Mutations Affecting Cellular Levels of Cobalamin (Vitamin B 12 ) Confer Tolerance to Bactericidal Antibiotics in Burkholderia cenocepacia .

Publisher: Korean Society for Microbiology and Biotechnology Country of Publication: Korea (South) NLM ID: 9431852 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1738-8872 (Electronic) Linking ISSN: 10177825 NLM ISO Abbreviation: J Microbiol Biotechnol Subsets: MEDLINE

Publication: 2002- : Seoul : Korean Society for Microbiology and Biotechnology
Original Publication: Seoul : Korean Society for Applied Microbiology, 1991-2001.

Vitamin B 12*/pharmacology ; Vitamin B 12*/metabolism ; Anti-Bacterial Agents*/pharmacology ; Mutation* ; Burkholderia cenocepacia*/drug effects ; Burkholderia cenocepacia*/genetics ; Burkholderia cenocepacia*/metabolism ; Tobramycin*/pharmacology ; Reactive Oxygen Species*/metabolism; Acyl Coenzyme A/metabolism ; Microbial Sensitivity Tests ; Drug Resistance, Bacterial/genetics ; Citric Acid Cycle/drug effects ; Humans ; Methylmalonyl-CoA Mutase/genetics ; Methylmalonyl-CoA Mutase/metabolism ; Burkholderia Infections/microbiology ; Burkholderia Infections/drug therapy ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism

The Burkholderia cepacia complex (Bcc) consists of opportunistic pathogens known to cause pneumonia in immunocompromised individuals, especially those with cystic fibrosis. Treating Bcc pneumonia is challenging due to the pathogens' high multidrug resistance. Therefore, inhalation therapy with tobramycin powder, which can achieve high antibiotic concentrations in the lungs, is a promising treatment option. In this study, we investigated potential mechanisms that could compromise the effectiveness of tobramycin therapy. By selecting for B. cenocepacia survivors against tobramycin, we identified three spontaneous mutations that disrupt a gene encoding a key enzyme in the biosynthesis of cobalamin (Vitamin B 12 ). This disruption may affect the production of succinyl-CoA by methylmalonyl-CoA mutase, which requires adenosylcobalamin as a cofactor. The depletion of cellular succinyl-CoA may impact the tricarboxylic acid (TCA) cycle, which becomes metabolically overloaded upon exposure to tobramycin. Consequently, the mutants exhibited significantly reduced reactive oxygen species (ROS) production. Both the wild-type and mutants showed tolerance to tobramycin and various other bactericidal antibiotics under microaerobic conditions. This suggests that compromised ROS-mediated killing, due to the impacted TCA cycle, underlies the mutants' tolerance to bactericidal antibiotics. The importance of ROS-mediated killing and the potential emergence of mutants that evade it through the depletion of cobalamin (Vitamin B 12 ) provide valuable insights for developing strategies to enhance antibiotic treatments of Bcc pneumonia.

BMC Genomics. 2011 Jul 22;12:373. (PMID: 21781329)
Nat Rev Microbiol. 2019 Jul;17(7):441-448. (PMID: 30980069)
Annu Rev Microbiol. 2010;64:357-72. (PMID: 20528688)
J Cyst Fibros. 2012 May;11(3):163-72. (PMID: 22138067)
Ann Med. 2024 Dec;56(1):2307503. (PMID: 38261606)
Clin Microbiol Infect. 2010 Jul;16(7):821-30. (PMID: 20880411)
Cell Chem Biol. 2017 Feb 16;24(2):195-206. (PMID: 28111098)
Arch Microbiol. 2022 Feb 17;204(3):178. (PMID: 35174425)
Lancet. 2005 Aug 6-12;366(9484):463-71. (PMID: 16084254)
Antimicrob Agents Chemother. 2018 Aug 27;62(9):. (PMID: 29914964)
Nat Rev Microbiol. 2010 Jun;8(6):423-35. (PMID: 20440275)
Nat Protoc. 2008;3(2):163-75. (PMID: 18274517)
J Cyst Fibros. 2011 Jan;10(1):54-61. (PMID: 21075062)
Cell. 2007 Sep 7;130(5):797-810. (PMID: 17803904)
Cochrane Database Syst Rev. 2019 Apr 18;4:CD009876. (PMID: 30997925)
PLoS One. 2013 Jul 25;8(7):e69763. (PMID: 23936095)
Cureus. 2020 May 16;12(5):e8158. (PMID: 32550075)
BMC Pharmacol Toxicol. 2016 Mar 28;17:14. (PMID: 27018049)
Proc Natl Acad Sci U S A. 2019 May 14;116(20):10064-10071. (PMID: 30948634)
Thorax. 2004 Nov;59(11):948-51. (PMID: 15516469)
J Clin Microbiol. 1999 Jul;37(7):2201-8. (PMID: 10364586)
Antimicrob Agents Chemother. 2018 May 25;62(6):. (PMID: 29581120)
J Infect. 2018 Sep;77(3):166-170. (PMID: 30012345)
Antibiotics (Basel). 2021 Mar 22;10(3):. (PMID: 33810116)
Vaccines (Basel). 2021 Jun 18;9(6):. (PMID: 34207253)
Am J Respir Crit Care Med. 2000 Apr;161(4 Pt 1):1206-12. (PMID: 10764313)
Nat Commun. 2018 Nov 21;9(1):4917. (PMID: 30464241)
Structure. 1996 Mar 15;4(3):339-50. (PMID: 8805541)
Ann Am Thorac Soc. 2020 Dec;17(12):1542-1548. (PMID: 32678679)
Chemotherapy. 1985;31(3):204-10. (PMID: 3888545)
Gene. 1988 Oct 15;70(1):191-7. (PMID: 2853689)
J Clin Microbiol. 2001 Oct;39(10):3427-36. (PMID: 11574551)
J Biol Chem. 2003 Oct 17;278(42):41148-59. (PMID: 12869542)
J Cyst Fibros. 2017 Jul;16(4):492-495. (PMID: 28262569)
Eur Respir J. 2005 Aug;26(2):305-8. (PMID: 16055880)
Ann Clin Microbiol Antimicrob. 2019 Feb 4;18(1):7. (PMID: 30717798)
J Cyst Fibros. 2010 Jan;9(1):73-4. (PMID: 19932062)
J Clin Microbiol. 2000 Feb;38(2):910-3. (PMID: 10655415)
BMC Pulm Med. 2018 Feb 14;18(1):35. (PMID: 29444656)
PLoS Genet. 2014 Sep 18;10(9):e1004640. (PMID: 25233343)
Microorganisms. 2021 Dec 16;9(12):. (PMID: 34946206)
Cell Rep. 2015 Nov 3;13(5):968-80. (PMID: 26565910)

Keywords: Burkholderia cenocepacia; Burkholderia cepacia complex (Bcc); cobalamin; pneumonia; tobramycin; vitamin B12

P6YC3EG204 (Vitamin B 12)
0 (Anti-Bacterial Agents)
VZ8RRZ51VK (Tobramycin)
0 (Reactive Oxygen Species)
0 (Acyl Coenzyme A)
BSI27HW5EQ (succinyl-coenzyme A)
EC 5.4.99.2 (Methylmalonyl-CoA Mutase)
0 (Bacterial Proteins)

Date Created: 20240725 Date Completed: 20240828 Latest Revision: 20240910

20240910

PMC11380519

10.4014/jmb.2406.06028

39049470