The MCR-3 inside linker appears as a facilitator of colistin resistance

Xu, Yongchang; Chen, Haiyi; Zhang, Huimin; Ullah, Saif; Hou, Tingjun; Feng, Youjun

doi:10.1016/j.celrep.2021.109135

Cited by 17 publications

(17 citation statements)

References 71 publications

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“…A recent structural study showed that the full-length structure of PbgA, an enigmatic inner membrane protein that is similar to MCR-1, assembles as a homotetrameric complex, and its lipid-A-binding motif interacts with LPS, affecting OM permeability [ 33 ]. Very recently, Xu et al [ 34 ] showed that the potential lipid-A-binding pocket of MCR-3 facilitates phenotypic colistin resistance. Because the crystal structure of full-length MCR-1 is unknown, the structure of MCR-1 was modelled using the EptA (PDB: 5FGN.1.A) enzyme as the structural template to determine whether MCR-1 contains a lipid-A-binding pocket.…”

Section: Resultsmentioning

confidence: 99%

MCR-1-dependent lipid remodelling compromises the viability of Gram-negative bacteria

Feng

Liang

et al. 2022

Emerging Microbes & Infections

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The global dissemination of the mobilized colistin resistance gene, mcr-1 , threatens human health. Recent studies by our group and others have shown that the withdrawal of colistin as a feed additive dramatically reduced the prevalence of mcr-1 . Although it is accepted that the rapid reduction in mcr-1 prevalence may have resulted, to some extent, from the toxic effects of MCR-1, the detailed mechanism remains unclear. Here, we found that MCR-1 damaged the outer membrane (OM) permeability in Escherichia coli and Klebsiella pneumonia and that this event was associated with MCR-1-mediated cell shrinkage and death during the stationary phase. Notably, the capacity of MCR-1-expressing cells for recovery from the stationary phase under improved conditions was reduced in a time-dependent manner. We also showed that mutations in the potential lipid-A-binding pocket of MCR-1, but not in the catalytic domain, restored OM permeability and cell viability. During the stationary phase, PbgA, a sensor of periplasmic lipid-A and LpxC production that performed the first step in lipid-A synthesis, was reduced after MCR-1 expression, suggesting that MCR-1 disrupted lipid homeostasis. Consistent with this, the overexpression of LpxC completely reversed the MCR-1-induced OM permeability defect. We propose that MCR-1 causes lipid remodelling that results in an OM permeability defect, thus compromising the viability of Gram-negative bacteria. These findings extended our understanding of the effect of MCR-1 on bacterial physiology and provided a potential strategy for eliminating drug-resistant bacteria.

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Section: Resultsmentioning

confidence: 99%

MCR-1-dependent lipid remodelling compromises the viability of Gram-negative bacteria

Feng

Liang

et al. 2022

Emerging Microbes & Infections

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“…[9,10,11] The transmembrane region, catalytic domain, and inside linker between them were determined by the function of MCR-3 on lipid A modification. [12] This modification of lipid A normally mediates low-level colistin resistance (minimum inhibitory concentrations (MICs) ≤8 mg L −1 ) in Enterobacteriaceae; [3,13,14] however, some MCR-producing Aeromonas spp. demonstrate high levels of resistance (MIC values ranging from 32 to >128 mg L −1 ).…”

Section: Introductionmentioning

confidence: 99%

Mobile Colistin Resistance Enzyme MCR‐3 Facilitates Bacterial Evasion of Host Phagocytosis

et al. 2021

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Mobile colistin resistance enzyme MCR-3 is a phosphoethanolamine transferase modifying lipid A in Gram-negative bacteria. MCR-3 generally mediates low-level (≤8 mg L −1 ) colistin resistance among Enterobacteriaceae, but occasionally confers high-level (>128 mg L −1 ) resistance in aeromonads. Herein, it is determined that MCR-3, together with another lipid A modification mediated by the arnBCADTEF operon, may be responsible for high-level colistin resistance in aeromonads. Lipid A is the critical site of pathogens for Toll-like receptor 4 recognizing. However, it is unknown whether or how MCR-3-mediated lipid A modification affects the host immune response. Compared with the wild-type strains, increased mortality is observed in mice intraperitoneally-infected with mcr-3-positive Aeromonas salmonicida and Escherichia coli strains, along with sepsis symptoms. Further, mcr-3-positive strains show decreased clearance rates than wild-type strains, leading to bacterial accumulation in organs. The increased mortality is tightly associated with the increased tissue hypoxia, injury, and post-inflammation. MCR-3 expression also impairs phagocytosis efficiency both in vivo and in vitro, contributing to the increased persistence of mcr-3-positive bacteria in tissues compared with parental strains. This study, for the first time, reveals a dual function of MCR-3 in bacterial resistance and pathogenicity, which calls for caution in treating the infections caused by mcr-positive pathogens.

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“…Recently a similar PBD domain, designated Linker 59, was detected in MCR-3 and implicated as a facilitator of colistin resistance 34 . The amino acid sequences comprising Linker 59 are very different from those found in the PBD structure of MCR-1 but they share strong overall structural similarity (Extended Data Fig.…”

Section: Discussionmentioning

confidence: 99%

A single residue within the MCR-1 protein confers anticipatory resilience

Frantz

Gwozdzinski

Gisch

et al. 2022

Preprint

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The envelope stress response (ESR) of Gram-negative enteric bacteria senses fluctuations in nutrient availability and environmental changes to avert damage and promote survival. It has a protective role towards antimicrobials but direct interactions between ESR components and antibiotic resistance genes have not been demonstrated. Here we report specific interactions between the two-component conjugative pilus expression (Cpx)RA signal transduction system and the recently described mobile colistin resistance (MCR-1) protein. Purified MCR-1 is specifically cleaved by the serine endoprotease DegP within a structurally conserved periplasmic bridging domain. Cleavage-site mutations in MCR-1 render derivatives either protease-resistant or degradation-susceptible with widely differing consequences for colistin resistance. Transfer of the degradation-susceptible mutant to strains that lack either DegP or its regulator CpxRA restores expression and colistin resistance. MCR-1 production in Escherichia coli induces a Cpx-dependent ESR and imposes growth restriction in strains lacking either DegP or CpxRA, effects that are reversed by transactive expression of DegP. MCR-1 production impairs bacterial motility indicating dissipation of cytoplasmic transmembrane potential. Indeed, growth in media with low pH dramatically increases both MCR-1-dependent phosphoethanolamine (PEA) modification of lipid A as well as colistin-resistance activity. In vitro transferase- and lipid A reconstitution- assays demonstrate that MCR-1 is highly active at acidic pH. Acquiring MCR-1 also renders strains more resistant to antimicrobial peptides. Thus, a conserved motif within MCR-1 induces components of the ESR to confer resilience to stimuili commonly encountered in the environment such as to changes in pH and towards antimicrobial peptides. Excipient allosteric activation of the DegP protease specifically inhibits growth of isolates carrying mcr-1 plasmids indicating that a targeted strategy can lead to the elimination of transferable colistin resistance in Gram-negative bacteria.

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The MCR-3 inside linker appears as a facilitator of colistin resistance

Cited by 17 publications

References 71 publications

MCR-1-dependent lipid remodelling compromises the viability of Gram-negative bacteria

MCR-1-dependent lipid remodelling compromises the viability of Gram-negative bacteria

Mobile Colistin Resistance Enzyme MCR‐3 Facilitates Bacterial Evasion of Host Phagocytosis

A single residue within the MCR-1 protein confers anticipatory resilience

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