biology Infectious Diseases Mutation Bacteria |
| Popis: | The flippase MurJ is responsible for transporting the cell wall intermediate lipid II from the cytoplasm to the outside of the cell. While essential for the survival of bacteria, it remains an underexploited target for antibacterial therapy. The humimycin antibiotics are lipid II flippase (MurJ) inhibitors that were synthesized on the basis of bioinformatic predictions derived from secondary metabolite gene clusters found in the human microbiome. Here, we describe an SAR campaign around humimycin A that produced humimycin 17S. Compared to humimycin A, 17S is a more potent β-lactam potentiator, has a broader spectrum of activity, which now includes both methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus faecalis (VRE), and did not lead to any detectable resistance when used in combination with a β-lactam. Combinations of β-lactam and humimycin 17S provide a potentially useful long-term MRSA regimen. |
| Databáze: | OpenAIRE |
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