Crystal Structures of Bacterial Peptidoglycan Amidase AmpD and an Unprecedented Activation Mechanism

Carrasco-López, César; Rojas-Altuve, A.; Zhang, Weilie; Hesek, Dušan; Lee, Mijoon; Barbe, Sophie; André, Isabelle; Ferrer, Pilar; Silva-Martin, N.; Castro, G.R.; Martı́nez-Ripoll, M.; Mobashery, Shahriar; Hermoso, J.A.

doi:10.1074/jbc.m111.264366

Cited by 50 publications

(53 citation statements)

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“…As in any other signal transduction event, conformational changes are key. Our recent report that a conformational change is involved in activation of the cytoplasmic zinc protease AmpD suggests that a similar process for activation of the cytoplasmic domain of BlaR1 might be operative (29).…”

Section: Discussionmentioning

confidence: 99%

Activation of BlaR1 Protein of Methicillin-resistant Staphylococcus aureus, Its Proteolytic Processing, and Recovery from Induction of Resistance

Llarrull¹,

Tóth

Champion

et al. 2011

Journal of Biological Chemistry

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107

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Section: Discussionmentioning

confidence: 99%

Activation of BlaR1 Protein of Methicillin-resistant Staphylococcus aureus, Its Proteolytic Processing, and Recovery from Induction of Resistance

Llarrull¹,

Tóth

Champion

et al. 2011

Journal of Biological Chemistry

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107

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“…5). Fifteen mutations affected either the substrate binding site or the two sequence motifs which critically stabilize protein conformation by salt bridges (42). The lipid A deacylase PagL synthesizes pentaacylated lipid A structures in CF lungs that are not observed in P. aeruginosa isolates from acute infections and the environment (15).…”

Section: Resultsmentioning

confidence: 99%

Molecular Epidemiology of Mutations in Antimicrobial Resistance Loci of Pseudomonas aeruginosa Isolates from Airways of Cystic Fibrosis Patients

Greipel

Fischer

Klockgether

et al. 2016

Antimicrob Agents Chemother

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bThe chronic airway infections with Pseudomonas aeruginosa in people with cystic fibrosis (CF) are treated with aerosolized antibiotics, oral fluoroquinolones, and/or intravenous combination therapy with aminoglycosides and ␤-lactam antibiotics. An international strain collection of 361 P. aeruginosa isolates from 258 CF patients seen at 30 CF clinics was examined for mutations in 17 antimicrobial susceptibility and resistance loci that had been identified as hot spots of mutation by genome sequencing of serial isolates from a single CF clinic. Combinatorial amplicon sequencing of pooled PCR products identified 1,112 sequence variants that were not present in the genomes of representative strains of the 20 most common clones of the global P. aeruginosa population. A high frequency of singular coding variants was seen in spuE, mexA, gyrA, rpoB, fusA1, mexZ, mexY, oprD, ampD, parR, parS, and envZ (amgS), reflecting the pressure upon P. aeruginosa in lungs of CF patients to generate novel protein variants. The proportion of nonneutral amino acid exchanges was high. Of the 17 loci, mexA, mexZ, and pagL were most frequently affected by independent stop mutations. Private and de novo mutations seem to play a pivotal role in the response of P. aeruginosa populations to the antimicrobial load and the individual CF host. C ystic fibrosis (CF) is a severe autosomal recessive trait that is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) (1). CFTR dysfunction affects many organs, but lung disease is responsible for the vast majority of morbidity and mortality in people with CF. The basic defect in CF predisposes to viral and bacterial airway infections (2). The most prevalent airway pathogen in adolescents and adults with CF is Pseudomonas aeruginosa (3, 4). The chronic airway colonization with P. aeruginosa has been associated with a rapid decline in lung function, heightened lung inflammation, and worse prognosis (1).Antipseudomonal chemotherapy in CF comprises intravenous combination therapy with ␤-lactam antibiotics and aminoglycosides, oral fluoroquinolones, immunomodulatory treatment with azithromycin and aerosolized antibiotics such as tobramycin, aztreonam, or colistin (4-8). The high antimicrobial pressure exerted on the microorganism, which can persist and diversify in the patient's airways for decades, drives the emergence of drug resistance phenotypes (9, 10). Typical targets are elements of replication, transcription, and translation, the cell wall, and transport and its regulation (9-11).During ongoing studies on the long-term microevolution of P. aeruginosa in lungs of 12 CF patients, we have identified 17 loci to be repetitively hit by mutations. These loci are known from the literature to be associated with the emergence of drug resistance in P. aeruginosa (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Hence, we became interested to know if and to what extent the global P. aeruginosa population in lungs of patients (CF lungs) carries mutations in these ge...

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“…2). Amino acid substitutions have been reported in many positions in AmpD from various species (37)(38)(39) (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

Cell Wall Recycling-Linked Coregulation of AmpC and PenB β-Lactamases through ampD Mutations in Burkholderia cenocepacia

Hwang

Kim

2015

Antimicrob Agents Chemother

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In many Gram-negative pathogens, mutations in the key cell wall-recycling enzyme AmpD (N-acetyl-anhydromuramyl-L-alanine amidase) affect the activity of the regulator AmpR, which leads to the expression of AmpC ␤-lactamase, conferring resistance to expanded-spectrum cephalosporin antibiotics. Burkholderia cepacia complex (Bcc) species also have these Amp homologs; however, the regulatory circuitry and the nature of causal ampD mutations remain to be explored. A total of 92 ampD mutants were obtained, representing four types of mutations: single nucleotide substitution (causing an amino acid substitution or antitermination of the enzyme), duplication, deletion, and IS element insertion. Duplication, which can go through reversion, was the most frequent type. Intriguingly, mutations in ampD led to the induction of two ␤-lactamases, AmpC and PenB. Coregulation of AmpC and PenB in B. cenocepacia, and likely also in many Bcc species with the same gene organization, poses a serious threat to human health. This resistance mechanism is of evolutionary optimization in that ampD is highly prone to mutations allowing rapid response to antibiotic challenge, and many of the mutations are reversible in order to resume cell wall recycling when the antibiotic challenge is relieved.

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Crystal Structures of Bacterial Peptidoglycan Amidase AmpD and an Unprecedented Activation Mechanism

Cited by 50 publications

References 50 publications

Activation of BlaR1 Protein of Methicillin-resistant Staphylococcus aureus, Its Proteolytic Processing, and Recovery from Induction of Resistance

Activation of BlaR1 Protein of Methicillin-resistant Staphylococcus aureus, Its Proteolytic Processing, and Recovery from Induction of Resistance

Molecular Epidemiology of Mutations in Antimicrobial Resistance Loci of Pseudomonas aeruginosa Isolates from Airways of Cystic Fibrosis Patients

Cell Wall Recycling-Linked Coregulation of AmpC and PenB β-Lactamases through ampD Mutations in Burkholderia cenocepacia

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