Border Control: Regulating LPS Biogenesis

Guest, Randi L.; Rutherford, Steven T.; Silhavy, Thomas J.

doi:10.1016/j.tim.2020.09.008

Cited by 54 publications

(48 citation statements)

References 131 publications

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“…To understand the basis of this difference in MIC values between E. coli isolates carrying mcr genes versus chromosomal mechanisms of colistin resistance, we determined the ratio of modified:unmodified LPS of both whole cells and spheroplasts in our strain panel (Table 1). Since most LPS is in the OM [12,24,25], values for whole cells are largely representative of this membrane, while values for spheroplasts are indicative of LPS modification in the CM. Comparison of values revealed significantly greater levels of LPS modification in both the OM and CM for strains resistant due to chromosomal mechanisms relative to E. coli mcr strains (Fig.…”

Section: Colistin Resistance Due To Chromosomal Mechanisms Is Associated With a Higher Proportion Of Lps Modification Compared To Acquisimentioning

confidence: 99%

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Colistin resistance in Escherichia coli confers protection of the cytoplasmic but not outer membrane from the polymyxin antibiotic

Humphrey

Larrouy-Maumus

Furniss

et al. 2021

Preprint

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Colistin is a polymyxin antibiotic of last resort for the treatment of infections caused by multi-drug resistant Gram-negative bacteria. By targeting lipopolysaccharide (LPS), the antibiotic disrupts both the outer and cytoplasmic membranes, leading to lysis and bacterial death. Colistin resistance in Escherichia coli occurs via mutations in the chromosome or the acquisition of mobilised colistin resistance (mcr) genes. Both these colistin resistance mechanisms result in chemical modifications to the LPS, with positively charged moieties added at the cytoplasmic membrane before the LPS is transported to the outer membrane. We have previously shown that MCR-1-mediated LPS modification protects the cytoplasmic but not the outer membrane from damage caused by colistin, enabling bacterial survival. However, it remains unclear whether this observation extends to colistin resistance conferred by other mcr genes, or resistance due to chromosomal mutations. Using a panel of clinical E. coli that had acquired mcr -1, -1.5, -2, -3, -3.2 or -5, or had acquired polymyxin resistance independently of mcr genes, we found that almost all isolates were susceptible to colistin-mediated permeabilisation of the outer, but not cytoplasmic, membrane. Furthermore, we showed that permeabilisation of the outer membrane of colistin resistant isolates by the polymyxin is in turn sufficient to sensitise bacteria to the antibiotic rifampicin, which normally cannot cross the LPS monolayer. These findings demonstrate that colistin resistance in E. coli is typically due to protection of the cytoplasmic but not outer membrane from colistin-mediated damage, regardless of the mechanism of resistance.

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Section: Colistin Resistance Due To Chromosomal Mechanisms Is Associated With a Higher Proportion Of Lps Modification Compared To Acquisimentioning

confidence: 99%

“…In both MCR-mediated and mutation-mediated colistin resistance, LPS modification occurs in the outer leaflet of the CM [20,24,25]. This results in the presence of modified LPS in both the CM and OM, although not all LPS molecules are modified in either membrane [12,23].…”

Section: Introductionmentioning

confidence: 99%

Colistin resistance in Escherichia coli confers protection of the cytoplasmic but not outer membrane from the polymyxin antibiotic

Humphrey

Larrouy-Maumus

Furniss

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…We examined LPS modification in both the CM and OM of isolates by determining the ratio of modified:unmodified LPS of both whole cells and spheroplasts in our strain panel () [23]. Since most LPS is in the OM [12, 24, 25], values for whole cells are largely representative of this membrane, while values for spheroplasts are indicative of LPS modification in the CM. As expected from previous work [23], lipidomic analysis of our strain panel demonstrated that E.…”

Section: Resultsmentioning

confidence: 99%

Colistin resistance in Escherichia coli confers protection of the cytoplasmic but not outer membrane from the polymyxin antibiotic

et al. 2021

View full text Add to dashboard Cite

Colistin is a polymyxin antibiotic of last resort for the treatment of infections caused by multi-drug-resistant Gram-negative bacteria. By targeting lipopolysaccharide (LPS), the antibiotic disrupts both the outer and cytoplasmic membranes, leading to bacterial death and lysis. Colistin resistance in Escherichia coli occurs via mutations in the chromosome or the acquisition of mobilized colistin-resistance (mcr) genes. Both these colistin-resistance mechanisms result in chemical modifications to the LPS, with positively charged moieties added at the cytoplasmic membrane before the LPS is transported to the outer membrane. We have previously shown that MCR-1-mediated LPS modification protects the cytoplasmic but not the outer membrane from damage caused by colistin, enabling bacterial survival. However, it remains unclear whether this observation extends to colistin resistance conferred by other mcr genes, or resistance due to chromosomal mutations. Using a panel of clinical E. coli that had acquired mcr −1, –1.5, −2, –3, −3.2 or −5, or had acquired polymyxin resistance independently of mcr genes, we found that almost all isolates were susceptible to colistin-mediated permeabilization of the outer, but not cytoplasmic, membrane. Furthermore, we showed that permeabilization of the outer membrane of colistin-resistant isolates by the polymyxin is in turn sufficient to sensitize bacteria to the antibiotic rifampicin, which normally cannot cross the LPS monolayer. These findings demonstrate that colistin resistance in these E. coli isolates is due to protection of the cytoplasmic but not outer membrane from colistin-mediated damage, regardless of the mechanism of resistance.

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“…By contrast, lapB and ftsH mutants result in toxic LPS accumulation, but they can be rescued by increasing phospholipid biosynthesis. These examples illustrate how the phospholipid/ LPS ratio is maintained in conjunction with feedback-mediated regulation exerted at LpxC to adjust the LPS flow to match that of the phospholipids 24,25 . The Mla retrograde phospholipid transport system has an important role in maintaining the outer membrane lipid asymmetry so it can resist antibiotics and detergents, and it can finally be appreciated in terms of structure-function relationships that are consistent with both the genetics and biochemistry.…”

Section: Russell E Bishopmentioning

confidence: 99%

Phospholipid transporter shifts into reverse

Bishop

2020

Nat Struct Mol Biol

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Border Control: Regulating LPS Biogenesis

Cited by 54 publications

References 131 publications

Colistin resistance in Escherichia coli confers protection of the cytoplasmic but not outer membrane from the polymyxin antibiotic

Colistin resistance in Escherichia coli confers protection of the cytoplasmic but not outer membrane from the polymyxin antibiotic

Colistin resistance in Escherichia coli confers protection of the cytoplasmic but not outer membrane from the polymyxin antibiotic

Phospholipid transporter shifts into reverse

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