Stimulating Aminoglycoside Uptake to Kill Staphylococcus aureus Persisters

Sidders, Ashelyn E; Radlinski, Lauren C.; Rowe, Sarah E.; Conlon, Brian P.

doi:10.1007/978-1-0716-1621-5_15

Cited by 4 publications

(5 citation statements)

References 26 publications

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“…1b-c). Importantly, the dual treatment eradicated the antibiotic tolerant persister populations as indicated by the absence of a characteristic persister plateau 36 (Fig. 1b-c).…”

Section: Resultsmentioning

confidence: 87%

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Antibiotic-induced accumulation of lipid II sensitizes bacteria to antimicrobial fatty acids

Sidders

Kedziora

Beam

et al. 2022

Preprint

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Antibiotic tolerance and antibiotic resistance are the two major obstacles to the efficient and reliable treatment of bacterial infections. Identifying antibiotic adjuvants that sensitize resistant and tolerant bacteria to antibiotic killing may lead to the development of superior treatments with improved outcomes. Vancomycin, a lipid II inhibitor, is of major clinical importance for the treatment of Gram-positive bacterial infections. Here we show that unsaturated fatty acids (UFAs) and vancomycin act synergistically to rapidly kill S. aureus, including vancomycin tolerant and resistant populations. Our results suggest that antibiotic-mediated accumulation of lipid II at the septum facilitates membrane invasion by antimicrobial UFAs. UFA-vancomycin dual treatment generates large fluid patches of flexible lipids in the membrane leading to protein delocalization, aberrant septal formation, and loss of membrane integrity. This mechanism of synergy may be exploited for the development of new antibiotic therapies that target lipid II to combat both antibiotic tolerance and resistance.

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“…1b-c). Importantly, the dual treatment eradicated the antibiotic tolerant persister populations as indicated by the absence of a characteristic persister plateau 36 (Fig. 1b-c).…”

Section: Resultsmentioning

confidence: 87%

“…Antibiotic survival assays were performed as previously described 36 . Briefly, overnight cultures were diluted 1:1000 into fresh media and grown to ∼2×10 8 CFU/ml aerobically at 37°C, 225rpm (unless otherwise indicated) prior to antibiotic challenge as indicated in the figure legends.…”

Section: Methodsmentioning

confidence: 99%

Antibiotic-induced accumulation of lipid II sensitizes bacteria to antimicrobial fatty acids

Sidders

Kedziora

Beam

et al. 2022

Preprint

Self Cite

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“…However, when these UFAs were combined with vancomycin, we observed over 99% killing of both methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) populations after only 30 min ( Figure 1B–C ). Importantly, the dual treatment eradicated the antibiotic-tolerant persister populations as indicated by the absence of a characteristic persister plateau ( Figure 1B–C ; Sidders et al, 2021 ). Additionally, we evaluated if dual treatment could bypass chemically induced tolerance using carbonyl cyanide m-chlorophenyl hydrazone (CCCP) to disrupt proton motive force or arsenate (AsKO) to deplete ATP ( Conlon et al, 2016 ).…”

Section: Resultsmentioning

confidence: 95%

“…Antibiotic survival assays were performed as previously described ( Sidders et al, 2021 ). Briefly, overnight cultures were diluted 1:1000 into fresh media and grown for 3–5 hr depending on the strain to yield a starting inoculum in late exponential phase (~2 × 10 8 CFU/ml).…”

Section: Methodsmentioning

confidence: 99%

Antibiotic-induced accumulation of lipid II synergizes with antimicrobial fatty acids to eradicate bacterial populations

Sidders

Kedziora

Arts

et al. 2023

eLife

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Antibiotic tolerance and antibiotic resistance are the two major obstacles to the efficient and reliable treatment of bacterial infections. Identifying antibiotic adjuvants that sensitize resistant and tolerant bacteria to antibiotic killing may lead to the development of superior treatments with improved outcomes. Vancomycin, a lipid II inhibitor, is a frontline antibiotic for treating methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacterial infections. However, vancomycin use has led to the increasing prevalence of bacterial strains with reduced susceptibility to vancomycin. Here we show that unsaturated fatty acids (UFAs) act as potent vancomycin adjuvants to rapidly kill a range of Gram-positive bacteria, including vancomycin-tolerant and resistant populations. The synergistic bactericidal activity relies on the accumulation of membrane-bound cell wall intermediates that generate large fluid patches in the membrane leading to protein delocalization, aberrant septal formation, and loss of membrane integrity. Our findings provide a natural therapeutic option that enhances vancomycin activity against difficult-to-treat pathogens and the underlying mechanism may be further exploited to develop antimicrobials that target recalcitrant infection.

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“…Fermenting S. aureus requires higher concentrations of aminoglycosides to eradicate infection, but these elevated concentrations lead to host nephrotoxicity and ototoxicity ( 7 – 9 ). A recent report showed that disruption of the S. aureus membrane prevents aminoglycoside tolerance ( 6 , 10 ). Here, we report that polyunsaturated fatty acids (PUFAs), major components of the host inflammatory burst ( 11 ), synergize with aminoglycosides to kill S. aureus .…”

Section: Observationmentioning

confidence: 99%

Host Polyunsaturated Fatty Acids Potentiate Aminoglycoside Killing of Staphylococcus aureus

et al. 2022

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Stimulating Aminoglycoside Uptake to Kill Staphylococcus aureus Persisters

Cited by 4 publications

References 26 publications

Antibiotic-induced accumulation of lipid II sensitizes bacteria to antimicrobial fatty acids

Antibiotic-induced accumulation of lipid II sensitizes bacteria to antimicrobial fatty acids

Antibiotic-induced accumulation of lipid II synergizes with antimicrobial fatty acids to eradicate bacterial populations

Host Polyunsaturated Fatty Acids Potentiate Aminoglycoside Killing of Staphylococcus aureus

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