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The bacterial actin homolog, MreB, is highly conserved among rod-shaped bacteria and essential for growth under normal growth conditions. MreB directs the localization of cell wall synthesis and loss of MreB results in round cells and death. Using the MreB depolymerizing drug, A22, we show that changes to central metabolism through deletion of malate dehydrogenase from the tricarboxylic acid (TCA) cycle results in cells with an increased tolerance to A22. We hypothesize that deletion of malate dehydrogenase leads to the upregulation of gluconeogenesis resulting in an increase in cell wall precursors. Consistent with this idea, metabolite analysis revealed that malate dehydrogenase (mdh) deletion cells possess elevated levels of several glycolysis/gluconeogenesis compounds and the cell wall precursor, uridine diphosphate N-acetylglucosamine (UDP-NAG). In agreement with these results, the increased A22 resistance phenotype can be recapitulated through the addition of glucose to the media. Finally, we show that this increase in antibiotic tolerance is not specific to A22 but also applies to the cell wall-targeting antibiotic, mecillinam.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Titel:	Disruption of the MreB Elongasome Is Overcome by Mutations in the Tricarboxylic Acid Cycle.
Autor/in / Beteiligte Person:	Barton, B ; Grinnell, A ; Morgenstein, RM
Link:	Full Text Finder (Volltext)
Zeitschrift:	Frontiers in microbiology, Jg. 12 (2021-04-23), S. 664281
Veröffentlichung:	Lausanne : Frontiers Research Foundation, 2021
Medientyp:	academicJournal
ISSN:	1664-302X (print)
DOI:	10.3389/fmicb.2021.664281
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Front Microbiol] 2021 Apr 23; Vol. 12, pp. 664281. <i>Date of Electronic Publication: </i>2021 Apr 23 (<i>Print Publication: </i>2021). References: Cell. 2014 Dec 4;159(6):1300-11. (PMID: 25480295) ; FEMS Microbiol Rev. 2008 Mar;32(2):168-207. (PMID: 18266853) ; Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):E2561-8. (PMID: 22908292) ; mBio. 2014 May 13;5(3):e00935-14. (PMID: 24825009) ; Infect Immun. 2004 Mar;72(3):1666-76. (PMID: 14977974) ; J Bacteriol. 1975 Jul;123(1):7-19. (PMID: 806582) ; Anal Chem. 2020 Apr 7;92(7):4829-4837. (PMID: 32125145) ; Nature. 2011 May 12;473(7346):216-20. (PMID: 21562562) ; Mol Microbiol. 2010 May;76(3):616-33. (PMID: 20233306) ; Nat Microbiol. 2016 Apr 18;1:16051. (PMID: 27572649) ; Arch Microbiol. 1975 Apr 7;103(2):155-62. (PMID: 1098602) ; mBio. 2012 Oct 16;3(5):e00280-12. (PMID: 23073764) ; J Bacteriol. 2002 Jul;184(13):3699-703. (PMID: 12057966) ; Sci Signal. 2019 Jul 30;12(592):. (PMID: 31363068) ; Sci Rep. 2017 Feb 24;7:43306. (PMID: 28233869) ; Nat Methods. 2012 Apr 08;9(5):480-2. (PMID: 22484850) ; J Bacteriol. 1993 Oct;175(20):6704-10. (PMID: 8407846) ; Cell. 1985 Oct;42(3):941-9. (PMID: 2996784) ; J Bacteriol. 1983 Jun;154(3):1284-90. (PMID: 6222035) ; Cell. 2007 Jul 27;130(2):335-47. (PMID: 17662947) ; J Bacteriol. 2008 Mar;190(5):1792-811. (PMID: 17993535) ; J Bacteriol. 1978 Aug;135(2):559-74. (PMID: 355233) ; Mol Syst Biol. 2006;2:2006.0008. (PMID: 16738554) ; Elife. 2014 May 02;3:e02634. (PMID: 24843005) ; J Antimicrob Chemother. 1977 Jul;3 Suppl B:13-9. (PMID: 330482) ; FEMS Microbiol Rev. 2005 Sep;29(4):765-94. (PMID: 16102602) ; EMBO J. 2015 Jul 2;34(13):1786-800. (PMID: 25953831) ; Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1239-44. (PMID: 19164570) ; Proc Natl Acad Sci U S A. 2015 Oct 6;112(40):12510-5. (PMID: 26396257) ; Mol Microbiol. 2012 Nov;86(3):594-610. (PMID: 22931116) ; J Gen Microbiol. 1958 Dec;19(3):592-606. (PMID: 13611202) ; Mol Gen Genet. 1984;197(2):254-60. (PMID: 6097794) ; Biosci Biotechnol Biochem. 2002 Dec;66(12):2658-62. (PMID: 12596863) ; Cell. 2005 Feb 11;120(3):329-41. (PMID: 15707892) ; J Bacteriol. 2016 Dec 13;199(1):. (PMID: 27795325) ; Antimicrob Agents Chemother. 1979 Nov;16(5):533-9. (PMID: 393164) ; mBio. 2017 Feb 7;8(1):. (PMID: 28174313) ; Nat Rev Microbiol. 2016 Apr;14(5):320-30. (PMID: 27080241) ; Biochemistry. 2009 Jun 9;48(22):4852-7. (PMID: 19382805) ; PLoS One. 2014 Jun 02;9(6):e98367. (PMID: 24887187) ; Mol Microbiol. 2004 Aug;53(4):1221-31. (PMID: 15306023) ; Nat Microbiol. 2020 Feb;5(2):282-290. (PMID: 31819212) ; Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18602-7. (PMID: 16344480) ; Nature. 2001 Sep 6;413(6851):39-44. (PMID: 11544518) ; J Bacteriol. 2008 Jun;190(11):3914-22. (PMID: 18390656) ; Mol Microbiol. 2005 Jan;55(1):78-89. (PMID: 15612918) ; Nat Microbiol. 2016 Sep 19;1:16172. (PMID: 27643381) ; Mol Microbiol. 2007 Oct;66(1):174-88. (PMID: 17880425) ; Nat Commun. 2018 Jul 18;9(1):2797. (PMID: 30022070) ; J Phys Chem B. 2016 Sep 22;120(37):9867-74. (PMID: 27600765) ; PLoS Genet. 2013;9(7):e1003663. (PMID: 23935518) ; Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):E1025-34. (PMID: 24550515) ; PLoS Genet. 2010 Sep 16;6(9):e1001119. (PMID: 20862359) ; Mol Microbiol. 2004 Mar;51(5):1321-32. (PMID: 14982627) ; J Gen Microbiol. 1986 May;132(5):1297-304. (PMID: 3534137) ; Mol Microbiol. 2009 Mar;71(5):1131-44. (PMID: 19192185) ; Nature. 2016 Sep 29;537(7622):634-638. (PMID: 27525505) ; PLoS Genet. 2017 Aug 21;13(8):e1006978. (PMID: 28827812) ; Int J Mol Sci. 2019 Mar 15;20(6):. (PMID: 30875875) ; J Bacteriol. 1962 Nov;84:877-81. (PMID: 13982383) ; BMC Biol. 2017 Feb 21;15(1):17. (PMID: 28222723) ; Antimicrob Agents Chemother. 1990 May;34(5):718-21. (PMID: 2113792) Grant Information: R15 GM129636 United States GM NIGMS NIH HHS Contributed Indexing: Keywords: MreB cytoskeleton; antibiotic resistance; elongasome; gluconeogenesis; tricarboxylic acid cycle Entry Date(s): Date Created: 20210510 Latest Revision: 20211022 Update Code: 20231215 PubMed Central ID: PMC8102728

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Disruption of the MreB Elongasome Is Overcome by Mutations in the Tricarboxylic Acid Cycle.