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Co-Inactivation of GlnR and CodY Regulators Impacts Pneumococcal Cell Wall Physiology

Lookup NU author(s): Christine Aldridge, Professor Waldemar Vollmer

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

CodY, a nutritional regulator highly conserved in low G+C Gram-positive bacteria, is essential in Streptococcus pneumoniae (the pneumococcus). A published codY mutant possessed suppressing mutations inactivating the fatC and amiC genes, respectively belonging to iron (Fat/Fec) and oligopeptide (Ami) ABC permease operons, which are directly repressed by CodY. Here we analyzed two additional published codY mutants to further explore the essentiality of CodY. We show that one, in which the regulator of glutamine/glutamate metabolism glnR had been inactivated by design, had only a suppressor in fecE (a gene in the fat/fecoperon), while the other possessed both fecE and amiC mutations. Independent isolation of three different fat/fec suppressors thus establishes that reduction of iron import is crucial for survival without CodY. We refer to these as primary suppressors, while inactivation of ami, which is not essential for survival of codY mutants and acquired after initial fat/fec inactivation, can be regarded as a secondary suppressor. The availability of codY-ami+ cells allowed us to establish that CodY activates competence for genetic transformation indirectly, presumably by repressing ami which is known to antagonize competence. The glnR codY fecE mutant was then found to be only partially viable on solid medium and hypersensitive to peptidoglycan (PG) targeting agents such as the antibiotic cefotaxime and the muramidase lysozyme. While analysis of PG and teichoic acid composition uncovered no alteration in the glnR codY fecE mutant compared to wildtype, electron microscopy revealed altered ultrastructure of the cell wall in the mutant, establishing that co-inactivation of GlnR and CodY regulators impacts pneumococcal cell wall physiology. In light of rising levels of resistance to PG-targeting antibiotics of natural pneumococcal isolates, GlnR and CodY constitute potential alternative therapeutic targets to combat this debilitating pathogen, as co-inactivation of these regulators renders pneumococci sensitive to iron and PG-targeting agents.


Publication metadata

Author(s): Johnston C, Bootsma HJ, Aldridge C, Manuse S, Gisch N, Schwudke D, Hermans PWM, Grangeasse C, Polard P, Vollmer W, Claverys JP

Publication type: Article

Publication status: Published

Journal: PLoS ONE

Year: 2015

Volume: 10

Issue: 4

Print publication date: 01/01/2015

Online publication date: 22/04/2015

Acceptance date: 06/03/2015

Date deposited: 29/06/2015

ISSN (print): 1932-6203

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pone.0123702

DOI: 10.1371/journal.pone.0123702


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