puc-header

Chemical Induction of Aminoglycoside Uptake Overcomes Antibiotic Tolerance and Resistance in Staphylococcus Aureus

48 Pages Posted: 18 May 2019 Sneak Peek Status: Review Complete

See all articles by Lauren C. Radlinski

Lauren C. Radlinski

University of North Carolina (UNC) at Chapel Hill - Department of Microbiology and Immunology

Sarah E. Rowe

University of North Carolina (UNC) at Chapel Hill - Department of Microbiology and Immunology

Robert Brzozowski

University of South Florida - Department of Cell Biology, Microbiology and Molecular Biology

Alec Wilkinson

University of North Carolina (UNC) at Chapel Hill - Department of Microbiology and Immunology

Rennica Huang

University of North Carolina (UNC) at Chapel Hill - Department of Microbiology and Immunology

Prahathees Eswara

University of South Florida - Department of Cell Biology, Microbiology and Molecular Biology

Brian P. Conlon

University of North Carolina (UNC) at Chapel Hill - Department of Microbiology and Immunology; University of North Carolina (UNC) at Chapel Hill - Marsico Lung Institute

More...

Abstract

Aminoglycoside antibiotics require proton motive force (PMF) for bacterial internalization. In non-respiring populations, PMF drops below the level required for drug influx, limiting the utility of aminoglycosides against strict and facultative anaerobes. We recently demonstrated that rhamnolipids (RLs), biosurfactant molecules produced by Pseudomonas aeruginosa, potentiate aminoglycoside activity against Staphylococcus aureus. Here, we demonstrate that RLs induce PMF-independent aminoglycoside uptake to restore sensitivity to otherwise tolerant persister, biofilm, small colony variant, and anaerobic populations of S. aureus. Furthermore, we show that this approach prevents the rise of resistance, restores sensitivity to highly resistant clinical isolates, and is effective against other gram-positive pathogens. Finally, while other membrane-acting agents can synergize with aminoglycosides, induction of PMF-independent uptake is uncommon, and distinct to RLs among several compounds tested. In all, small molecule induction of PMF-independent aminoglycoside uptake circumvents phenotypic tolerance, overcomes genotypic resistance, and expands the utility of aminoglycosides against intrinsically recalcitrant bacterial populations.

Keywords: Aminoglycosides, antibiotics, Staphylococcus aureus, resistance, tolerance, persisters, biofilm, rhamnolipids

Suggested Citation

Radlinski, Lauren C. and Rowe, Sarah E. and Brzozowski, Robert and Wilkinson, Alec and Huang, Rennica and Eswara, Prahathees and Conlon, Brian P., Chemical Induction of Aminoglycoside Uptake Overcomes Antibiotic Tolerance and Resistance in Staphylococcus Aureus (May 16, 2019). CELL-CHEMICAL-BIOLOGY-D-19-00158. Available at SSRN: https://ssrn.com/abstract=3389379 or http://dx.doi.org/10.2139/ssrn.3389379
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Lauren C. Radlinski

University of North Carolina (UNC) at Chapel Hill - Department of Microbiology and Immunology ( email )

Chapel Hill, NC
United States

Sarah E. Rowe

University of North Carolina (UNC) at Chapel Hill - Department of Microbiology and Immunology

Chapel Hill, NC
United States

Robert Brzozowski

University of South Florida - Department of Cell Biology, Microbiology and Molecular Biology ( email )

Tampa, FL
United States

Alec Wilkinson

University of North Carolina (UNC) at Chapel Hill - Department of Microbiology and Immunology

Chapel Hill, NC
United States

Rennica Huang

University of North Carolina (UNC) at Chapel Hill - Department of Microbiology and Immunology

Chapel Hill, NC
United States

Prahathees Eswara

University of South Florida - Department of Cell Biology, Microbiology and Molecular Biology

Tampa, FL
United States

Brian P. Conlon (Contact Author)

University of North Carolina (UNC) at Chapel Hill - Department of Microbiology and Immunology ( email )

Chapel Hill, NC
United States

University of North Carolina (UNC) at Chapel Hill - Marsico Lung Institute ( email )

Chapel Hill, NC
United States

Click here to go to Cell.com

Go to Cell.com

Paper statistics

Abstract Views
55
PlumX Metrics
Downloads
0
!

Under construction: SSRN citations while be offline until July when we will launch a brand new and improved citations service, check here for more details.

For more information