Inactivation of the Mla system and outer-membrane phospholipase A results in disrupted outer-membrane lipid asymmetry and hypervesiculation in Bordetella pertussis

Jonge, Eline F. de; Vogrinec, Lana; Boxtel, Ria van; Tommassen, Jan

doi:10.1016/j.crmicr.2022.100172

Cited by 8 publications

(10 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have shown that the Mla system helps in making the membrane less permeable to harmful substances, as has been observed for other Gram-negative bacteria ( Malinverni and Silhavy, 2009 ; Bernier et al., 2018 ; Fernández-Calvet et al., 2018 ; Baarda et al., 2019 ; Kamischke et al., 2019 ; Yero et al., 2021 ; de Jonge et al., 2022 ), and that this role affects physiological aspects of these bacteria and their interaction with other microorganisms. Among the interfering agents evaluated, the action of divalent-ion chelators stood out as the most sensitive to the Mla function.…”

Section: Discussionsupporting

confidence: 68%

“…The Mla system in S. maltophilia may help to prevent the entry of these interfering molecules into cells while regulating the diffusion of hydrophobic heterologous QS autoinducers. It has been postulated that the Mla system contributes to the regulation of glycerophospholipid bilayer composition in the OM through which lipophilic molecules can pass ( de Jonge et al., 2022 ; Guest et al., 2023 ). An increased diffusion of certain molecules in the S. maltophilia mutant could explain the reduction seen in biomass of P. aeruginosa in the mixed biofilm, although this requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Mla system and its role in maintaining outer membrane barrier function in Stenotrophomonas maltophilia

Coves,

Mamat,

Conchillo-Solé

et al. 2024

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Stenotrophomonas maltophilia are ubiquitous Gram-negative bacteria found in both natural and clinical environments. It is a remarkably adaptable species capable of thriving in various environments, thanks to the plasticity of its genome and a diverse array of genes that encode a wide range of functions. Among these functions, one notable trait is its remarkable ability to resist various antimicrobial agents, primarily through mechanisms that regulate the diffusion across cell membranes. We have investigated the Mla ABC transport system of S. maltophilia, which in other Gram-negative bacteria is known to transport phospholipids across the periplasm and is involved in maintaining outer membrane homeostasis. First, we structurally and functionally characterized the periplasmic substrate-binding protein MlaC, which determines the specificity of this system. The predicted structure of the S. maltophilia MlaC protein revealed a hydrophobic cavity of sufficient size to accommodate the phospholipids commonly found in this species. Moreover, recombinant MlaC produced heterologously demonstrated the ability to bind phospholipids. Gene knockout experiments in S. maltophilia K279a revealed that the Mla system is involved in baseline resistance to antimicrobial and antibiofilm agents, especially those with divalent-cation chelating activity. Co-culture experiments with Pseudomonas aeruginosa also showed a significant contribution of this system to the cooperation between both species in the formation of polymicrobial biofilms. As suggested for other Gram-negative pathogenic microorganisms, this system emerges as an appealing target for potential combined antimicrobial therapies.

show abstract

Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

The Mla system and its role in maintaining outer membrane barrier function in Stenotrophomonas maltophilia

Coves,

Mamat,

Conchillo-Solé

et al. 2024

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

show abstract

“…Later, in 2009, the Mla system in E. coli was found to help maintain GPL homeostasis in Gram-negative bacteria [ 9 ]. The Mla system is thought to be involved in the retrograde trafficking of GPLs; in retrograde trafficking, GPLs are transported from the OM to the IM in an ATP-dependent manner [ 9 , 66 ] as demonstrated in life-threatening bacteria such as E. coli [ 46 ], P. aeruginosa [ 20 , 24 , 52 ], Acinetobacter baumannii [ 67 ], N. gonorrhoeae [ 14 ] and Bordetella pertussis [ 16 ].…”

Section: Maintenance Of Om Asymmetry: the Mla Systemmentioning

confidence: 99%

Maintenance of bacterial outer membrane lipid asymmetry: insight into MlaA

Kaur,

Mingeot -Leclercq

2024

BMC Microbiol

View full text Add to dashboard Cite

The outer membrane (OM) of Gram-negative bacteria acts as an effective barrier to protect against toxic compounds. By nature, the OM is asymmetric with the highly packed lipopolysaccharide (LPS) at the outer leaflet and glycerophospholipids at the inner leaflet. OM asymmetry is maintained by the Mla system, in which is responsible for the retrograde transport of glycerophospholipids from the OM to the inner membrane. This system is comprised of six Mla proteins, including MlaA, an OM lipoprotein involved in the removal of glycerophospholipids that are mis-localized at the outer leaflet of the OM. Interestingly, MlaA was initially identified - and called VacJ - based on its role in the intracellular spreading of Shigella flexneri.Many open questions remain with respect to the Mla system and the mechanism involved in the translocation of mislocated glycerophospholipids at the outer leaflet of the OM, by MlaA. After summarizing the current knowledge on MlaA, we focus on the impact of mlaA deletion on OM lipid composition and biophysical properties of the OM. How changes in OM lipid composition and biophysical properties can impact the generation of membrane vesicles and membrane permeability is discussed. Finally, we explore whether and how MlaA might be a candidate for improving the activity of antibiotics and as a vaccine candidate.Efforts dedicated to understanding the relationship between the OM lipid composition and the mechanical strength of the bacterial envelope and, in turn, how such properties act against external stress, are needed for the design of new targets or drugs for Gram-negative infections.

show abstract

“…While the Mla system is not required for growth in lysogeny broth, bacteria lacking a functional Mla system are more sensitive to the membrane stress SDS/EDTA ( 16 , 17 , 21 – 23 ). Inactivating mlaF or mlaC in multiple species results in the loss of function of the Mla system and increased sensitivity to membrane stressors, antibiotics, and the host ( 21 , 24 – 26 ). Additionally, dominant negative mutations in mlaA ( mlaA *) have been shown to increase outer membrane permeability and susceptibility to erythromycin and rifampicin in Escherichia coli ( 27 ).…”

Section: Introductionmentioning

confidence: 99%

Genetic synergy between Acinetobacter baumannii undecaprenyl phosphate biosynthesis and the Mla system impacts cell envelope and antimicrobial resistance

Noel,

Keerthi,

Ren

et al. 2024

mBio

View full text Add to dashboard Cite

Acinetobacter baumannii is a Gram-negative bacterial pathogen that poses a major health concern due to increasing multidrug resistance. The Gram-negative cell envelope is a key barrier to antimicrobial entry and includes an inner and outer membrane. The maintenance of lipid asymmetry (Mla) system is the main homeostatic mechanism by which Gram-negative bacteria maintain outer membrane asymmetry. Loss of the Mla system in A. baumannii results in attenuated virulence and increased susceptibility to membrane stressors and some antibiotics. We recently reported two strain variants of the A. baumannii type strain ATCC 17978: 17978VU and 17978UN. Here, ∆ mlaF mutants in the two ATCC 17978 strains display different phenotypes for membrane stress resistance, antibiotic resistance, and pathogenicity in a murine pneumonia model. Although allele differences in obgE were previously reported to synergize with ∆ mlaF to affect growth and stringent response, obgE alleles do not affect membrane stress resistance. Instead, a single-nucleotide polymorphism (SNP) in the essential gene encoding undecaprenyl pyrophosphate (Und-PP) synthase, uppS , results in decreased enzymatic rate and decrease in total Und-P levels in 17978UN compared to 17978VU. The UppS UN variant synergizes with ∆ mlaF to reduce capsule and lipooligosaccharide (LOS) levels, increase susceptibility to membrane stress and antibiotics, and reduce persistence in a mouse lung infection. Und-P is a lipid glycan carrier required for the biosynthesis of A. baumannii capsule, cell wall, and glycoproteins. These findings uncover synergy between Und-P and the Mla system in maintaining the A. baumannii cell envelope and antibiotic resistance. IMPORTANCE Acinetobacter baumannii is a critical threat to global public health due to its multidrug resistance and persistence in hospital settings. Therefore, novel therapeutic approaches are urgently needed. We report that a defective undecaprenyl pyrophosphate synthase (UppS) paired with a perturbed Mla system leads to synthetically sick cells that are more susceptible to clinically relevant antibiotics and show reduced virulence in a lung infection model. These results suggest that targeting UppS or undecaprenyl species and the Mla system may resensitize A. baumannii to antibiotics in combination therapies. This work uncovers a previously unknown synergistic relationship in cellular envelope homeostasis that could be leveraged for use in combination therapy against A. baumannii .

show abstract

Inactivation of the Mla system and outer-membrane phospholipase A results in disrupted outer-membrane lipid asymmetry and hypervesiculation in Bordetella pertussis

Cited by 8 publications

References 69 publications

The Mla system and its role in maintaining outer membrane barrier function in Stenotrophomonas maltophilia

The Mla system and its role in maintaining outer membrane barrier function in Stenotrophomonas maltophilia

Maintenance of bacterial outer membrane lipid asymmetry: insight into MlaA

Genetic synergy between Acinetobacter baumannii undecaprenyl phosphate biosynthesis and the Mla system impacts cell envelope and antimicrobial resistance

Contact Info

Product

Resources

About