Carbon Monoxide Gas Is Not Inert, but Global, in Its Consequences for Bacterial Gene Expression, Iron Acquisition, and Antibiotic Resistance

Wareham, LK, Begg, R, Jesse, HE, Van Beilen, JWA, Ali, S, Svistunenko, D, McLean, S ORCID: https://orcid.org/0000-0001-8551-4307, Hellingwerf, KJ, Sanguinetti, G and Poole, RK, 2016. Carbon Monoxide Gas Is Not Inert, but Global, in Its Consequences for Bacterial Gene Expression, Iron Acquisition, and Antibiotic Resistance. Antioxidants & Redox Signaling, 24 (17), pp. 1013-1028. ISSN 1523-0864

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Abstract

Aims:
Carbon monoxide is a respiratory poison and gaseous signaling molecule. Although CO-releasing molecules (CORMs) deliver CO with temporal and spatial specificity in mammals, and are proven antimicrobial agents, we do not understand the modes of CO toxicity. Our aim was to explore the impact of CO gas per se, without intervention of CORMs, on bacterial physiology and gene expression.
Results:
We used tightly controlled chemostat conditions and integrated transcriptomic datasets with statistical modeling to reveal the global effects of CO. CO is known to inhibit bacterial respiration, and we found expression of genes encoding energy-transducing pathways to be significantly affected via the global regulators, Fnr, Arc, and PdhR. Aerobically, ArcA—the response regulator—is transiently phosphorylated and pyruvate accumulates, mimicking anaerobiosis. Genes implicated in iron acquisition, and the metabolism of sulfur amino acids and arginine, are all perturbed. The global iron-related changes, confirmed by modulation of activity of the transcription factor Fur, may underlie enhanced siderophore excretion, diminished intracellular iron pools, and the sensitivity of COchallenged
bacteria to metal chelators. Although CO gas (unlike H2S and NO) offers little protection from
antibiotics, a ruthenium CORM is a potent adjuvant of antibiotic activity. Innovation: This is the first detailed exploration of global bacterial responses to CO, revealing unexpected targets with implications for employing CORMs therapeutically.
Conclusion:
This work reveals the complexity of bacterial responses to CO and provides a basis for understanding the impacts of CO from CORMs, heme oxygenase activity, or environmental sources.

Item Type:	Journal article
Publication Title:	Antioxidants & Redox Signaling
Creators:	Wareham, L.K., Begg, R., Jesse, H.E., Van Beilen, J.W.A., Ali, S., Svistunenko, D., McLean, S., Hellingwerf, K.J., Sanguinetti, G. and Poole, R.K.
Publisher:	Mary Ann Liebert, Inc. publishers
Date:	13 June 2016
Volume:	24
Number:	17
ISSN:	1523-0864
Identifiers:	Number Type 10.1089/ars.2015.6501 DOI
Rights:	© Lauren K. Wareham et al., 2016; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.
Divisions:	Schools > School of Science and Technology
Record created by:	Jill Tomkinson
Date Added:	14 Dec 2016 16:01
Last Modified:	09 Jun 2017 14:09
URI:	https://irep.ntu.ac.uk/id/eprint/29384

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