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Crucial role for central carbon metabolism in the bacterial L-form switch and killing by β-lactam antibiotics

Lookup NU author(s): Dr Yoshikazu Kawai, Dr Katarzyna Mickiewicz, Professor Jeff Errington

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature Publishing Group, 2019.

For re-use rights please refer to the publisher's terms and conditions.


Abstract

© 2019, The Author(s), under exclusive licence to Springer Nature Limited.The peptidoglycan cell wall is an essential structure for the growth of most bacteria. However, many are capable of switching into a wall-deficient L-form state in which they are resistant to antibiotics that target cell wall synthesis under osmoprotective conditions, including host environments. L-form cells may have an important role in chronic or recurrent infections. The cellular pathways involved in switching to and from the L-form state remain poorly understood. This work shows that the lack of a cell wall, or blocking its synthesis with β-lactam antibiotics, results in an increased flux through glycolysis. This leads to the production of reactive oxygen species from the respiratory chain, which prevents L-form growth. Compensating for the metabolic imbalance by slowing down glycolysis, activating gluconeogenesis or depleting oxygen enables L-form growth in Bacillus subtilis, Listeria monocytogenes and Staphylococcus aureus. These effects do not occur in Enterococcus faecium, which lacks the respiratory chain pathway. Our results collectively show that when cell wall synthesis is blocked under aerobic and glycolytic conditions, perturbation of cellular metabolism causes cell death. We provide a mechanistic framework for many anecdotal descriptions of the optimal conditions for L-form growth and non-lytic killing by β-lactam antibiotics.


Publication metadata

Author(s): Kawai Y, Mercier R, Mickiewicz K, Serafini A, Sorio de Carvalho LP, Errington J

Publication type: Article

Publication status: Published

Journal: Nature Microbiology

Year: 2019

Pages: epub ahead of print

Online publication date: 08/07/2019

Acceptance date: 28/05/2019

Date deposited: 03/10/2019

ISSN (electronic): 2058-5276

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41564-019-0497-3

DOI: 10.1038/s41564-019-0497-3


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