Extracellular zinc induces phosphoethanolamine addition to <scp><i>P</i></scp><i>seudomonas aeruginosa</i> lipid <scp>A</scp> via the <scp>ColRS</scp> two‐component system

Nowicki, Emily M.; O’Brien, John P.; Brodbelt, Jennifer S.; Trent, M. Stephen

doi:10.1111/mmi.13018

Cited by 66 publications

(76 citation statements)

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“…More recently, the ParRS, ColRS, and CprRS TCSs have been recognized as making additional contributions to Pm resistance, although the ParRS effect is modest, and the ColRS effect appears to be dependent on the PhoPQ TCS (27)(28)(29)31). The ColRS TCS was also recently shown to promote phosphoethanolamine addition at the 4= position of lipid A under specific environmental conditions, through positive regulation of the newly defined eptA gene (corresponding to the PA1972 ORF) and negative regulation of arn, but without a detected effect on Pm resistance (53). These prior studies indicate that most of these TCSs regulate both the arn operon and the cprA gene, although some of the regulatory effects may be indirect.…”

Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa High-Level Resistance to Polymyxins and Other Antimicrobial Peptides Requires cprA , a Gene That Is Disrupted in the PAO1 Strain

Gutu

Rodgers

Park

et al. 2015

Antimicrob Agents Chemother

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The arn locus, found in many Gram-negative bacterial pathogens, mediates resistance to polymyxins and other cationic antimicrobial peptides through 4-amino-L-arabinose modification of the lipid A moiety of lipopolysaccharide. In Pseudomonas aeruginosa, several two-component regulatory systems (TCSs) control the arn locus, which is necessary but not sufficient for these resistance phenotypes. A previous transposon mutagenesis screen to identify additional polymyxin resistance genes that these systems regulate implicated an open reading frame designated PA1559 in the genome of the P. aeruginosa PAO1 strain. Resequencing of this chromosomal region and bioinformatics analysis for a variety of P. aeruginosa strains revealed that in the sequenced PAO1 strain, a guanine deletion at the end of PA1559 results in a frameshift and truncation of a full-length open reading frame that also encompasses PA1560 in non-PAO1 strains, such as P. aeruginosa PAK. Deletion analysis in the PAK strain showed that this full-length open reading frame, designated cprA, is necessary for polymyxin resistance conferred by activating mutations in the PhoPQ, PmrAB, and CprRS TCSs. The cprA gene was also required for PmrAB-mediated resistance to other cationic antimicrobial peptides in the PAK strain. Repair of the mutated cprA allele in the PAO1 strain restored polymyxin resistance conferred by an activating TCS mutation. The deletion of cprA did not affect the arn-mediated lipid A modification, indicating that the CprA protein is necessary for a different aspect of polymyxin resistance. This protein has a domain structure with a strong similarity to the extended short-chain dehydrogenase/reductase family that comprises isomerases, lyases, and oxidoreductases. These results suggest a new avenue through which to pursue targeted inhibition of polymyxin resistance. P olymyxins (Pm) are acylated cationic peptides active against Pseudomonas aeruginosa and other Gram-negative pathogens. As pharmaceuticals, Pm B sulfate (PMB) and colistimethate, the prodrug form of colistin (also known as Pm E), are increasingly used to treat multidrug-resistant strains of P. aeruginosa that cause serious infections in critically ill patients and in those with cystic fibrosis (CF) (1, 2). Multidrug-resistant strains emerge when firstline agents, such as antipseudomonal ␤-lactams, aminoglycosides, and fluoroquinolones, are used repeatedly, imposing major selective pressure (3-5). Unfortunately, the prevalence of clinical isolates of P. aeruginosa and other Gram-negative pathogens resistant to PMB and colistin is increasing (6-13).Pm binds to lipopolysaccharide (LPS), the major constituent of the Gram-negative outer membrane, promoting its own uptake and diffusion through the periplasm to the inner membrane, where it disrupts cellular respiration and leads to cell lysis (14). The resistance of Gram-negative pathogens to Pm and other cationic antimicrobial peptides (CAPs) is associated with covalent modification of LPS, namely, the addition of 4-amino-L-arabinose (L-Ara4...

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Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa High-Level Resistance to Polymyxins and Other Antimicrobial Peptides Requires cprA , a Gene That Is Disrupted in the PAO1 Strain

Gutu

Rodgers

Park

et al. 2015

Antimicrob Agents Chemother

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“…174, 175 Additionally, phosphoethanolamine was reported to be incorporated into the LPS in response to the presence of cationic molecules, under the regulation of the two-component system ColRS ( P. aeruginosa ) or PmrAB ( E. coli , Salmonella enterica ). 176 …”

Section: Cell Membrane Modificationmentioning

confidence: 99%

Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives

2016

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Aminoglycoside (AG) antibiotics are used to treat many Gram-negative and some Gram-positive infections and, importantly, multidrug-resistant tuberculosis. Among various bacterial species, resistance to AGs arises through a variety of intrinsic and acquired mechanisms. The bacterial cell wall serves as a natural barrier for small molecules such as AGs and may be further fortified via acquired mutations. Efflux pumps work to expel AGs from bacterial cells, and modifications here too may cause further resistance to AGs. Mutations in the ribosomal target of AGs, while rare, also contribute to resistance. Of growing clinical prominence is resistance caused by ribosome methyltransferases. By far the most widespread mechanism of resistance to AGs is the inactivation of these antibiotics by AG-modifying enzymes. We provide here an overview of these mechanisms by which bacteria become resistant to AGs and discuss their prevalence and potential for clinical relevance.

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“…For example, Yersinia pestis differs from Salmonella in lacking a pmrC gene and in its pbgP promoter being directly activated by both the PhoP and PmrA proteins (32). In P. aeruginosa , the LpxT enzyme can transfer an additional phosphate to lipid A (33), and the pmrC gene is activated by the ColR/ColS two-component system but not by PmrA/PmrB (34). …”

Section: Resultsmentioning

confidence: 99%

Gene expression kinetics governs stimulus-specific decoration of the Salmonella outer membrane

2018

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Lipid A is the innermost component of the lipopolysaccharide (LPS) molecules that occupy the outer leaflet of the outer membrane in Gram-negative bacteria. It is recognized by the host immune system and targeted by cationic antimicrobial compounds. In Salmonella enterica serovar Typhimurium, the phosphates of lipid A are chemically modified by enzymes encoded by targets of the transcriptional regulator PmrA. These modifications increase resistance to the cationic peptide antibiotic polymyxin B by reducing the negative charge of the LPS. We now report the mechanism by which Salmonella produces different lipid A profiles when PmrA is activated by low Mg2+ versus a mildly acidic pH. Low Mg2+ favored modification of the lipid A phosphates with 4-aminoarabinose (L-Ara4N) by activating the regulatory protein PhoP, which initially increased the LPS negative charge by promoting transcription of lpxT, encoding an enzyme that adds an additional phosphate group to lipid A. Later, PhoP activated PmrA post-translationally, resulting in expression of PmrA-activated genes including pmrR, encoding an LpxT inhibitor, and those responsible for the incorporation of L-Ara4N. By contrast, a mildly acidic pH favored modification of the lipid A phosphates with a mixture of L-Ara4N and phosphoethanolamine (pEtN) by simultaneously inducing the PhoP-activated lpxT and PmrA-activated pmrR genes. Although L-Ara4N reduces the LPS negative charge more than does pEtN, modification of lipid A phosphates solely with L-Ara4N required a prior increase in lipid A negative charge. Our findings demonstrate how bacteria tailor their cell surface to different stresses such as those faced inside phagocytic cells.

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Extracellular zinc induces phosphoethanolamine addition to Pseudomonas aeruginosa lipid A via the ColRS two‐component system

Cited by 66 publications

References 68 publications

Pseudomonas aeruginosa High-Level Resistance to Polymyxins and Other Antimicrobial Peptides Requires cprA , a Gene That Is Disrupted in the PAO1 Strain

Pseudomonas aeruginosa High-Level Resistance to Polymyxins and Other Antimicrobial Peptides Requires cprA , a Gene That Is Disrupted in the PAO1 Strain

Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives

Gene expression kinetics governs stimulus-specific decoration of the Salmonella outer membrane

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