Conformation control of the histidine kinase BceS of Bacillus subtilis by its cognate ABC‐transporter facilitates need‐based activation of antibiotic resistance

• Published in: Molecular microbiology Vol. 115; no. 1; pp. 157 - 174
• Main Authors: Koh, Alan, Gibbon, Marjorie J., Van der Kamp, Marc W., Pudney, Christopher R., Gebhard, Susanne
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.01.2021
• Subjects: Antibiotic resistance; Antibiotics; Antimicrobial agents; antimicrobial peptide; Bacillus subtilis; Catalytic converters; cell envelope stress; Conformation; Coupling (molecular); Decision making; Detoxification; Drug resistance; Energy conservation; Experimentation; Fluctuations; Flux; flux‐sensing; Gene expression; Histidine; Histidine kinase; Kinases; Physiological responses; signal transduction; Signaling; flux-sensing; cell envelope stress; antimicrobial peptide; signal transduction
• ISSN: 0950-382X; 1365-2958
• DOI: 10.1111/mmi.14607

Bacteria closely control gene expression to ensure optimal physiological responses to their environment. Such careful gene expression can minimize the fitness cost associated with antibiotic resistance. We previously described a novel regulatory logic in Bacillus subtilis enabling the cell to directly monitor its need for detoxification. This cost‐effective strategy is achieved via a two‐component regulatory system (BceRS) working in a sensory complex with an ABC‐transporter (BceAB), together acting as a flux‐sensor where signaling is proportional to transport activity. How this is realized at the molecular level has remained unknown. Using experimentation and computation we here show that the histidine kinase is activated by piston‐like displacements in the membrane, which are converted to helical rotations in the catalytic core via an intervening HAMP‐like domain. Intriguingly, the transporter was not only required for kinase activation, but also to actively maintain the kinase in its inactive state in the absence of antibiotics. Such coupling of kinase activity to that of the transporter ensures the complete control required for transport flux‐dependent signaling. Moreover, we show that the transporter likely conserves energy by signaling with sub‐maximal sensitivity. These results provide the first mechanistic insights into transport flux‐dependent signaling, a unique strategy for energy‐efficient decision making. One of the main counteracting forces working against the development and spread of antibiotic resistance is the associated cost in fitness, which can be minimized through careful gene regulation. We here investigated fine‐tuned signaling via a sensory complex consisting of a transporter and a histidine kinase. We show how the kinase is activated upon antibiotic attack, that the transporter exerts complete control over the kinase, and also has itself evolved to conserve energy.