Resistance to β-Lactams in Neisseria ssp Due to Chromosomally Encoded Penicillin-Binding Proteins

Zapun, André; Morlot, Cécile; Taha, Muhamed‐Kheir

doi:10.3390/antibiotics5040035

Cited by 50 publications

(48 citation statements)

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“…To conclude, from this study, we show that for the meningococcus Lnt is a promising drug target and for the gonococcus we highlight the importance of targeting enzymes that act earlier in the lipoprotein processing pathway, such as Lgt, to prevent any sorting of diacylated lipoproteins to the cell surface. Our study is very timely given the continuing rise in antibiotic resistance in both N. meningitidis and N. gonorrhoeae and the ever increasing need to develop new antimicrobials against these organisms (Zapun et al, ).…”

Section: Discussionmentioning

confidence: 98%

The role of apolipoprotein N‐acyl transferase, Lnt, in the lipidation of factor H binding protein of Neisseria meningitidis strain MC58 and its potential as a drug target

Silva

Churchward

Karlyshev

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEThe level of cell surface expression of the meningococcal vaccine antigen, Factor H binding protein (FHbp) varies between and within strains and this limits the breadth of strains that can be targeted by FHbp-based vaccines. The molecular pathway controlling expression of FHbp at the cell surface, including its lipidation, sorting to the outer membrane and export, and the potential regulation of this pathway have not been investigated until now. This knowledge will aid our evaluation of FHbp vaccines. EXPERIMENTAL APPROACHA meningococcal transposon library was screened by whole cell immuno-dot blotting using an anti-FHbp antibody to identify a mutant with reduced binding and the disrupted gene was determined. KEY RESULTSIn a mutant with markedly reduced binding, the transposon was located in the lnt gene which encodes apolipoprotein N-acyl transferase, Lnt, responsible for the addition of the third fatty acid to apolipoproteins prior to their sorting to the outer membrane. We provide data indicating that in the Lnt mutant, FHbp is diacylated and its expression within the cell is reduced 10 fold, partly due to inhibition of transcription. Furthermore the Lnt mutant showed 64 fold and 16 fold increase in susceptibility to rifampicin and ciprofloxacin respectively. CONCLUSION AND IMPLICATIONSWe speculate that the inefficient sorting of diacylated FHbp in the meningococcus results in its accumulation in the periplasm inducing an envelope stress response to down-regulate its expression. We propose Lnt as a potential novel drug target for combination therapy with antibiotics. LINKED ARTICLESThis article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro-organisms. To view the other articles in this section visit

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Section: Discussionmentioning

confidence: 98%

The role of apolipoprotein N‐acyl transferase, Lnt, in the lipidation of factor H binding protein of Neisseria meningitidis strain MC58 and its potential as a drug target

Silva

Churchward

Karlyshev

et al. 2016

British J Pharmacology

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“…gonorrhoeae might determine a genetic exchange between the two Neisseria spp. in the urethra (4, 9). …”

Section: Textmentioning

confidence: 99%

Neisseria meningitidis Antimicrobial Resistance in Italy, 2006 to 2016

Vacca

Fazio

Neri

et al. 2018

Antimicrob Agents Chemother

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“…Pneumococcus and related oral streptococci resist ␤-lactams by expression of altered PBPs (5) encoded by mosaic genes that result from multiple events of homologous recombination with genes from close species combined with additional point mutations (6). A similar mechanism of ␤-lactam resistance operates in Neisseria species (7). Mosaic PBPs from resistant strains typically harbor tens of amino acid substitutions amounting to more than 10% of the primary sequence in some instances (5).…”

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confidence: 99%

Substitutions in PBP2b from β-Lactam-resistant Streptococcus pneumoniae Have Different Effects on Enzymatic Activity and Drug Reactivity

Calvez

Breukink

Roper

et al. 2017

Journal of Biological Chemistry

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Edited by Gerald W. HartPneumococcus resists ␤-lactams by expressing variants of its target enzymes, the penicillin-binding proteins (PBPs), with many amino acid substitutions. Up to 10% of the sequence can be modified. These altered PBPs have a much reduced reactivity with the drugs but retain their physiological activity of crosslinking the peptidoglycan, the major constituent of the bacterial cell wall. However, because ␤-lactams are chemical and structural mimics of the natural substrate, resistance mediated by altered PBPs raises the following paradox: how PBPs that react poorly with the drugs maintain a sufficient level of activity with the physiological substrate. This question is addressed for the first time in this study, which compares the peptidoglycan crosslinking activity of PBP2b from susceptible and resistant strains with their inhibition by different ␤-lactams. Unexpectedly, the enzymatic activity of the variants did not correlate with their antibiotic reactivity. This finding indicates that some of the numerous amino acid substitutions were selected to restore a viable level of enzymatic activity by a compensatory molecular mechanism.

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Resistance to β-Lactams in Neisseria ssp Due to Chromosomally Encoded Penicillin-Binding Proteins

Cited by 50 publications

References 61 publications

The role of apolipoprotein N‐acyl transferase, Lnt, in the lipidation of factor H binding protein of Neisseria meningitidis strain MC58 and its potential as a drug target

The role of apolipoprotein N‐acyl transferase, Lnt, in the lipidation of factor H binding protein of Neisseria meningitidis strain MC58 and its potential as a drug target

Neisseria meningitidis Antimicrobial Resistance in Italy, 2006 to 2016

Substitutions in PBP2b from β-Lactam-resistant Streptococcus pneumoniae Have Different Effects on Enzymatic Activity and Drug Reactivity

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