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

Radlinski, Lauren C.; Rowe, Sarah E.; Brzozowski, R; Wilkinson, Alec; Huang, Rennica; Eswara, Prahathees J.; Conlon, Brian P.

doi:10.1016/j.chembiol.2019.07.009

Cited by 72 publications

(85 citation statements)

References 69 publications

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“…In this regard, indole-induced aminoglycoside potentiation represents a unique mechanism. Notably, Conlon and colleagues recently reported that rhamnolipid-induced aminoglycoside potentiation was also independent of the PMF and only effective against gram-positive, but not gram-negative, pathogens (Radlinski et al, 2019), in agreement with our present findings. Nevertheless, this approach, as the metabolitebased approach, takes several hours to achieve a significant potentiating effect.…”

Section: Discussionsupporting

confidence: 94%

“…Further, various metabolites, such as glucose and alanine, were found to facilitate aminoglycoside antibiotics to eradicate different pathogenic persister cells by enhancing proton motive force (PMF)-dependent aminoglycoside uptake (Allison et al, 2011;Barraud et al, 2013;Peng et al, 2015;Meylan et al, 2017;Su et al, 2018). Notably, rhamnolipids, synthesized by Pseudomonas aeruginosa, potentiate aminoglycoside against Staphylococcus aureus persisters by enhancing aminoglycoside uptake in a PMFindependent manner (Radlinski et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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5-Methylindole Potentiates Aminoglycoside Against Gram-Positive Bacteria Including Staphylococcus aureus Persisters Under Hypoionic Conditions

Sun

Bian

et al. 2020

Front. Cell. Infect. Microbiol.

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Antibiotic resistance/tolerance has become a severe threat to human and animal health. To combat antibiotic-resistant/tolerant bacteria, it is of significance to improve the efficacy of traditional antibiotics. Here we show that indole potentiates tobramycin to kill stationary-phase Staphylococcus aureus cells after a short, combined treatment, with its derivative 5-methylindole being the most potent compound tested and with the absence of ions as a prerequisite. Consistently, this combined treatment also kills various types of S. aureus persister cells as induced by the protonophore CCCP, nutrient shift, or starvation, as well as methicillin-resistant S. aureus (MRSA) cells. Importantly, 5-methylindole potentiates tobramycin killing of S. aureus persisters in a mouse acute skin wound model. Furthermore, 5-methylindole facilitates killing of many strains of gram-positive pathogens such as Staphylococcus epidermidis, Enterococcus faecalis, and Streptococcus pyogenes by aminoglycoside antibiotics, whereas it suppresses the action of aminoglycoside against the gram-negative pathogens Escherichia coli and Shigella flexneri. In conclusion, our work may pave the way for the development of indole derivatives as adjuvants to potentiate aminoglycosides against gram-positive pathogens.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

5-Methylindole Potentiates Aminoglycoside Against Gram-Positive Bacteria Including Staphylococcus aureus Persisters Under Hypoionic Conditions

Sun

Bian

et al. 2020

Front. Cell. Infect. Microbiol.

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“…For this reason, anaerobic bacteria are generally resistant to aminoglycosides. Small molecule induced aminoglycoside uptake has been a useful strategy to overcome drug resistance relating to poor drug transport into bacterial cells (Lebeaux et al, 2014;Radlinski et al, 2019). EDTA, a small molecule metal ion chelator, has been reported as a highly effective additive that increases bacterial membrane permeability and improves the efficacy of antibiotics (Brown and Richards, 1965;Leive, 1965;Sparks et al, 1994;Lambert et al, 2004;Martin-Visscher et al, 2011;Lebeaux et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Exploration of Antibiotic Activity of Aminoglycosides, in Particular Ribostamycin Alone and in Combination With Ethylenediaminetetraacetic Acid Against Pathogenic Bacteria

Kong

Wei

et al. 2020

Front. Microbiol.

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The emergence of infections caused by bacterial pathogens that are resistant to current antibiotic therapy is a critical healthcare challenge. Aminoglycosides are natural antibiotics with broad spectrum of activity; however, their clinical use is limited due to considerable nephrotoxicity. Moreover, drug-resistant bacteria that cause infections in human as well as livestock are less responsive to conventional antibiotics. Herein, we report the in vitro antibacterial evaluation of five different aminoglycosides, including ribostamycin, against a panel of Gram-positive and Gram-negative pathogens. Eight of the tested bacterial strains are linked to gastrointestinal (GI) infections. The minimum inhibitory concentration (MIC) of ribostamycin against three different Escherichia coli strains is in the range of 0.9-7.2 μM and against a strain of Haemophilus influenzae is 0.5 μM. We also found that the MIC of ribostamycin was considerably enhanced from 57.2 to 7.2 μM, an 8-fold improvement, when bacteria were treated with a combination of ribostamycin and ethylenediaminetetraacetic acid (EDTA). These findings demonstrate a promising approach to enhance the clinical potential of ribostamycin and provide a rational for its antibiotic reclassification from special level to non-restricted level.

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“…There are a series of evidence indicate that increasing the transmembrane PMF stimulates the internalization of aminoglycoside antibiotics (Allison et al, 2011;Radlinski et al, 2019). In particular, the PMF is the sum of two components: the electric potential (△ψ) and the transmembrane proton gradient (△pH; Farha et al, 2013).…”

Section: Amino Acid Supplementationmentioning

confidence: 99%

Combating Antibiotic Tolerance Through Activating Bacterial Metabolism

et al. 2020

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The emergence of antibiotic tolerance enables genetically susceptible bacteria to withstand the killing by clinically relevant antibiotics. As is reported, an increasing body of evidence sheds light on the critical and underappreciated role of antibiotic tolerance in the disease burden of bacterial infections. Considering this tense situation, new therapeutic strategies are urgently required for combating antibiotic tolerance. Herein, we provide an insightful illustration to distinguish between antibiotic resistance and tolerance, and highlight its clinical significance and complexities of drug-tolerant bacteria. Then, we discuss the close relationship between antibiotic tolerance and bacterial metabolism. As such, a bacterial metabolism-based approach was proposed to counter antibiotic tolerance. These exogenous metabolites including amino acids, tricarboxylic acid cycle (TCA cycle) metabolites, and nucleotides effectively activate bacterial metabolism and convert the tolerant cells to sensitive cells, and eventually restore antibiotic efficacy. A better understanding of molecular mechanisms of antibiotic tolerance particularly in vivo would substantially drive the development of novel strategies targeting bacterial metabolism.

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

Cited by 72 publications

References 69 publications

5-Methylindole Potentiates Aminoglycoside Against Gram-Positive Bacteria Including Staphylococcus aureus Persisters Under Hypoionic Conditions

5-Methylindole Potentiates Aminoglycoside Against Gram-Positive Bacteria Including Staphylococcus aureus Persisters Under Hypoionic Conditions

Exploration of Antibiotic Activity of Aminoglycosides, in Particular Ribostamycin Alone and in Combination With Ethylenediaminetetraacetic Acid Against Pathogenic Bacteria

Combating Antibiotic Tolerance Through Activating Bacterial Metabolism

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