Discovery of antibiotics that selectively kill metabolically dormant bacteria

Zheng, Erica J.; Valeri, Jacqueline A.; Andrews, Ian W.; Krishnan, Aarti; Bandyopadhyay, Parijat; Anahtar, Melis N.; Herneisen, Alice; Schulte, Fabian; Linnehan, Brooke; Wong, Felix; Stokes, Jonathan M.; Renner, Lars D.; Lourido, Sebastian; Collins, James J.

doi:10.1016/j.chembiol.2023.10.026

Cited by 6 publications

(2 citation statements)

References 117 publications

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“…Furthermore, our findings are specific to ampicillin, a β-lactam drug just like penicillin that targets growing cells [ 74 ]. Whether the heightened persistence phenotype will appear when exposed to other antibiotics [ 75 ] is also unknown.…”

Section: Discussionmentioning

confidence: 99%

Emergent antibiotic persistence in a spatially structured synthetic microbial mutualism

Xiong,

Othmer,

Harcombe

2024

The ISME Journal

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Antibiotic persistence (heterotolerance) allows a sub-population of bacteria to survive antibiotic-induced killing and contributes to the evolution of antibiotic resistance. Although bacteria typically live in microbial communities with complex ecological interactions, little is known about how microbial ecology affects antibiotic persistence. Here, we demonstrated within a synthetic two-species microbial mutualism of Escherichia coli and Salmonella enterica that the combination of cross-feeding and community spatial structure can emergently cause high antibiotic persistence in bacteria by increasing the cell-to-cell heterogeneity. Tracking ampicillin-induced death for bacteria on agar surfaces, we found that E. coli forms up to 55 times more antibiotic persisters in the cross-feeding coculture than in monoculture. This high persistence could not be explained solely by the presence of S. enterica, the presence of cross-feeding, average nutrient starvation, or spontaneous resistant mutations. Time-series fluorescent microscopy revealed increased cell-to-cell variation in E. coli lag time in the mutualistic co-culture. Furthermore, we discovered that an E. coli cell can survive antibiotic killing if the nearby S. enterica cells on which it relies die first. In conclusion, we showed that the high antibiotic persistence phenotype can be an emergent phenomenon caused by a combination of cross-feeding and spatial structure. Our work highlights the importance of considering spatially structured interactions during antibiotic treatment and understanding microbial community resilience more broadly.

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Section: Discussionmentioning

confidence: 99%

Emergent antibiotic persistence in a spatially structured synthetic microbial mutualism

Xiong,

Othmer,

Harcombe

2024

The ISME Journal

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“…Moreover, growth rate and metabolism have been shown to influence antimicrobial efficacy 92 , with starved or slow growing stationary phase bacteria becoming transiently insensitive to antimicrobials when metabolites or ATP become unavailable 93 . Due to the heightened resistance of starved and stationary phase cells, successful attempts have been made to selectively target metabolically dormant bacteria 94 or to sensitise recalcitrant cells via metabolites as a potential therapeutic strategy 95 . Likewise, we found that stationary phase cells supplemented with glucose and casamino acids were more sensitive to treatment with tachyplesin.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous efflux pump expression underpins phenotypic resistance to antimicrobial peptides

Lee,

Łapińska,

Tolle

et al. 2024

Preprint

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Antimicrobial resistance threatens the viability of modern medical interventions. There is a dire need of developing novel approaches to counter resistance mechanisms employed by starved or slow-growing pathogens that are refractory to conventional antimicrobial therapies. Antimicrobial peptides have been advocated as potential therapeutic solutions due to low levels of genetic resistance observed in bacteria against these compounds. However, here we show that subpopulations of stationary phase Escherichia coli and Pseudomonas aeruginosa survive tachyplesin treatment without genetic mutations. These phenotypic variants induce efflux, outer membrane vesicles secretion and membrane modifications in response to tachyplesin exposure, sequestering the peptide in their membranes where it cannot exert its antimicrobial activity. We discovered that formation of these phenotypic variants could be prevented by administering tachyplesin in combination with sertraline, an existing clinically used inhibitor of transmembrane transporters, suggesting a novel approach for combatting antimicrobial-refractory stationary phase bacteria.

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Antibiotic resistance: A key microbial survival mechanism that threatens public health

Abbas,

Barkhouse,

Hackenberger

et al. 2024

Cell Host & Microbe

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Discovery of antibiotics that selectively kill metabolically dormant bacteria

Cited by 6 publications

References 117 publications

Emergent antibiotic persistence in a spatially structured synthetic microbial mutualism

Emergent antibiotic persistence in a spatially structured synthetic microbial mutualism

Heterogeneous efflux pump expression underpins phenotypic resistance to antimicrobial peptides

Antibiotic resistance: A key microbial survival mechanism that threatens public health

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