Human Microbiome Inspired Antibiotics with Improved β-Lactam Synergy against MDR Staphylococcus aureus

John Chu; Xavier Vila-Farres; Daigo Inoyama; Ricardo Gallardo-Macias; Mark Jaskowski; Shruthi Satish; Joel S. Freundlich; Sean F. Brady

doi:10.1021/acsinfecdis.7b00056

Human Microbiome Inspired Antibiotics with Improved β-Lactam Synergy against MDR Staphylococcus aureus

John Chu, Xavier Vila-Farres, Daigo Inoyama, Ricardo Gallardo-Macias, Mark Jaskowski, Shruthi Satish, Joel S. Freundlich, Sean F. Brady

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	33-38
Number of pages	6
Journal	ACS Infectious Diseases
Volume	4
Issue number	1
DOIs	https://doi.org/10.1021/acsinfecdis.7b00056
State	Published - Jan 12 2018
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by NIH U19AI109713. We thank the following laboratories and facilities for strains and technical support: Rockefeller University, Tomasz Lab (S. aureus), Fischetti Lab (S. aureus), Hang Lab (Enterococcus species), and High-Throughput and Spectroscopy Resource Center (NMR); Memorial Sloan Kettering Cancer Center, NMR Analytical Core Facility (HRMS).

Publisher Copyright:
© 2017 American Chemical Society.

Keywords

MRSA
NRPS
Syn-BNP
antibiotics
β-lactam

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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abstract = "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.",

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Human Microbiome Inspired Antibiotics with Improved β-Lactam Synergy against MDR Staphylococcus aureus

Abstract

Bibliographical note

Keywords

UN SDGs

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