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 represses 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1355-1364.e4 |
| Journal | Cell Chemical Biology |
| Volume | 26 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 17 2019 |
Funding
This work was funded by the US NIH (F31AI140520 [L.C.R.], R01AI137273 [B.P.C.], and R01GM128037 [P.E.]) as well as by a start-up grant from the University of South Florida (P.E.). We thank Nikki Wagner, Jenna Beam, Natalia Maldonado-Vazquez, and Ashelyn Sidders for advice with this project. Conceptualization and methodology, L.C.R. S.E.R. and B.P.C.; Investigation, L.C.R. R.B. A.D.W. and R.H.; Writing, L.C.R. and B.P.C.; Visualization, L.C.R.; Funding Acquisition, L.C.R. P.E. and B.P.C.; Supervision, P.E. and B.P.C. L.C.R. S.E.R. and B.P.C. are inventors on a patent describing rhamnolipid potentiation of aminoglycoside killing (Radlinski LC, Conlon SR, Conlon BP. Potentiation of antibiotic effect, US 62/534450, filed July 19, 2017). The other authors declare no competing interests. This work was funded by the US NIH ( F31AI140520 [L.C.R.], R01AI137273 [B.P.C.], and R01GM128037 [P.E.]) as well as by a start-up grant from the University of South Florida (P.E.). We thank Nikki Wagner, Jenna Beam, Natalia Maldonado-Vazquez, and Ashelyn Sidders for advice with this project.
| Funders | Funder number |
|---|---|
| R01AI137273, R01GM128037 | |
| F31AI140520 | |
| University of South Florida | US 62/534450 |
Keywords
- Staphylococcus aureus
- aminoglycosides
- antibiotics
- biofilm
- persisters
- resistance
- rhamnolipids
- tolerance