Abstract
Lantibiotics are antimicrobial peptides produced by Gram-positive bacteria. Interestingly, several clinically relevant and human pathogenic strains are inherently resistant towards lantibiotics. The expression of the genes responsible for lantibiotic resistance is regulated by a specific two-component system consisting of a histidine kinase and a response regulator. Here, we focused on a response regulator involved in lantibiotic resistance, NsrR from Streptococcus agalactiae, and determined the crystal structures of its N-terminal receiver domain and C-terminal DNA-binding effector domain. The C-terminal domain exhibits a fold that classifies NsrR as a member of the OmpR/PhoB subfamily of regulators. Amino acids involved in phosphorylation, dimerization, and DNA-binding were identified and demonstrated to be conserved in lantibiotic resistance regulators. Finally, a model of the full-length NsrR in the active and inactive state provides insights into protein dimerization and DNA-binding.
Highlights
The dramatic rise in antibiotic resistance has posed a major threat to the treatment of infectious diseases
Values in parentheses are for the highest resolution shell. a Rmerge is defined as Rsym = ∑hkl∑i|Ii(hkl) − hI(hkl)i|/∑hkl∑iIi(hkl) and b RF as Rf = ∑hklkFobs|−|Fcalck/∑hkl|Fobs| doi:10.1371/journal.pone.0149903.t001
The analysis revealed that the larger fragment (ÃÃ) represents the N-terminal receiver domain whereas the smaller fragment (ÃÃÃ) contained the C-terminal DNA-binding effector domain of NsrR (Fig 1C)
Summary
The dramatic rise in antibiotic resistance has posed a major threat to the treatment of infectious diseases. This has led to the search for novel antibiotics that can be used as pharmaceuticals against human pathogenic bacteria. Lantibiotics are small antimicrobial peptides (30–50 amino acids in length), which are produced by several Gram-positive bacterial strains. They are post-translationally modified and contain specific lanthionine/methyl-lanthionine rings, which are crucial for their high antimicrobial activity [2]. The high potency of lantibiotics for medical usage has already been noticed, and several lantibiotics are already included in clinical trials [4,5].
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