PMID:21149452

Citation	Weatherspoon-Griffin, N, Zhao, G, Kong, W, Kong, Y, Morigen, H, Andrews-Polymenis, M, McClelland, Y and Shi, (2011) The CpxR/CpxA two-component system up-regulates two Tat-dependent peptidoglycan amidases to confer bacterial resistance to antimicrobial peptide.J. Biol. Chem. 286:5529-39
Abstract	We demonstrate that the twin arginine translocation (Tat) system contributes to bacterial resistance to cationic antimicrobial peptides (CAMPs). Our results show that a deletion at the tatC gene, which encodes a subunit of the Tat complex, caused Salmonella and Escherichia coli to become susceptible to protamine. We screened chromosomal loci that encode known and predicted Tat-dependent proteins and found that two N-acetylmuramoyl-l-alanine amidases, encoded by amiA and amiC, elevated bacterial resistance to protamine and α-helical peptides magainin 2 and melittin but not to β-sheet defensin HNP-1 and lipopeptide polymyxin B. Genetic analysis suggests that transcription of both amiA and amiC loci in Salmonella is up-regulated by the CpxR/CpxA two-component system when nlpE is overexpressed. A footprinting analysis reveals that CpxR protein can interact with amiA and amiC promoters at the CpxR box, which is localized between the predicted -10 and -35 regions but present on different strands in these two genes. In addition, our results show that activation of the CpxR/CpxA system can facilitate protamine resistance because nlpE overexpression elevates this resistance in the wild-type strain but not the cpxR deletion mutant. Thus, we uncover a new transcriptional regulation pathway in which the Cpx envelope stress response system modulates the integrity of the cell envelope in part by controlling peptidoglycan amidase activity, which confers bacterial resistance to protamine and α-helical CAMPs. Our studies have important implications for understanding transcriptional regulation of peptidoglycan metabolism and also provide new insights into the role of the bacterial envelope in CAMP resistance.
Links	PubMed Online version:10.1074/jbc.M110.200352
Keywords	Antimicrobial Cationic Peptides; Bacterial Proteins; Drug Resistance, Bacterial; Escherichia coli; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Genetic Loci; N-Acetylmuramoyl-L-alanine Amidase; Promoter Regions, Genetic; Protein Kinases; Salmonella typhimurium; Up-Regulation
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Phenotype Annotations

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Phenotype of	Taxon Information	Genotype Information (if known)	Condition Information	OMP ID	OMP Term Name	ECO ID	ECO Term Name	Notes	Status
a mutation or genetic difference within a strain	Taxon: Escherichia coli Strain: K-12 Substrain: BW25113 NCBI Taxon ID: 83333	Genotype of Reference Strain: tatC+ Genotype of Experimental Strain : tatC(del)::kan	Reference Condition:	OMP:0007173	decreased resistance to antimicrobial peptide			tatC(del) increases susceptibility to protamine (data not shown). tatC(del) mutant was from the Keio collection.
a mutation or genetic difference within a strain	Taxon: Escherichia coli Strain: K-12 Substrain: NCBI Taxon ID: 83333	Genotype of Reference Strain: tatA+ Genotype of Experimental Strain : tatA(del)::kan	Reference Condition:	OMP:0007173	decreased resistance to antimicrobial peptide			tatA(del) mutant has increased susceptibility to protamine (data not shown). Mutant was from the Keio collection.
	Taxon: Escherichia coli Strain: K-12 Substrain: NCBI Taxon ID: 83333	Genotype of Reference Strain: tatB+ Genotype of Experimental Strain : tatB(del)::kan	Reference Condition:	OMP:0007173	decreased resistance to antimicrobial peptide			taatB(del) mutant has increased susceptibility to protamine (data not shown). The mutant strain was from the Keio collection.
a mutation or genetic difference within a strain	Taxon: Escherichia coli Strain: K-12 Substrain: NCBI Taxon ID: 83333	Genotype of Reference Strain: amiA+ Genotype of Experimental Strain : ami(del)::lam	Reference Condition: 0.8 mg/ml protamine Experimental Condition: same	OMP:0007173	decreased resistance to antimicrobial peptide			Increased susceptibility to protamine (results in text). Mutant was from the Keio collection.
a mutation or genetic difference within a strain	Taxon: Escherichia coli Strain: Substrain: NCBI Taxon ID: 83333	Genotype of Reference Strain: amiC+ Genotype of Experimental Strain : amiC(del)::kan	Reference Condition: protamine (0.8 mg/ml) Experimental Condition: same	OMP:0007173	decreased resistance to antimicrobial peptide			Increased susceptibility to protamine (results in text). Mutant was from the Keio collection.
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