The Interplay Between ZigA and SltB Promotes Zinc Homeostasis and Cell Envelope Integrity

Overview

Journal Infect Immun

Publisher American Society for Microbiology

Date 2025 Jan 23

PMID 39846731

Authors

Jeanette M Critchlow

Juan P Barraza

Matthew J Munneke

Evan Krystofiak

Erin R Green

Eric P Skaar

Affiliations

Soon will be listed here.

Abstract

is an opportunistic human pathogen that acquires nutrient metals from the vertebrate host amid infection. During zinc (Zn) scarcity, upregulates the expression of the predicted Zn metallochaperone, . Loss of compromises fitness during Zn deficiency, highlighting its role in this condition. To assess the contribution of ZigA to Zn-deficient , a multiparallel transposon sequencing and genetic interaction mapping approach was used. Transposon insertions in , encoding a predicted soluble lytic transglycosylase that tailors the bacterial cell wall, were enriched in the Zn-starved Δ transposon library. Based on previous studies as well as structural and sequence homology, we designated A1S_3027 as oluble ytic ransglycosylase (SltB). Further analyses revealed that inactivating rescued Δ fitness defects during Zn starvation. An ΔΔ mutant demonstrated altered cell envelope structures and increased cellular permeability, highlighting the roles of ZigA and SltB in maintaining cell envelope integrity. Furthermore, these mutants exhibited heightened resistance to β-lactam antibiotics and other cell wall-targeting agents. Alterations in cell envelope integrity in the ΔΔ mutant improved fitness in a murine pneumonia infection model, emphasizing the contribution of ZigA and SltB to pathogenesis. This study elucidates how functional interactions between ZigA and SltB modulate cell envelope integrity and pathogenesis of during Zn depletion. These findings reveal an interplay between metal homeostasis and cell envelope integrity, offering insights into how ZigA contributes to these critical cellular processes.

References

Nairn B, Lonergan Z, Wang J, Braymer J, Zhang Y, Calcutt M . The Response of Acinetobacter baumannii to Zinc Starvation. Cell Host Microbe. 2016; 19(6):826-36. PMC: 4901392. DOI: 10.1016/j.chom.2016.05.007. View

Hood M, Skaar E . Nutritional immunity: transition metals at the pathogen-host interface. Nat Rev Microbiol. 2012; 10(8):525-37. PMC: 3875331. DOI: 10.1038/nrmicro2836. View

Tajuelo A, Terron M, Lopez-Siles M, McConnell M . Role of peptidoglycan recycling enzymes AmpD and AnmK in virulence features. Front Cell Infect Microbiol. 2023; 12:1064053. PMC: 9880065. DOI: 10.3389/fcimb.2022.1064053. View

Lhospice S, Oswaldo Gomez N, Ouerdane L, Brutesco C, Ghssein G, Hajjar C . Pseudomonas aeruginosa zinc uptake in chelating environment is primarily mediated by the metallophore pseudopaline. Sci Rep. 2017; 7(1):17132. PMC: 5719457. DOI: 10.1038/s41598-017-16765-9. View

Lopes A, Yoshii Y, Yamada S, Nagakura M, Kinjo Y, Mizunoe Y . Roles of lytic transglycosylases in biofilm formation and β-lactam resistance in methicillin-resistant . Antimicrob Agents Chemother. 2019; 63(12). PMC: 6879220. DOI: 10.1128/AAC.01277-19. View

Guo L, Lim K, Gunn J, Bainbridge B, Darveau R, Hackett M . Regulation of lipid A modifications by Salmonella typhimurium virulence genes phoP-phoQ. Science. 1997; 276(5310):250-3. DOI: 10.1126/science.276.5310.250. View

Maret W . The Metals in the Biological Periodic System of the Elements: Concepts and Conjectures. Int J Mol Sci. 2016; 17(1). PMC: 4730311. DOI: 10.3390/ijms17010066. View

Das D, Herve M, Feuerhelm J, Farr C, Chiu H, Elsliger M . Structure and function of the first full-length murein peptide ligase (Mpl) cell wall recycling protein. PLoS One. 2011; 6(3):e17624. PMC: 3060825. DOI: 10.1371/journal.pone.0017624. View

Corbin B, Seeley E, Raab A, Feldmann J, Miller M, Torres V . Metal chelation and inhibition of bacterial growth in tissue abscesses. Science. 2008; 319(5865):962-5. DOI: 10.1126/science.1152449. View

10.

Baumann P . Isolation of Acinetobacter from soil and water. J Bacteriol. 1968; 96(1):39-42. PMC: 252249. DOI: 10.1128/jb.96.1.39-42.1968. View

11.

Mortensen B, Rathi S, Chazin W, Skaar E . Acinetobacter baumannii response to host-mediated zinc limitation requires the transcriptional regulator Zur. J Bacteriol. 2014; 196(14):2616-26. PMC: 4097591. DOI: 10.1128/JB.01650-14. View

12.

Martinez-Bond E, Soriano B, Williams A . The mechanistic landscape of Lytic transglycosylase as targets for antibacterial therapy. Curr Opin Struct Biol. 2022; 77:102480. DOI: 10.1016/j.sbi.2022.102480. View

13.

Padovani D, Banerjee R . A G-protein editor gates coenzyme B12 loading and is corrupted in methylmalonic aciduria. Proc Natl Acad Sci U S A. 2009; 106(51):21567-72. PMC: 2799806. DOI: 10.1073/pnas.0908106106. View

14.

Wang T, Si M, Song Y, Zhu W, Gao F, Wang Y . Type VI Secretion System Transports Zn2+ to Combat Multiple Stresses and Host Immunity. PLoS Pathog. 2015; 11(7):e1005020. PMC: 4489752. DOI: 10.1371/journal.ppat.1005020. View

15.

Dalebroux Z, Edrozo M, Pfuetzner R, Ressl S, Kulasekara B, Blanc M . Delivery of cardiolipins to the Salmonella outer membrane is necessary for survival within host tissues and virulence. Cell Host Microbe. 2015; 17(4):441-51. PMC: 4978220. DOI: 10.1016/j.chom.2015.03.003. View

16.

Cavallo I, Oliva A, Pages R, Sivori F, Truglio M, Fabrizio G . in the critically ill: complex infections get complicated. Front Microbiol. 2023; 14:1196774. PMC: 10325864. DOI: 10.3389/fmicb.2023.1196774. View

17.

Sycuro L, Pincus Z, Gutierrez K, Biboy J, Stern C, Vollmer W . Peptidoglycan crosslinking relaxation promotes Helicobacter pylori's helical shape and stomach colonization. Cell. 2010; 141(5):822-33. PMC: 2920535. DOI: 10.1016/j.cell.2010.03.046. View

18.

van Asselt E, Dijkstra B . Binding of calcium in the EF-hand of Escherichia coli lytic transglycosylase Slt35 is important for stability. FEBS Lett. 1999; 458(3):429-35. DOI: 10.1016/s0014-5793(99)01198-9. View

19.

Nocadello S, Minasov G, Shuvalova L, Dubrovska I, Sabini E, Anderson W . Crystal Structures of the SpoIID Lytic Transglycosylases Essential for Bacterial Sporulation. J Biol Chem. 2016; 291(29):14915-26. PMC: 4946911. DOI: 10.1074/jbc.M116.729749. View

20.

Barreteau H, Kovac A, Boniface A, Sova M, Gobec S, Blanot D . Cytoplasmic steps of peptidoglycan biosynthesis. FEMS Microbiol Rev. 2008; 32(2):168-207. DOI: 10.1111/j.1574-6976.2008.00104.x. View