title: Anatomy of the bacitracin resistance network in Bacillus subtilis.
abstract: Protection against antimicrobial peptides (AMPs) often involves the parallel production of multiple, well-characterized resistance determinants. So far, little is known about how these resistance modules interact and how they jointly protect the cell. Here, we studied the interdependence between different layers of the envelope stress response of Bacillus subtilis when challenged with the lipid II cycle-inhibiting AMP bacitracin. The underlying regulatory network orchestrates the production of the ABC transporter BceAB, the UPP phosphatase BcrC and the phage-shock proteins LiaIH. Our systems-level analysis reveals a clear hierarchy, allowing us to discriminate between primary (BceAB) and secondary (BcrC and LiaIH) layers of bacitracin resistance. Deleting the primary layer provokes an enhanced induction of the secondary layer to partially compensate for this loss. This study reveals a direct role of LiaIH in bacitracin resistance, provides novel insights into the feedback regulation of the Lia system, and demonstrates a pivotal role of BcrC in maintaining cell wall homeostasis. The compensatory regulation within the bacitracin network can also explain how gene expression noise propagates between resistance layers. We suggest that this active redundancy in the bacitracin resistance network of B. subtilis is a general principle to be found in many bacterial antibiotic resistance networks.
authors.affiliation: Technische Universität Dresden, Institute of Microbiology, Dresden, Germany.|Ludwig-Maximilians-Universität Mänchen, Department Biology I, Mänchen, Germany.
authors.forename: Jara
authors.initials: J
authors.lastname: Radeck
authors.affiliation: University of Bath, Department of Biology and Biochemistry, Milner Centre for Evolution, Bath, United Kingdom.
authors.forename: Susanne
authors.initials: S
authors.lastname: Gebhard
authors.affiliation: Ludwig-Maximilians-Universität Mänchen, Department Biology I, Mänchen, Germany.
authors.forename: Peter Shevlin
authors.initials: PS
authors.lastname: Orchard
authors.affiliation: Ludwig-Maximilians-Universität Mänchen, Department Biology I, Mänchen, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Kirchner
authors.affiliation: Ludwig-Maximilians-Universität Mänchen, Department Biology I, Mänchen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bauer
authors.affiliation: Technische Universität Dresden, Institute of Microbiology, Dresden, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Mascher
authors.affiliation: Philipps-Universität Marburg, LOEWE-Center for Synthetic Microbiology (SYNMIKRO), Marburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Fritz
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects* / Q000235:genetics*; D001414:Bacitracin / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D002473:Cell Wall / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001414:Bacitracin