Bacillus anthracis Responds to Targocil-Induced Envelope Damage through EdsRS Activation of Cardiolipin Synthesis

• Published in: mBio 2020-03, Vol.11 (2)
• Main Authors: Laut, Clare L, Perry, William J, Metzger, Alexander L, Weiss, Andy, Stauff, Devin L, Walker, Suzanne, Caprioli, Richard M, Skaar, Eric P
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacology; antimicrobial agents; Bacillus anthracis; Bacillus anthracis - drug effects; Bacillus anthracis - physiology; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Cardiolipins - biosynthesis; cell envelope; Cell Wall - drug effects; Cell Wall - metabolism; Gene Expression Regulation, Bacterial - drug effects; Gene Order; Molecular Biology and Physiology; Permeability - drug effects; phospholipids; Quinazolines - pharmacology; Signal Transduction - drug effects; Spores, Bacterial - drug effects; Spores, Bacterial - growth & development; Transcription, Genetic; Triazoles - pharmacology; two-component regulatory systems
• ISSN: 2161-2129; 2150-7511
• DOI: 10.1128/mBio.03375-19

is a spore-forming bacterium that causes devastating infections and has been used as a bioterror agent. This pathogen can survive hostile environments through the signaling activity of two-component systems, which couple environmental sensing with transcriptional activation to initiate a coordinated response to stress. In this work, we describe the identification of a two-component system, EdsRS, which mediates the response to the antimicrobial compound targocil. Targocil is a cell envelope-targeting compound that is toxic to at high concentrations. Exposure to targocil causes damage to the cellular barrier and activates EdsRS to induce expression of a previously uncharacterized cardiolipin synthase, which we have named ClsT. Both EdsRS and ClsT are required for protection against targocil-dependent damage. Induction of by EdsRS during targocil treatment results in an increase in cardiolipin levels, which protects from envelope damage. Together, these results reveal that a two-component system signaling response to an envelope-targeting antimicrobial induces production of a phospholipid associated with stabilization of the membrane. Cardiolipin is then used to repair envelope damage and promote viability. Compromising the integrity of the bacterial cell barrier is a common action of antimicrobials. Targocil is an antimicrobial that is active against the bacterial envelope. We hypothesized that , a potential weapon of bioterror, senses and responds to targocil to alleviate targocil-dependent cell damage. Here, we show that targocil treatment increases the permeability of the cellular envelope and is particularly toxic to spores during outgrowth. In vegetative cells, two-component system signaling through EdsRS is activated by targocil. This results in an increase in the production of cardiolipin via a cardiolipin synthase, ClsT, which restores the loss of barrier function, thereby reducing the effectiveness of targocil. By elucidating the response to targocil, we have uncovered an intrinsic mechanism that this pathogen employs to resist toxicity and have revealed therapeutic targets that are important for bacterial defense against structural damage.