Biophysical Impact of Lipid A Modification Caused by Mobile Colistin Resistance Gene on Bacterial Outer Membranes

Ma, Wendong; Jiang, Xukai; Dou, Yujiang; Li, Jian; Yuan, Bing; Yang, Kai

doi:10.1021/acs.jpclett.1c03295

Cited by 9 publications

(6 citation statements)

References 34 publications

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“…Several lines of evidence supported this conclusion. First, to clarify the mechanism of the MCR-1-mediated OM permeability defect, we initially hypothesized that pEtN modification of lipid-A damaged OM, because the overexpression of MCR-1 caused substantial changes to the morphology and physicochemical properties of the OM [ 52 ]. However, the OM permeability was not restored in E. coli E246A, an MCR-1 mutant without pEtN transferase activity.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…Lipid A modification is a known resistance mechanism for colistin resistance . Because HSD1624 and 1625 were able to potentiate colistin, in colistin-resistant Gram-negative bacteria, we wondered if the compounds were causing sensitization via lipid A modification.…”

Section: Resultsmentioning

confidence: 99%

“…Lipid A modification is a known resistance mechanism for colistin resistance. 30 Because HSD1624 and 1625 were able to potentiate colistin, in colistin-resistant Gram-negative bacteria, we wondered if the compounds were causing sensitization via lipid A modification. Matrix-assisted laser desorption/ionization (MALDI)−time of flight (ToF) analysis of lipid A was carried out to determine if there was any change in either the phosphoethanolamine (PetN) or aminoarabinose (Ara4N) content on the lipid A anchor of the LPS component of the bacterial outer membrane in the most re-sensitized colistin-resistant strain (P. aeruginosa TRPA161).…”

Section: Lipid a Analysis Of Trpa161 By Maldi-tof Mass Spectrometrymentioning

confidence: 99%

Re-sensitization of Multidrug-Resistant and Colistin-Resistant Gram-Negative Bacteria to Colistin by Povarov/Doebner-Derived Compounds

et al. 2023

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Colistin, typically viewed as the antibiotic of last resort to treat infections caused by multidrug-resistant (MDR) Gram-negative bacteria, had fallen out of favor due to toxicity issues. The recent increase in clinical usage of colistin has resulted in colistin-resistant isolates becoming more common. To counter this threat, we have investigated previously reported compounds, HSD07 and HSD17, and developed 13 compounds with more desirable drug-like properties for colistin sensitization against 16 colistin-resistant bacterial strains, three of which harbor the plasmid-borne mobile colistin resistance (mcr-1). Lead compound HSD1624, which has a lower LogDpH7.4 (2.46) compared to HSD07 (>5.58), reduces the minimum inhibitory concentration (MIC) of colistin against Pseudomonas aeruginosa strain TRPA161 to 0.03 μg/mL from 1024 μg/mL (34,000-fold reduction). Checkerboard assays revealed that HSD1624 and analogues are also synergistic with colistin against colistin-resistant strains of Escherichia coli, Acinetobacter baumannii, and Klebsiella pneumoniae. Preliminary mechanism of action studies indicate that HSD1624 exerts its action differently depending on the bacterial species. Time-kill studies suggested that HSD1624 in combination with 0.5 μg/mL colistin was bactericidal to extended-spectrum beta-lactamase (ESBL)-producing E. coli, as well as to E. coli harboring mcr-1, while against P. aeruginosa TRPA161, the combination was bacteriostatic. Mechanistically, HSD1624 increased membrane permeability in K. pneumoniae harboring a plasmid containing the mcr-1 gene but did not increase radical oxygen species (ROS), while a combination of 15 μM HSD1624 and 0.5 μg/mL colistin significantly increased ROS in P. aeruginosa TRPA161. HSD1624 was not toxic to mammalian red blood cells (up to 226 μM).

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“…MCR-1, ArnT and diacylglycerol kinase A (DgkA)]. The interactions of colistin with lipid model membranes have been described thoroughly by structural biology studies ( 48 ), which have shown how these interactions change when pEtN is added to the phosphate groups of lipid A ( 49 , 50 ) and how changes in LPS charge renders polymyxins ineffective. Therefore, in theory, for polymyxins to regain their efficacy these changes need to be prevented.…”

Section: Promising Targets In Lipid a Structural Modification Systems...mentioning

confidence: 99%

Untying the anchor for the lipopolysaccharide: lipid A structural modification systems offer diagnostic and therapeutic options to tackle polymyxin resistance

Rogga,

Kosalec

2023

Archives of Industrial Hygiene and Toxicology

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Polymyxin antibiotics are the last resort for treating patients in intensive care units infected with multiple-resistant Gram-negative bacteria. Due to their polycationic structure, their mode of action is based on an ionic interaction with the negatively charged lipid A portion of the lipopolysaccharide (LPS). The most prevalent polymyxin resistance mechanisms involve covalent modifications of lipid A: addition of the cationic sugar 4-amino-L-arabinose (L-Ara4N) and/or phosphoethanolamine (pEtN). The modified structure of lipid A has a lower net negative charge, leading to the repulsion of polymyxins and bacterial resistance to membrane disruption. Genes encoding the enzymatic systems involved in these modifications can be transferred either through chromosomes or mobile genetic elements. Therefore, new approaches to resistance diagnostics have been developed. On another note, interfering with these enzymatic systems might offer new therapeutic targets for drug discovery. This literature review focuses on diagnostic approaches based on structural changes in lipid A and on the therapeutic potential of molecules interfering with these changes.

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Biophysical Impact of Lipid A Modification Caused by Mobile Colistin Resistance Gene on Bacterial Outer Membranes

Cited by 9 publications

References 34 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

Re-sensitization of Multidrug-Resistant and Colistin-Resistant Gram-Negative Bacteria to Colistin by Povarov/Doebner-Derived Compounds

Untying the anchor for the lipopolysaccharide: lipid A structural modification systems offer diagnostic and therapeutic options to tackle polymyxin resistance

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